PAX1 methylation as a robust predictor: developing and validating a nomogram for assessing endocervical curettage (ECC) necessity in human papillomavirus16/18-positive women undergoing colposcopy.

OBJECTIVE: The major challenge in routine endocervical curettage (ECC) among Human Papillomavirus (HPV) 16/18-positive patients is that only a small fraction benefit. Nevertheless, current reported models often overestimate the validity and necessity of ECC, making it difficult to improve benefits for patients. This research hypothesized that assessing paired boxed gene 1 methylation levels (PAX1m) and clinical characteristics could enhance the predictive accuracy of detecting additional high-grade squamous intraepithelial lesions or worse (HSIL +) through ECC that were not identified by colposcopy-directed biopsy (CDB). METHODS: Data from 134 women with HPV16/18 positivity undergoing CDB and ECC between April 2018 and April 2022 were collected and analyzed. Quantitative methylation-specific polymerase chain reaction (qMSP) was utilized to measure PAX1m, expressed as ΔCp. Univariate and multivariate regression analyses were conducted to screen variables and select predictive factors. A nomogram was constructed using multivariate logistic regression to predict additional HSIL + detected by ECC. The discrimination, calibration, and clinical utility of the nomogram were evaluated using receiver operating characteristic curves (ROC) and the calibration plot. RESULTS: Age (odds ratio [OR], 5.654; 95% confidence interval [CI], 1.131-37.700), cytology (OR, 24.978; 95% CI, 3.085-540.236), and PAX1 methylation levels by grade (PAX1m grade) (OR, 7.801; 95% CI, 1.548-44.828) were independent predictive factors for additional detection of HSIL + by ECC. In HPV16/18-positive women, the likelihood of additional detection of HSIL + through ECC increased with the severity of cytological abnormalities, peaking at 43.8% for high-grade cytological lesions. Moreover, when cytological findings indicated low-grade lesions, PAX1 methylation levels were positively correlated with the additional detection of HSIL + by ECC (P value < 0.001). A nomogram prediction model was developed (area under curve (AUC) = 0.946; 95% CI, 0.901-0.991), demonstrating high sensitivity (90.9%) and specificity (90.5%) at the optimal cutoff point of 107. Calibration analysis confirmed the model's strong agreement between predicted and observed probabilities. CONCLUSION: The clinical nomogram presented promising predictive performance for the additional detection of HSIL + through ECC among women with HPV16/18 infection. PAX1 methylation level could serve as a valuable tool in guiding individualized clinical decisions regarding ECC for patients with HPV 16/18 infection, particularly in cases of low-grade cytological findings.

Glial growth factor 2 treatment alleviates ischemia and reperfusion-damaged integrity of the blood-brain barrier through decreasing Mfsd2a/caveolin-1-mediated transcellular and Pdlim5/YAP/TAZ-mediated paracellular permeability.

The impairment of blood-brain barrier (BBB) integrity is the pathological basis of hemorrhage transformation and vasogenic edema following thrombolysis and endovascular therapy. There is no approved drug in the clinic to reduce BBB damage after acute ischemic stroke (AIS). Glial growth factor 2 (GGF2), a recombinant version of neuregulin-1ß that can stimulates glial cell proliferation and differentiation, has been shown to alleviate free radical release from activated microglial cells. We previously found that activated microglia and proinflammatory factors could disrupt BBB after AIS. In this study we investigated the effects of GGF2 on AIS-induced BBB damage as well as the underlying mechanisms. Mouse middle cerebral artery occlusion model was established: mice received a 90-min ischemia and 22.5 h reperfusion (I/R), and were treated with GGF2 (2.5, 12.5, 50 ng/kg, i.v.) before the reperfusion. We showed that GGF2 treatment dose-dependently decreased I/R-induced BBB damage detected by Evans blue (EB) and immunoglobulin G (IgG) leakage, and tight junction protein occludin degradation. In addition, we found that GGF2 dose-dependently reversed AIS-induced upregulation of vesicular transcytosis increase, caveolin-1 (Cav-1) as well as downregulation of major facilitator superfamily domain containing 2a (Mfsd2a). Moreover, GGF2 decreased I/R-induced upregulation of PDZ and LIM domain protein 5 (Pdlim5), an adaptor protein that played an important role in BBB damage after AIS. In addition, GGF2 significantly alleviated I/R-induced reduction of YAP and TAZ, microglial cell activation and upregulation of inflammatory factors. Together, these results demonstrate that GGF2 treatment alleviates the I/R-compromised integrity of BBB by inhibiting Mfsd2a/Cav-1-mediated transcellular permeability and Pdlim5/YAP/TAZ-mediated paracellular permeability.

