STING Contributes to Pulmonary Hypertension by Targeting the Interferon and BMPR2 Signaling through Regulating F2RL3.

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. PH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and in the TNF-α induced PAECs in vitro. Specifically, STING expression was significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-κB axis, which activated the interferon signaling and repressed the BMPR2 signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/interferon-stimulated genes (ISGs) was observed in vivo. Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

Lutein Modulates Cellular Functionalities and Regulates NLRP3 Inflammasome in a H2O2-Challenged Three-Dimensional Retinal Pigment Epithelium Model.

Excessive hydrogen peroxide (H2O2) generated during retinal cell metabolic activity could lead to oxidative degeneration of retinal pigment epithelium (RPE) tissue, a specific pathological process implicated in various retinal diseases resulting in blindness, which can be mitigated by taking dietary antioxidants to prevent inflammation and impaired cellular dysfunction. This study tested the hypothesis that damages induced by oxidative stresses can be mitigated by lutein in a H2O2-challenged model, which was based on an ARPE-19 cell monolayer cultured on three-dimensional (3D)-printed fibrous scaffolds. Pretreating these models with lutein (0.5 µM) for 24 h can significantly lower the oxidative stress and maintain phagocytosis and barrier function. Moreover, lutein can modulate the NLRP3 inflammasome, leading to a ∼40% decrease in the pro-inflammatory cytokine (IL-1ß and IL-18) levels. Collectively, this study suggests that the 3D RPE model is an effective tool to examine the capability of lutein to modulate cellular functionalities and regulate NLRP3 inflammation.

Hepatic arterial infusion chemotherapy combined with lenvatinib and PD-1 inhibitors versus lenvatinib and PD-1 inhibitors for HCC refractory to TACE.

BACKGROUND AND AIM: The study aims to investigate the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and immune checkpoint inhibitors (ICIs) versus lenvatinib and ICIs for hepatocellular carcinoma (HCC) with transarterial chemoembolization (TACE) refractoriness. METHODS: Patients with intermediate or advanced TACE-refractory HCC who received lenvatinib and ICIs with or without HAIC between 2020 and 2022 were retrospectively reviewed. The tumor response, overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were evaluated and compared between the two groups. Factors affecting OS and PFS were identified with univariate and multivariate Cox regression analyses. RESULTS: A total of 121 patients were enrolled, with 58 patients assigned to the HAIC-Len-ICI group and 63 patients assigned to the Len-ICI group. A higher objective response rate and disease control rate were found in the HAIC-Len-ICI group than in the Len-ICI group (48.30% vs 23.80%, P = 0.005; 87.90% vs 69.80%, P = 0.02, respectively). The median OS was 24.0 months in the HAIC-Len-ICI group and 13.0 months in the Len-ICI group (P = 0.001). The median PFS was 13.0 months in the HAIC-Len-ICI group and 7.2 months in the Len-ICI group (P < 0.001). Multivariable analyses suggested that the presence of cirrhosis, Child-Pugh B stage, and HAIC-Len-ICI therapy option were prognostic factors for OS and PFS. The incidences of any grade and grade 3/4 TRAEs were both comparable between the two groups. CONCLUSIONS: HAIC combined with lenvatinib and ICIs yielded better OS, PFS, ORR, and DCR than lenvatinib-ICI therapy in patients with HCC refractory to TACE, with manageable adverse events.

Phenotypic Variation Analysis and Excellent Clone Selection of Alnus cremastogyne from Different Provenances.

