Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia.

Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.

Dielectric-Enhanced, High-Sensitivity, Wide-Bandwidth, and Moisture-Resistant Noncontact Triboelectric Sensor for Vibration Signal Acquisition.

Noncontact triboelectric sensors (TESs) have the potential to enhance self-powered sensing performance by eliminating the need for physical contact. This study demonstrates a strategy to construct noncontact TES that enables self-powered sensing and vibration signal acquisition with high sensitivity and wide bandwidth. The incorporation of carbon nanotubes into nitrocellulose (CNTs/NC) endows the tribopositive layer with larger inner micro/nanocapacitances, consequently augmenting the charge storage capacity. As a result, the contactless sensing performance of CNTs/NC-based TES (CNTs/NC-TES) was enhanced by 146%. Correspondingly, the related theory and working mechanism of noncontact sensing were demonstrated. Furthermore, the CNTs/NC-TES exhibits optimal distance response sensitivity of 57.10 V mm-1, a wide-bandwidth response from 0.1 to 4000 Hz, and relative humidity (RH) stability. This contactless CNTs/NC-TES has the potential for high sensitivity and wide frequency vibration monitoring in a high-RH environment.

miR-205-5p inhibits homocysteine-induced pulmonary microvascular endothelium dysfunction by targeting FOXO1.

Homocysteine (Hcy) is a risk factor for multiple chronic diseases, and vascular endothelial cell injury has been regarded as the initiating step for this process. miRNAs are involved in Hcy-induced endothelial dysfunction, while the underlying mechanism and roles of miRNAs in pulmonary endothelial dysfunction induced by homocysteine are unknown. Here, we find that miR-205-5p alleviates pulmonary endothelial dysfunction by targeting FOXO1 in CBS +/‒ mice to protect against Hcy-induced pulmonary endothelial dysfunction. Mechanistically, we show that Hcy can lead to DNA hypermethylation of the miR-205-5p promoter due to the increased binding of DNMT1 to its promoter, which contributes to reduction of miR-205-5p expression. In summary, miR-205-5p promoter hypermethylation causes downregulation of miR-205-5p expression, resulting in a reduction in miR-205-5p binding to FOXO1 during homocysteine-induced pulmonary endothelial dysfunction. Our data indicate that miR-205-5p may be a potential therapeutic target against Hcy-induced pulmonary injury.

Lateral incision 1-stage urethroplasty with oral mucosal graft for patients with penile urethral stricture after hypospadias repair-a preliminary report.

PURPOSE: To report our early experience of a novel surgical approach for penile urethral strictures after hypospadias repair, using a lateral incision to keep the ventral tissue and vasculature of the penis intact and to avoid the need for tissue interposition. PATIENTS AND METHODS: A total of 21 patients underwent lateral incision 1-stage urethroplasty with oral mucosal graft. The median age of the patients was 21 years old (range, 13-47). The median number of prior procedures for hypospadias repair was 3 (range, 1-9) with 18 of 21 patients (85.7%) undergoing greater than 1 prior reconstructive procedure. The mean length of the penile urethral strictures was 4.5 ± 1.7 cm, with a range of 1.0 to 8.0 cm. Selection criteria for lateral incision 1-stage urethroplasty include: non-obliterative stricture, no or mild penile curvature and no urethrocutaneous fistula. RESULTS: Median follow-up was 30 months (range, 6-73). Success was achieved in 17 of 21 patients (80.9%). The 4 (19.0%) patients with treatment failure developed recurrent urethral strictures. Of the 4 men with recurrent strictures, 3 were ultimately treated successfully by DVIU (2) or two-stage urethroplasty (1), and one patient chose repeated dilation. CONCLUSIONS: For patients with penile urethral stricture after hypospadias repair with non-obliterative stricture, no significant penile curvature and no urethrocutaneous fistula, a lateral approach with oral mucosal graft is a simple technique that avoids the need for tissue interposition and keeps the penile ventral tissue and vasculature intact, resulting in a low risk of complications.