Unravelling the molecular landscape of endometrial cancer subtypes: insights from multi-omics analysis.

BACKGROUND: Endometrial cancer (EC) as one of the most common gynecologic malignancies is increasing in incidence during the past 10 years. Genome-Wide Association Studies (GWAS) extended to metabolic and protein phenotypes inspired us to employ multi-omics methods to analyze the causal relationships of plasma metabolites and proteins with EC to advance our understanding of EC biology and pave the way for more targeted approaches to its diagnosis and treatment by comparing the molecular profiles of different EC subtypes. METHODS: Two-sample Mendelian randomization (MR) was performed to investigate the effects of plasma metabolites and proteins on risks of different subtypes of EC (endometrioid and non-endometrioid). Pathway analysis, transcriptomic analysis, and network analysis were further employed to illustrate gene-protein-metabolites interactions underlying the pathogenesis of distinct EC histological types. RESULTS: We identified 66 causal relationships between plasma metabolites and endometrioid EC, and 132 causal relationships between plasma proteins and endometrioid EC. Additionally, 40 causal relationships between plasma metabolites and non-endometrioid EC, and 125 causal relationships between plasma proteins and non-endometrioid EC were observed. Substantial differences were observed between endometrioid and non-endometrioid histological types of EC at both the metabolite and protein levels. We identified 7 overlapping proteins (RGMA, NRXN2, EVA1C, SLC14A1, SLC6A14, SCUBE1, FGF8) in endometrioid subtype and 6 overlapping proteins (IL32, GRB7, L1CAM, CCL25, GGT2, PSG5) in non-endometrioid subtype and network analysis of above proteins and metabolites to identify coregulated nodes. CONCLUSIONS: Our findings observed substantial differences between endometrioid and non-endometrioid EC at the metabolite and protein levels, providing novel insights into gene-protein-metabolites interactions that could influence future EC treatments.

Fibroblast growth factor-21 alleviates proteasome injury via activation of autophagy flux in Parkinson's disease.

Parkinson's disease (PD) is one of the most common and complex Neurodegeneration, with an inherited metabolic disorder. Fibroblast growth factor 21 (FGF21), an endocrine hormone that belongs to the fibroblast growth factor superfamily, plays an extensive role in metabolic regulation. However, our understandings of the specific function and mechanisms of FGF21 on PD are still quite limited. Here, we aimed to elucidate the actions and the underlying mechanisms of FGF21 on dopaminergic neurodegeneration using cellular models of parkinsonism. To investigate the effects of FGF21 on dopaminergic neurodegeneration in vitro, proteasome impairment models of PD were utilized. Human dopaminergic neuroblastoma SH-SY5Y cells were treated with the proteasome inhibitor lactacystin (5 µmol/L) for 12 h, then with 50 ng/ml FGF-21 with or without 5 mmol/L of 3-methyladenine.The cells were dissected to assess alterations in autophagy using immunofluorescence, immunoblotting and electron microscopy assays. Our data indicate that FGF21 prevents dopaminergic neuron loss and shows beneficial effects against proteasome impairment induced PD syndrome, indicating it might be a potent candidate for developing novel drugs to deal with PD.

Triage method for endometrial biopsy in postmenopausal women: a multicenter retrospective cohort study.