Alnus cremastogyne is a rapidly growing broad-leaved tree species that is widely distributed in southwest China. It has a significant economic and ecological value. However, with the expansion of the planting area, the influence of phenotypic variation and differentiation on Alnus cremastogyne has increased, resulting in a continuous decline in its genetic quality. Therefore, it is crucial to investigate the phenotypic variation of Alnus cremastogyne and select excellent breeding materials for genetic improvement. Herein, four growth-related phenotypic traits (diameter at breast height, the height of trees, volume, height under the branches) and twelve reproductive-related phenotypic traits (fresh weight of single cone, dry weight of single cone, seed weight per plant, thousand kernel weight, cone length, cone width, cone length × cone width, fruit shape index, seed rate, germination rate, germination potential, germination index) of 40 clones from four provenances were measured and analyzed. The phenotypic variation was comprehensively evaluated by correlation analysis, principal component analysis and cluster analysis, and excellent clones were selected as breeding materials. The results revealed that there were abundant phenotypic traits variations among and within provenances. Most of the phenotypic traits were highly significant differences (p < 0.01) among provenances. The phenotypic variation among provenances (26.36%) was greater than that of within provenances clones (24.80%). The average phenotypic differentiation coefficient was accounted for 52.61% among provenances, indicating that the phenotypic variation mainly came from among provenances. The coefficient of variation ranged from 9.41% (fruit shape index) to 97.19% (seed weight per plant), and the repeatability ranged from 0.36 (volume) to 0.77 (cone width). Correlation analysis revealed a significantly positive correlation among most phenotypic traits. In principal component analysis, the cumulative contribution rate of the first three principal components was 79.18%, representing the main information on the measured phenotypic traits. The cluster analysis revealed four groups for the 40 clones. Group I and group II exhibited better performance phenotypic traits as compared with group III and group IV. In addition, the four groups are not clearly clustered following the distance from the provenance. Employing the multi-trait comprehensive evaluation method, 12 excellent clones were selected, and the average genetic gain for each phenotypic trait ranged from 4.78% (diameter at breast height) to 32.05% (dry weight of single cone). These selected excellent clones can serve as candidate materials for the improvement and transformation of Alnus cremastogyne seed orchards. In addition, this study can also provide a theoretical foundation for the genetic improvement, breeding, and clone selection of Alnus cremastogyne.

Targeting the Na+/K+ ATPase DR-region with DR-Ab improves doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a potent chemotherapeutic drug for various cancers. Yet, the cardiotoxic side effects limit its application in clinical uses, in which ferroptosis serves as a crucial pathological mechanism in DOX-induced cardiotoxicity (DIC). A reduction of Na+/K + ATPase (NKA) activity is closely associated with DIC progression. However, whether abnormal NKA function was involved in DOX-induced cardiotoxicity and ferroptosis remains unknown. Here, we aim to decipher the cellular and molecular mechanisms of dysfunctional NKA in DOX-induced ferroptosis and investigate NKA as a potential therapeutic target for DIC. A decrease activity of NKA further aggravated DOX-triggered cardiac dysfunction and ferroptosis in NKAα1 haploinsufficiency mice. In contrast, antibodies against the DR-region of NKAα-subunit (DR-Ab) attenuated the cardiac dysfunction and ferroptosis induced by DOX. Mechanistically, NKAα1 interacted with SLC7A11 to form a novel protein complex, which was directly implicated in the disease progression of DIC. Furthermore, the therapeutic effect of DR-Ab on DIC was mediated by reducing ferroptosis by promoting the association of NKAα1/SLC7A11 complex and maintaining the stability of SLC7A11 on the cell surface. These results indicate that antibodies targeting the DR-region of NKA may serve as a novel therapeutic strategy to alleviate DOX-induced cardiotoxicity.

Network Pharmacology and Experimental Validation to Explore That Celastrol Targeting PTEN is the Potential Mechanism of Tripterygium wilfordii (Lév.) Hutch Against IgA Nephropathy.

Purpose: Accumulating clinical evidence showed that Tripterygium hypoglaucum (Lév.) Hutch (THH) is effective against IgA nephropathy (IgAN), but the mechanism is still unclear. This study is to evaluate the renal protective effect and molecular mechanism of THH against IgAN via network pharmacology, molecular docking strategy and experimental validation. Methods: Several databases were used for obtaining the active ingredients of THH, the corresponding targets, as well as the IgAN-related genes. The critical active ingredients, functional pathways, and potential for the combination of the hub genes and their corresponding active components were determined through bioinformatics analysis and molecular docking. The IgAN mouse model was treated with celastrol (1 mg/kg/d) for 21 days, and the aggregated IgA1-induced human mesangial cell (HMC) was treated with various concentrations of celastrol (25, 50 or 75 nM) for 48 h. The immunohistochemistry and Western blot techniques were applied to evaluate the protein expression of the predicted target. The cell counting kit 8 (CCK8) was used to detect HMC proliferation. Results: A total of 17 active ingredients from THH were screened, covering 165 IgAN-related targets. The PPI network identified ten hub targets, including PTEN. The binding affinity between the celastrol and PTEN was the highest (-8.69 kJ/mol). The immunohistochemistry showed that celastrol promoted the expression of PTEN in the glomerulus of IgAN mice. Furthermore, the Western blot techniques showed that celastrol significantly elevated the expression of PTEN and inhibited PCNA and Cyclin D1 in vitro and in vivo. The CCK8 assay determined that celastrol decreased HMC proliferation in a concentration-dependent manner. Conclusion: This study suggests that activating PTEN by celastrol may play a pivotal role in THH alleviating IgAN renal injury.