Rap1A accelerates homocysteine-induced ANA-1 cells inflammation via synergy of FoxO1 and DNMT3a.

Abnormal elevation of homocysteine (Hcy) level accelerates atherosclerosis through promote macrophage inflammation, while the precise mechanisms remain to be well elucidated. Previous study revealed that Rap1A is involved in the development of atherosclerosis, but little is known regarding the regulation of macrophage inflammation induced by Hcy and its potential mechanisms. In the present study, we demonstrated that Hcy upregulates Rap1A expression and knockdown of Rap1A inhibited pro-inflammatory cytokines IL-6 and TNF-α levels in ANA-1 cells. Mechanistically, DNMT3a-mediated DNA hypomethylation of Rap1A promoter accelerates Hcy-induced ANA-1 cells inflammation. Furthermore, FoxO1 transcriptionally activate Rap1A by direct binding to its promoter. More importantly, Hcy could enhance FoxO1 interaction with DNMT3a and synergistically promote the expression of Rap1A resulting in accelerate ANA-1 cells inflammation. These data indicate that Rap1A is a novel and important regulator in Hcy-induced ANA-1 cells inflammation.

Cooperation between NSPc1 and DNA methylation represses HOXA11 expression and promotes apoptosis of trophoblast cells during preeclampsia.

Accumulating evidence has shown that the apoptosis of trophoblast cells plays an important role in the pathogenesis of preeclampsia, and an intricate interplay between DNA methylation and polycomb group (PcG) protein-mediated gene silencing has been highlighted recently. Here, we provide evidence that the expression of nervous system polycomb 1 (NSPc1), a BMI1 homologous polycomb protein, is significantly elevated in trophoblast cells during preeclampsia, which accelerates trophoblast cell apoptosis. Since NSPc1 acts predominantly as a transcriptional inactivator that specifically represses HOXA11 expression in trophoblast cells during preeclampsia, we further show that NSPc1 is required for DNMT3a recruitment and maintenance of the DNA methylation in the HOXA11 promoter in trophoblast cells during preeclampsia. In addition, we find that the interplay of DNMT3a and NSPc1 represses the expression of HOXA11 and promotes trophoblast cell apoptosis. Taken together, these results indicate that the cooperation between NSPc1 and DNMT3a reduces HOXA11 expression in preeclampsia pathophysiology, which provides novel therapeutic approaches for targeted inhibition of trophoblast cell apoptosis during preeclampsia pathogenesis.

Ischemic Postconditioning Protects against Aged Myocardial Ischemia/Reperfusion Injury by Transcriptional and Epigenetic Regulation of miR-181a-2-3p.

Ischemic postconditioning (IPostC) has been proposed as a strategy to mitigate the risk of ischemia/reperfusion (I/R) injury, and autophagy is involved in I/R-induced aged myocardial injury, while the underlying mechanism of IPostC-regulated autophagy is unknown. Here, we implemented miRNA sequencing analysis in aged cardiomyocytes to identify a novel miR-181a-2-3p after HPostC, which inhibits autophagy by targeting AMBRA1 in aged myocardium to protect I/R-induced aged myocardial injury. Mechanistically, we identified that IPostC can induce DNA hypomethylation and H3K14 hyperacetylation of miR-181a-2-3p promoter due to the decreased binding of DNMT3b and HDAC2 at its promoter, which contributes to enhancing the expression of miR-181a-2-3p. More importantly, cooperation of DNMT3b and HDAC2 inhibits the binding of c-Myc at the miR-181a-2-3p promoter in aged cardiomyocytes. In summary, IPostC attenuates I/R-induced aged myocardial injury through upregulating miR-181a-2-3p expression, which is an attribute to transcriptional and epigenetic regulation of its promoter. Our data indicate that miR-181a-2-3p may be a potential therapeutic target against I/R injury in aged myocardium.

Outcomes of early endoscopic realignment for blunt straddle injuries to the bulbar urethra: a single-center retrospective study.

BACKGROUND: The optimal acute management of patients with blunt straddle injury to the bulbar urethra remains in question. Conventionally, suprapubic diversion with delayed urethroplasty can always be considered, if necessary, but the role of early endoscopic realignment (EER) in the acute management of blunt straddle injuries to bulbar urethra is controversial. We report our clinical experience and outcomes with EER for patients with straddle injury to the bulbar urethra in a level one trauma center. METHODS: We retrospectively reviewed 44 male patients who were transferred to our trauma center between January 2013 and January 2019 for acute management of blunt straddle injury to the perineum leading to bulbar urethra injuries. We reviewed the medical records of those patients to identify demographics, emergency management and clinical outcomes. RESULTS: The most common injury mechanism was falling onto the perineum (n = 27, 61.4%), followed by motorcycle accident (n = 11, 25.0%) and bicycle accident (n = 6, 13.6%). Of the 44 patients, 14 (31.8%) were partial bulbar urethral ruptures and 30 (68.2%) were complete bulbar urethral ruptures. 31 (70.5%) patients successfully underwent EER and 13 (29.5%) patients failed attempted EER. the difference between successful EER attempts and failed ones in term of injured urethral mucosa integrity was statistically significant (P = 0.035, OR 8.667,95% CI: 0.998-75.235). In patients who underwent successful EER, urethral stricture occurred after catheter removal at a median of 8 (1-28) months in 24 (77.4%) patients and the mean stricture length was 1.8 ± 0.8 (0.5-3.0), which was not statistically significant when compared with those who failed EER (P = 0.103). Overall, 21 out of 24 (87.5%) patients with strictures after EER were successfully managed by urethroplasty. CONCLUSIONS: Although achieving a successful EER attempt is relatively easy for most patients with straddle injury to the bulbar urethra, it does not improve urethral healing significantly. Most patients with stricture formation after EER have to be cured with urethroplasty.

[Overexpression of ephrin-A receptor 2 (EphA2) in invasive breast cancer tissues and its negative correlation with pyroptosis].

Objective To investigate how ephrin-A receptor 2 (EphA2) involves in pyroptosis in invasive breast cancer tissues. Methods The protein expression levels of EphA2, NLR family pyrin domain containing 3 (NLRP3), caspase-1, interleukin-1ß (IL-1ß), and intercellular adhesion molecule-1 (ICAM-1) in cancer tissues, paracancerous tissues, and normal breast tissues of breast cancer patients were detected by Western blot; the expression of EPHA2 in cancer tissues and paracancerous tissues of 45 patients with breast cancer was detected by immunofluorescence assay; and the correlation between protein expression of EphA2 and NLRP3, caspase-1, and IL-1ß in patients' cancer tissues was analyzed by Pearson correlation coefficient. Results The protein expression levels of NLRP3, caspase-1, IL-1ß, and ICAM-1 were significantly decreased and the protein expression of EphA2 was significantly increased in cancer tissues compared with those in normal breast tissues and paracancerous tissues. EphA2 level was negatively correlated with the levels of NLRP3, caspase-1 and IL-1ß. Conclusion EphA2 is overexpressed in breast cancer tissues and negatively correlated with pyroptosis.

Clinical application of "Double R" anastomosis technique in laparoscopic pancreaticoduodenectomy procedure.