Role of Na+/K+-ATPase in ischemic stroke: in-depth perspectives from physiology to pharmacology.

Na+/K+-ATPase (NKA) is a large transmembrane protein expressed in all cells. It is well studied for its ion exchanging function, which is indispensable for the maintenance of electrochemical gradients across the plasma membrane and herein neuronal excitability. The widely recognized pump function of NKA closely depends on its unique structure features and conformational changes upon binding of specific ions. Various Na+-dependent secondary transport systems are rigorously controlled by the ionic gradients generated by NKA and are essential for multiple physiological processes. In addition, roles of NKA as a signal transducer have also been unveiled nowadays. Plethora of signaling cascades are defined including Src-Ras-MAPK signaling, IP3R-mediated calcium oscillation, inflammation, and autophagy though most underlying mechanisms remain elusive. Ischemic stroke occurs when the blood flow carrying nutrients and oxygen into the brain is disrupted by blood clots, which is manifested by excitotoxicity, oxidative stress, inflammation, etc. The protective effect of NKA against ischemic stress is emerging gradually with the application of specific NKA inhibitor. However, NKA-related research is limited due to the opposite effects caused by NKA inhibitor at lower doses. The present review focuses on the recent progression involving different aspects about NKA in cellular homeostasis to present an in-depth understanding of this unique protein. Moreover, essential roles of NKA in ischemic pathology are discussed to provide a platform and bright future for the improvement in clinical research on ischemic stroke.

Risk factor for vital signs elevation during percutaneous microwave ablation of liver tumor under deep sedation.

PURPOSE: To evaluate the frequency and the degree of vital signs elevation, as well as to elucidate the risk factors for elevation of cardiopulmonary parameters. MATERIALS AND METHODS: We retrospectively evaluated the medical records of 101 patients who received microwave ablation (MWA) under deep sedation with propofol. Univariate analysis followed by multivariate linear regression analysis was performed to determine the risk factors associated with the elevation of cardiopulmonary parameters. RESULTS: The heart rate (HR), mean blood pressure (BP) and respiratory rate (RR) were elevated in 53.5%, 45.5% and 30.7%. Hyperhemodynamic state (mean BP or HR increased > 30% of the baseline) and high RR (RR > 20 times/min) were detected in 23.8% and 13.9%. Age ≤ 50 years was signifiant for mean BP and HR elevation (p = 0.032; p = 0.027), ablation zone abutting the parietal peritoneum (p = 0.001; p = 0.001; p < 0.001) and the diaphragm (p = 0.001) were risk factors for BP and RR elevation. CONCLUSIONS: Elevations in HR and BP are common. Risk factors for vital signs elevation include ablation zone abutting the parietal peritoneum and the diaphragm, as well as young age. These findings help devise strategies for anesthetic management.

Prostatic Artery Embolization to Achieve Freedom from Catheterization in Patients with Acute Urinary Retention Caused by Benign Prostatic Hyperplasia.

PURPOSE: To determine the ability of prostatic artery embolization (PAE) to achieve freedom from catheterization in patients with acute urinary retention (AUR) caused by benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: This retrospective single-center study was performed between June 2014 and March 2019 in patients with lower urinary tract symptoms (LUTS) caused by BPH. PAE was performed in 154 eligible patients, of which 76 suffered from spontaneous AUR and had indwelling catheters placed and kept until the procedure, owing to clinical failure in the removal of the previous intermittent catheter. Each patient was followed for at least 12 months. The first trial without catheter was performed 3 days after PAE. Successful catheter removal within the first 30 days after PAE was considered a clinical success. The rate of patients free from catheterization, LUTS relief, prostate volume, and adverse events was recorded. RESULTS: Clinical success was achieved in 70 (92.1%) patients. The rates of freedom from catheterization were 90.3% (65/72), 83.3% (60/72), and 80.6% (58/72) at 3-, 6-, and 12-months follow-up, respectively. The median elapsed time from PAE to catheter removal was 10 days. However, 18 patients needed further interventions. Symptom scores revealed a continuous improvement in urinary symptoms. The mean prostate volume showed a statistically significant decrease at 3 and 12 months compared with its baseline value. No severe adverse events occurred. CONCLUSIONS: PAE can achieve freedom from catheterization in patients with AUR caused by BPH.

Three-Dimensional RAW264.7 Cell Model on Electrohydrodynamic Printed Poly(ε-Caprolactone) Scaffolds for In Vitro Study of Anti-Inflammatory Compounds.

Inflammation plays an essential role in the human immune system, and anti-inflammatory compounds are important to promote health. However, the in vitro screening of these compounds is largely dependent on flat biology. Herein, we report our efforts in establishing a 3D inflammation murine macrophage model. Murine macrophage RAW 264.7 cells were cultured on poly(ε-caprolactone) (PCL) scaffolds fabricated through an electrohydrodynamic jetting 3D printer and their behavior were examined. Cells on PCL scaffolds showed a 3D shape and morphology with multilayers and a lower proliferation rate. Moreover, macrophages were not activated by scaffold material PCL and 3D microenvironment. The 3D cells showed greater sensitivity to lipopolysaccharide stimulation with higher production activity of nitric oxide (NO), nitric oxide synthases (iNOS), and cyclooxygenase-2 (COX-2). Additionally, the 3D macrophage model showed lower drug sensitivity to commercial anti-inflammatory drugs including aspirin, ibuprofen, and dexamethasone, and natural flavones apigenin and luteolin with higher IC50 for NO production and lower iNOS and COX-2 inhibition efficacy. Overall, the 3D macrophage model showed promise for higher accurate screening of anti-inflammatory compounds. We developed, for the first time, a 3D macrophage model based on a 3D-printed PCL scaffold that provides an extracellular matrix environment for cells to grow in the 3D dimension. 3D-grown RAW 264.7 cells showed different sensitivities and responses to anti-inflammatory compounds from its 2D model. The 3D cells have lower sensitivity to both commercial and natural anti-inflammatory compounds. Consequently, our 3D macrophage model could be applied to screen anti-inflammatory compounds more accurately and thus holds great potential in next-generation drug screening applications.

Engineered Nanotopography on the Microfibers of 3D-Printed PCL Scaffolds to Modulate Cellular Responses and Establish an In Vitro Tumor Model.

Scaffold-based three-dimensional (3D) cell culture systems have gained increased interest in cell biology, tissue engineering, and drug screening fields as a replacement of two-dimensional (2D) monolayer cell culture and as a way to provide biomimetic extracellular matrix environments. In this study, microscale fibrous scaffolds were fabricated via electrohydrodynamic printing, and nanoscale features were created on the fiber surface by simply leaching gliadin of poly(ε-caprolactone) (PCL)/gliadin composites in ethanol solution. The microstructure of the printed scaffolds could be precisely controlled by printing parameters, and the surface nanotopography of the printed fiber could be tuned by varying the PCL/gliadin ratios. By seeding mouse embryonic fibroblast (NIH/3T3) cells and human nonsmall cell lung cancer (A549) cells on the printed scaffolds, the cellular responses showed that the fiber nanotopography on printed scaffolds efficiently favored cell adhesion, migration, proliferation, and tissue formation. Quantitative analysis of the transcript expression levels of A549 cells seeded on nanoporous scaffolds further revealed the upregulation of integrin-ß1, focal adhesion kinase, Ki-67, E-cadherin, and epithelial growth factor receptors over what was observed in the cells grown on the pure PCL scaffold. Furthermore, a significant difference was found in the relevant biomarker expression on the developed scaffolds compared with that in the monolayer culture, demonstrating the potential of cancer cell-seeded scaffolds as 3D in vitro tumor models for cancer research and drug screening.

Prostatic Artery Embolization for the Treatment of Recurrent Lower Urinary Tract Symptoms following Transurethral Resection of the Prostate.