ABSTRACT: Laparoscopic pancreaticoduodenectomy (LPD) is widely used as a treatment for periampullary tumors and pancreatic head tumors. However, postoperative pancreatic fistula (POPF), which significantly affects mortality and length of hospital stay of patients, remains one of the most common and serious complications following LPD. Though numerous technical modifications for pancreaticojejunostomy (PJ) have been proposed, POPF is still the "Achilles heel" of LPD.To reduce POPF rate and other postoperative complications following LPD by exploring the best approach to manage with the pancreatic remnant, a novel duct-to-mucosa anastomosis technique named Double Layer Running Suture (Double R) for the PJ was established. During 2018 and 2020, a totally 35 patients who underwent LPD with Double R were included, data on the total operative time, PJ duration, estimated blood loss, recovery of bowel function, postoperative complications, and length of hospital stay were collected and analyzed.The average duration of surgery was (380 ±â€Š69) minutes. The mean time for performing PJ was (34 ±â€Š5) minutes. The average estimated blood loss was (180 ±â€Š155) mL. The overall POPF rate was 8.6% (3/35), including 8.6% (3/35) for the biochemical leak, 0% (0/35) for Grade B, and 0% (0/35) for Grade C. No patient suffered from biliary fistula, post-pancreatectomy hemorrhage, and intra-abdominal infection, the 30-day mortality was 0%.Double R anastomosis is potentially a safe, reliable, and rapid anastomosis with a low rate of POPF and post-pancreatectomy hemorrhage. It provides surgeons more options when performing LPD. However, its safety and effectiveness should be verified further by a larger prospective multicenter study.

Low-intensity extracorporeal shock wave therapy for male chronic pelvic pain syndrome: a systematic review and meta-analysis.

BACKGROUND: A systematic review of the evidence was conducted to evaluate the efficacy of low-intensity extracorporeal shock wave therapy (LI-ESWT) for patients with chronic pelvic pain syndrome (CPPS). METHODS: A comprehensive search was undertaken of the Cochrane Register, PubMed, and Embase databases for controlled trials that evaluated patients with CPPS who were treated with LI-ESWT and that were published before August 2019. The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) was the most frequently used tool to evaluate the treatment efficacy of LI-ESWT. The NIH-CPSI comprises subscales for pain [using a visual analog scale (VAS)], urinary function, and quality of life (QoL). RESULTS: Six studies analyzing 317 patients were published from 2009 to 2019. The overall meta-analysis of the data indicated that LI-ESWT demonstrated efficacy in the treatment of CPPS at 12 weeks [risk difference (RD): 0.46; 95% confidence interval (CI), 0.28-0.63; P<0.00001]. The studies were divided into 3 groups based on time after LI-ESWT (1, 12, and 24 weeks) and were compared in total NIH-CPSI scores, QoL, VAS scores, and urinary symptoms. The total NIH-CPSI scores, QoL, VAS scores, and urinary symptom scores improved significantly at 12 weeks after LI-ESWT (P<0.05), but not at 1 week or 24 weeks (P>0.05). CONCLUSIONS: Based on these studies, LI-ESWT may transiently improve the total NIH-CPSI scores, QoL, pain scores, and urinary symptom scores of patients with CPPS. Future research may elucidate the mechanisms underlying the effects of LI-ESWT on CPPS. Well-designed and long-term multicenter randomized controlled trials are urgently needed to estimate the real potential and ultimate use of these devices in patients with CPPS.

Traditional Chinese medicine formula Xiaoqinglong decoction for cough caused by COVID-19: A protocol for a systematic review and meta-analysis.

BACKGROUND: Assessing the effectiveness and safety of Traditional Chinese medicine formula Xiaoqinglong decoction for cough caused by COVID-19 is the main purpose of this systematic review protocol. METHODS: The following electronic databases will be searched from their respective inception dates to October 1, 2020: PubMed, MEDLINE, the Cochrane Library, Embase, WorldSciNet, Ovid, the Allied and Complementary Medicine Database, the Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), the Wanfang Database, and the China Biology Medicine Disc. All published randomized controlled trials in English or Chinese related to Traditional Chinese medicine formula Xiaoqinglong decoction for cough caused by COVID-19 will be included. The primary outcome is the time and rate of appearance of coughing. The secondary outcomes are the length of hospital stay. Two reviewers will conduct the study selection, data extraction, and assessment independently. The assessment of risk of bias and data synthesis will be conducted with RevMan V.5.2. RESULTS: The results will provide a high-quality synthesis of current evidence for researchers in this subject area. CONCLUSION: The conclusion of our study will provide an evidence to judge whether traditional Chinese medicine formula Xiaoqinglong decoction is an effective intervention for patients with cough caused by COVID-19. ETHICS AND DISSEMINATION: Formal ethical approval is not necessary as the data cannot be individualized. The results of this protocol will be disseminated in a peer-reviewed journal or presented at relevant conferences. PROSPERO REGISTRATION NUMBER: CRD42020202079.

Comparison of transcatheter arterial chemoembolization with raltitrexed plus liposomal doxorubicin vs. tegafur plus pirarubicin for unresectable hepatocellular carcinoma.

BACKGROUND: There is still no general consensus on the optimal chemotherapeutic agent selection for transcatheter arterial chemoembolization (TACE) in unresectable hepatocellular carcinoma (HCC). The present study aimed to compare the efficacy and safety of TACE with raltitrexed plus liposomal doxorubicin (R + PGLD) vs. tegafur plus pirarubicin (T + P) in patients with unresectable HCC. METHODS: A total of 148 patients with unresectable HCC treated with TACE between January 2012 and December 2016 were retrospectively analyzed. Of them, 74 patients were in the R + PGLD group and 74 patients were in the T + P group (1:1). The treatment response of the tumor, overall survival (OS) time, and adverse effects were compared between the two groups. RESULTS: There were no significant differences in patient characteristics or embolization effect (lipiodol deposition) between the two groups (P>0.05). R + PGLD treatment had a better clinical efficacy than T + P treatment (OR: 64.9% vs. 45.9%, P=0.031; DC: 89.2% vs. 74.3%, P=0.032). Portal vein invasion, hepatic vein invasion, tumor size and BCLC stage were associated with OR or DC after TACE using R + PGLD treatment. Survival analysis revealed that patients who received TACE with R + PGLD had a better prognosis than those treated with T + P. Moreover, some complications in the R + PGLD group, including vomiting, myelosuppression and cardiotoxicity, were significantly lower than those in the T + P group (P<0.05). CONCLUSIONS: TACE with raltitrexed and liposomal doxorubicin could reduce the incidence of adverse reactions and significantly improve the OS of patients with unresectable HCC.

Low-intensity extracorporeal shock wave therapy for III B chronic pelvic pain syndrome.

BACKGROUND: To analyze the efficiency of low-intensity shock wave therapy (LI-ESWT) for patients with III B chronic pelvic pain syndrome (CPPS). METHODS: The study included an uncontrolled population of 32 patients who had suffered with CPPS for ≥3 months. LI-ESWT was performed without anesthesia via a perineal approach. The operation was carried out in four weeks by administering 12,000 shock waves. Using the Visual Analog Scale (VAS) and NIH-developed Chronic Prostatitis Symptom Index (NIH-CPSI), subsequent tests were performed at 1, 2, 4, and 12 weeks after the first LI-ESWT session. RESULTS: All patients who received the four week course as treatment responded actively on the pain VAS and the NIH-CPSI, and both were significantly improved (P<0.05). Compared with the baseline parameters, the NIH-CPSI total score and VAS exhibited substantial improvement at 4 and 12 weeks, where a total improvement at four weeks was reached. It is easy and safe to perform LI-ESWT without anesthesia on an outpatient basis. CONCLUSIONS: LI-ESWT should be regarded as a promising new therapy for CPPS, as it is convenient to perform without any side-effects.

Oleic acid promotes cell invasion through an integrin-linked kinase signaling pathway in renal cell carcinoma.