PURPOSE: To evaluate the safety and efficacy of prostatic artery embolization (PAE) in patients with recurrent lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) who underwent a previous transurethral resection of the prostate (TURP). MATERIALS AND METHODS: This retrospective study analyzed 15 of 19 patients who underwent PAE for recurrent LUTS after TURP between February 2014 and April 2019. The technical and clinical success rates and complications related to the procedure were recorded. International Prostate Symptom Score (IPSS), quality of life (QoL), and prostatic volume (PV) were evaluated at baseline and 3- and 12-mo follow-up. RESULTS: The intervals from TURP to recurrent symptoms and from TURP to PAE were 4.3 y ± 3.2 and 5.6 y ± 3.8, respectively. Technical success was achieved in all patients. The clinical success rate for LUTS relief at 12 mo was 93.3% (14 of 15). IPSS significantly reduced from 22.5 ± 4.1 at baseline to 9.9 ± 4.9 at 12-mo follow-up, and QoL score improved from 4.7 ± 1.0 to 2.1 ± 1.1 (P < .05 for both). There was a significant mean reduction of 26.6% in PV at 12 mo, improving from 100.7 cm3 ± 38.5 to 73.9 cm3 ± 29.4 (P < .05). No severe complications were encountered. CONCLUSIONS: PAE may be a safe and effective treatment option for the management of recurrent LUTS secondary to BPH in patients who have previously undergone TURP.

Protective Effect of Astragaloside IV on High Glucose-Induced Endothelial Dysfunction via Inhibition of P2X7R Dependent P38 MAPK Signaling Pathway.

Vascular endothelial dysfunction is associated with increased mortality in patients with diabetes. Astragaloside IV (As-IV) is a bioactive saponin with therapeutic potential as an anti-inflammatory and antiendothelial dysfunction. However, the underlying mechanism for how As-IV ameliorated endothelial dysfunction is still unclear. Therefore, in this study, we examined the protective effect of As-IV against endothelial dysfunction and explored potential molecular biology mechanism. In vivo, rats were intraperitoneally injected with streptozotocin (STZ) at a dose of 65 mg/kg body weight to establish a diabetic model. In vitro studies, rat aortic endothelial cells (RAOEC) were pretreated with As-IV, SB203580 (p38 MAPK inhibitor) for 2 h prior to the addition of high glucose (33 mM glucose). Our findings indicated that As-IV improved impaired endothelium-dependent relaxation and increased the levels of endothelial NO synthase (eNOS) and nitric oxide (NO) both in vivo and in vitro. Besides, As-IV treatment inhibited the elevated inflammation and oxidative stress in diabetic model both in vivo and in vitro. Moreover, As-IV administration reversed the upregulated expression of P2X7R and p-p38 MAPK in vivo and in vitro. Additionally, the effects of both P2X7R siRNA and SB203580 on endothelial cells were similar to As-IV. Collectively, our study demonstrated that As-IV rescued endothelial dysfunction induced by high glucose via inhibition of P2X7R dependent p38 MAPK signaling pathway. This provides a theoretical basis for the further study of the vascular endothelial protective effects of As-IV.

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKß.

Cisplatin, a widely used chemotherapy for the treatment of various tumors, is clinically limited due to its extensive nephrotoxicity. Inflammatory response in tubular cells is a driving force for cisplatin-induced nephrotoxicity. The plant-derived agents are widely used to relieve cisplatin-induced renal dysfunction in preclinical studies. Polysulfide and hydrogen sulfide (H2S) are ubiquitously expressed in garlic, and both of them are documented as potential agents for preventing and treating inflammatory disorders. This study was designed to determine whether polysulfide and H2S could attenuate cisplatin nephrotoxicity through suppression of inflammatory factors. In renal proximal tubular cells, we found that sodium tetrasulfide (Na2S4), a polysulfide donor, and sodium hydrosulfide (NaHS) and GYY4137, two H2S donors, ameliorated cisplatin-caused renal toxicity through suppression of the massive production of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Mechanistically, the anti-inflammatory actions of Na2S4 and H2S may be mediated by persulfidation of signal transducer and activator of transcription 3 (STAT3) and inhibitor kappa B kinase ß (IKKß), followed by decreased phosphorylation of STAT3 and IKKß. Moreover, the nuclear translocation of nuclear transcription factor kappa B (NF-κB), and phosphorylation and degradation of nuclear factor kappa B inhibitor protein alpha (IκBα) induced by cisplatin, were also mitigated by both polysulfide and H2S. In mice, after treatment with polysulfide and H2S donors, cisplatin-associated renal dysfunction was strikingly ameliorated, as evidenced by measurement of serum blood urea nitrogen (BUN) and creatinine levels, renal morphology, and the expression of renal inflammatory factors. Our present work suggests that polysulfide and H2S could afford protection against cisplatin nephrotoxicity, possibly via persulfidating STAT3 and IKKß and inhibiting NF-κB-mediated inflammatory cascade. Our results might shed light on the potential benefits of garlic-derived polysulfide and H2S in chemotherapy-induced renal damage.

Nitroxyl as a Potential Theranostic in the Cancer Arena.

Significance: As one-electron reduced molecule of nitric oxide (NO), nitroxyl (HNO) has gained enormous attention because of its novel physiological or pharmacological properties, ranging from cardiovascular protective actions to antitumoricidal effects. Recent Advances: HNO is emerging as a new entity with therapeutic advantages over its redox sibling, NO. The interests in the chemical, pharmacological, and biological characteristics of HNO have broadened our current understanding of its role in physiology and pathophysiology. Critical Issues: In particular, the experimental evidence suggests the therapeutic potential of HNO in tumor pharmacology, such as neuroblastoma, gastrointestinal tumor, ovarian, lung, and breast cancers. Indeed, HNO donors have been demonstrated to attenuate tumor proliferation and angiogenesis. Future Directions: In this review, the generation and detection of HNO are outlined, and the roles of HNO in cancer progression are further discussed. We anticipate that the completion of this review might give novel insights into the roles of HNO in cancer pharmacology and open up a novel field of cancer therapy based on HNO.

Astragaloside IV protects against hyperglycemia-induced vascular endothelial dysfunction by inhibiting oxidative stress and Calpain-1 activation.

AIMS: Vascular endothelial cells act as a selective barrier between circulating blood and vessel wall and play an important role in the occurrence and development of cardiovascular diseases. Astragaloside IV (As-IV) has a protective effect on vascular endothelial cells, but its underlying mechanism remains unclear. This study is aimed at investigating the effect of As-IV on endothelial dysfunction (ED). METHODS: Male Sprague-Dawley (SD) were injected intraperitoneally with 65 mg/kg streptozotocin (STZ) to induce diabetes and then administered orally with As-IV (40, 80 mg/kg) for 8 weeks. Vascular function was evaluated by vascular reactivity in vivo and in vitro. The expression of calpain-1 and eNOS in the aorta of diabetic rats was examined by western blot. NO production was measured using nitrate reductase method. Oxidative stress was determined by measuring SOD, GSH-px and ROS. RESULTS: Our results showed that As-IV administration significantly improved diabetes associated ED in vivo, and both NAC (an antioxidant) and MDL-28170 (calpain-1 inhibitor) significantly attenuated hyperglycemia-induced ED in vitro. Meanwhile, pretreatment with the inhibitor l-NAME nearly abolished vasodilation to ACh in all groups of rats. Furthermore, As-IV increased NO production and the expression of eNOS in the thoracic aorta of diabetic rats. In addition, the levels of ROS were significantly increased, and the activity of SOD and GSH-px were decreased in diabetic rats, while As-IV administration reversed this change in a concentration-dependent manner. CONCLUSION: These results suggest that As-IV improves endothelial dysfunction in thoracic aortas from diabetic rats by reducing oxidative stress and calpain-1.

Prostatic Artery Embolization for Control of Gross Hematuria in Patients with Benign Prostatic Hyperplasia: A Single-Center Retrospective Study in 20 Patients.