The change of fatty acid composition has been regarded as an indicator of altered lipid metabolism during human tumourigenesis, but the details are still unclear. We have previously demonstrated a monounsaturated fatty acid (MUFA) named oleic acid (OA) was involved in renal cell carcinoma (RCC) cell growth, as an extracellular signaling molecule to regulate 786-O cell proliferation via the integrin-linked kinase (ILK) pathway. In this study, we further observe the effects of OA on cell invasion of RCC and the potential mechanism by which OA worked was determined. The transwell invasion assay showed OA increased cell invasion of RCC in a dose-dependent manner. Western blotting results indicated ILK, COX-2, and MMP-9 proteins were involved for their high expressions and these effects were reversed when down-regulating the expression of ILK by special siRNA. The MMPs inhibitor GM6001 could weaken the abilities of OA on RCC cells invasion. These results suggested MUFA indeed affected cell invasion of RCC, which was depended by the regulation of ILK pathway.

Aberrant MFN2 transcription facilitates homocysteine-induced VSMCs proliferation via the increased binding of c-Myc to DNMT1 in atherosclerosis.

It is well-established that homocysteine (Hcy) is an independent risk factor for atherosclerosis. Hcy can promote vascular smooth muscle cell (VSMC) proliferation, it plays a key role in neointimal formation and thus contribute to arteriosclerosis. However, the molecular mechanism on VSMCs proliferation underlying atherosclerosis is not well elucidated. Mitofusin-2 (MFN2) is an important transmembrane GTPase in the mitochondrial outer membrane and it can block cells in the G0/G1 stage of the cell cycle. To investigate the contribution of aberrant MFN2 transcription in Hcy-induced VSMCs proliferation and the underlying mechanisms. Cell cycle analysis revealed a decreased proportion of VSMCs in G0/G1 and an increased proportion in S phase in atherosclerotic plaque of APOE-/- mice with hyperhomocystinaemia (HHcy) as well as in VSMCs exposed to Hcy in vitro. The DNA methylation level of MFN2 promoter was obviously increased in VSMCs treated with Hcy, leading to suppressed promoter activity and low expression of MFN2. In addition, we found that the expression of c-Myc was increased in atherosclerotic plaque and VSMCs treated with Hcy. Further study showed that c-Myc indirectly regulates MFN2 expression is duo to the binding of c-Myc to DNMT1 promoter up-regulates DNMT1 expression leading to DNA hypermethylation of MFN2 promoter, thereby inhibits MFN2 expression in VSMCs treated with Hcy. In conclusion, our study demonstrated that Hcy-induced hypermethylation of MFN2 promoter inhibits the transcription of MFN2, leading to VSMCs proliferation in plaque formation, and the increased binding of c-Myc to DNMT1 promoter is a new and relevant molecular mechanism.

SULT2B1b promotes epithelial-mesenchymal transition through activation of the ß-catenin/MMP7 pathway in hepatocytes.

Epithelial-mesenchymal transition (EMT) occurs in the progression of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The hydroxysteroid sulfotransferase 2B1b (SULT2B1b) promotes the proliferation of hepatocarcinoma cells both in vitro and in vivo. However, the correlation between SULT2B1b and the EMT in hepatocytes has not yet been addressed. The present study demonstrated that the SULT2B1b overexpression promoted the EMT process in mouse primary hepatocytes in the absence or presence of TGF-ß1 treatment. Moreover, SULT2B1b interference suppressed the EMT and attenuated the migration and invasion abilities of human hepatocarcinoma BEL-7402 cells by inhibiting the activation of the ß-catenin/MMP-7 pathway. In summary, SULT2B1b enhanced the EMT of hepatocytes and promoted the migration and invasion abilities of BEL-7402 cells by activing the ß-catenin/MMP-7 pathway. Therefore, inhibition of SULT2B1b has therapeutic potential for the treatment of HCC.

Retraction Note: Association between serum vitamin D levels and the risk of kidney stone: evidence from a meta-analysis.

The Editors are retracting this article [1] because post-publication peer review has identified multiple errors in the methodology of this meta-analysis, which invalidate the conclusions drawn.