PURPOSE: To evaluate the efficacy and safety of prostatic artery embolization (PAE) performed to treat gross hematuria secondary to benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: Between February 2014 and December 2017, 20 patients with gross hematuria secondary to BPH refractory to medical treatment underwent PAE in our institution. Technical success was defined as bilateral PAE. International Prostate Symptom Score (IPSS), quality of life (QoL), and clinical review were assessed before PAE and at 3 and 12 months after procedure. Short- and medium-term clinical successes were defined as resolution of gross hematuria with no recurrence at 3 and 12 months, respectively. RESULTS: Technical success rate was 100%. No major adverse events were recorded. Minor complications included gluteal pain, nausea, and fever in 7 patients. At 3 months, there were improvements in IPSS (21.1 ± 6.6 to 9.8 ± 4.7, P < .001) and QoL (5.1 ± 1.7 to 2.4 ± 1.3, P < .001). At 12 months, there were improvements in IPSS (8.1 ± 2.5, P < .001) and QoL (2.1 ± 1.0, P < .001). At 3 months, recurrent hematuria was reported in 3 of 20 patients (85% short-term clinical success rate). One of the remaining 17 patients had developed recurrent hematuria by 12 months (80% medium-term clinical success rate). CONCLUSIONS: PAE is a safe and effective means of treating gross hematuria caused by BPH refractory to medical treatment. PAE offers a reasonable option for such patients who are not suitable for surgical therapy.

Astragaloside IV Suppresses High Glucose-Induced NLRP3 Inflammasome Activation by Inhibiting TLR4/NF-κB and CaSR.

Long-term exposure to high glucose induces vascular endothelial inflammation that can result in cardiovascular disease. Astragaloside IV (As-IV) is widely used for anti-inflammatory treatment of cardiovascular diseases. However, its mechanism of action is still not fully understood. In this study, we investigated the effect of As-IV on high glucose-induced endothelial inflammation and explored its possible mechanisms. In vivo, As-IV (40 and 80 mg/kg/d) was orally administered to rats for 8 weeks after a single intraperitoneal injection of streptozotocin (STZ, 65 mg/kg). In vitro, human umbilical vein endothelial cells (HUVECs) were treated with high glucose (33 mM glucose) in the presence or absence of As-IV, NPS2143 (CaSR inhibitor), BAY 11-7082 (NF-κB p65 inhibitor), and INF39 (NLRP3 inhibitor), and overexpression of CaSR was induced by infection of CaSR-overexpressing lentiviral vectors to further discuss the anti-inflammatory property of As-IV. The results showed that high glucose increased the expression of interleukin-18 (IL-18), interleukin-1ß (IL-1ß), NLRP3, caspase-1, and ASC, as well as the protein level of TLR4, nucleus p65, and CaSR. As-IV can reverse these changes in vivo and in vitro. Meanwhile, NPS2143, BAY 11-7082, and INF39 could significantly abolish the high glucose-enhanced NLRP3, ASC, caspase-1, IL-18, and IL-1ß expression in vitro. In addition, both NPS2143 and BAY 11-7082 attenuated high glucose-induced upregulation of NLRP3, ASC, caspase-1, IL-18, and IL-1ß expression. In conclusion, this study suggested that As-IV could inhibit high glucose-induced NLRP3 inflammasome activation and subsequent secretion of proinflammatory cytokines via inhibiting TLR4/NF-κB signaling pathway and CaSR, which provides new insights into the anti-inflammatory activity of As-IV.

Klotho protein inhibits H2O2-induced oxidative injury in endothelial cells via regulation of PI3K/AKT/Nrf2/HO-1 pathways.

Klotho protein secreted in the blood could act as a hormone to regulate various target organs and have a protective effect on the cardiovascular system. Numerous studies had shown that Klotho protein had antioxidative stress, anti-inflammatory, and antiapoptotic effects on vascular endothelial cells. The purpose of this study was to investigate the protective mechanism of Klotho protein on oxidative damage of vascular endothelial cells induced by H2O2. Klotho protein significantly enhanced human umbilical vein endothelial cells viability and increased the activities of antioxidant enzymes (superoxide dismutase, catalase, and heme oxygenase-1 (HO-1)), scavenged reactive oxygen species, and inhibited tumor necrosis factor alpha and interleukin 6 secretion. Klotho protein also reduced the rate of apoptosis of cells and improved the function of vascular endothelial cells (increased nitric oxide secretion). Klotho protein activated nuclear translocation of Nrf2 and increased HO-1 expression. Klotho protein also activated phosphorylation of protein kinase B (AKT), whereas the addition of LY294002, a pharmacological inhibitor of phosphatidylinositol 3-kinase (PI3K), blocked Klotho-protein-induced Nrf2/HO-1 activation and cytoprotection. Klotho protein enhanced the antioxidant defense ability of the cells by activating the PI3K/AKT pathway, which upregulated the expression of Nrf2/HO-1, thereby inhibiting H2O2-induced oxidative damage.