OBJECTIVE: To identify the optimal triage procedure for endometrial biopsies in postmenopausal women. METHODS: The clinical information of 470 postmenopausal women with endometrial biopsy results and postmenopausal bleeding (PMB) and/or transvaginal ultrasonography (TVU) abnormalities were collected at the gynecology departments of four general hospitals from March 2021 to March 2022. In the validation cohort, 112 women with TVU abnormalities who underwent endometrial biopsy at Xiangya hospital between May 2022 and May 2023 were enrolled. The endpoint was the final diagnosis based on hysteroscopy reports and biopsy pathology results. The sensitivity, specificity, positive predictive value, and negative predictive value were compared among the three triage methods. A nomogram prediction model was developed and validated. RESULTS: Referring women with TVU abnormalities for endometrial biopsy identified 100% malignant/premalignant lesions despite low specificity (19.7%). Among women with measurable endometrial thickness (ET), we suggest that the ET cutoff value for biopsy referral should be ≥4 mm. The PMB (odds ratio [OR], 3.241; 95% confidence interval [CI], 1.073-9.789), diabetes (OR, 10.915; 95% CI, 3.389-35.156), and endometrial thickness (OR, 1.277; 95% CI, 1.156-1.409) were independent predictive factors for endometrial (pre)malignancy. A nomogram prediction model was constructed (area under curve [AUC] = 0.802, 95% CI: 0.715 to 0.889). The ideal cutoff point was 22.5, with a sensitivity of 100.0% and a specificity of 15.7%. The external validation achieved an AUC of 0.798 (95% CI, 0.685-0.911). CONCLUSIONS: It was possible to refer all postmenopausal women with TVU abnormity (ET ≥ 4 mm or other abnormal findings) for endometrial biopsy. Among women with TVU abnormalities, a nomogram was constructed, and a score greater than 22.5 suggested the need for referral for endometrial biopsy, while a score less than 22.5 suggested that regular follow-up was required, further improving the triage procedure.

Preemptive QP001, a fast-acting meloxicam formulation, provides analgesia and reduces opioid consumption following abdominal surgery: a randomized controlled trial.

BACKGROUND: QP001, a novel meloxicam formulation, has been developed to manage moderate to severe postoperative pain. This study aimed to evaluate the efficacy and safety of QP001 injections for moderate to severe pain following abdominal surgery. METHOD: This prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial enlisted patients experiencing moderate to severe pain following abdominal surgery. These patients were randomized to receive either QP001 injections (30 mg or 60 mg) or a placebo pre-surgery. The primary efficacy endpoint was the total morphine consumption within 24 h after the first administration. RESULTS: A total of 108 patients were enrolled, and 106 patients completed the study. The total morphine consumption in the QP001 30 mg group and 60 mg group, versus placebo group, were significantly lower over the following 24 h (5.11[5.46] vs 8.86[7.67], P = 0.011; 3.11[3.08] vs 8.86[7.67], P < 0.001), respectively. The total morphine consumption in the QP001 30 mg and 60 mg groups, versus placebo group, was also significantly decreased over the following 48 h, including the 24-48 h period (P ≤ 0.001). The QP001 30 mg and 60 mg groups, versus placebo, showed a significant decrease in the area under the curve for pain intensity-time as well as a significant decrease in the effective pressing times of the analgesic pump over the 24 h and 48 h periods (P < 0.05). The QP001 groups, versus placebo, show no significant different in Adverse Events or Adverse Drug Reactions (P > 0.05). CONCLUSION: Preoperative/preemptive QP001 provides analgesia and reduces opioid consumption in patients with moderate to severe pain following abdominal surgery, while maintaining a favorable safety profile.

Minimally invasive approaches for the early detection of endometrial cancer.

Endometrial cancer (EC) is one of the most common gynecologic cancers and its incidence is rising globally. Although advanced EC has a poor prognosis; diagnosing EC at an earlier stage could improve long-term patient outcomes. However, there is no consensus on the early detection strategies for EC and the current diagnostic practices such as transvaginal ultrasound, hysteroscopy and endometrial biopsy are invasive, costly and low in specificity. Thus, accurate and less invasive screening tests that detect EC in women with early stages of the disease are needed. Current research has revolutionized novel EC early detection methodologies in many aspects. This review aims to comprehensively characterizes minimally invasive screening techniques that can be applied to EC in the future, and fully demonstrate their potential in the early detection of EC.

Breast-conserving in centrally located breast cancer patients confirmed safe by SEER based study.

BACKGROUND: Due to the lack of high-level data, there is still controversy over the oncological safety of breast conservation in patients with centrally located breast cancer. This study aimed to assess the safety of breast-conserving surgery in patients with centrally located breast cancer based on the data from the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: We collected data for all cases diagnosed with breast cancer who underwent breast-conserving surgery from 2012-2014 in the SEER database. The primary outcome of our study was disease-specific survival (DSS) and overall survival (OS). The PSM was used to eliminate the effects of non-random statistics. Chi-square test, Kaplan-Meier method and Cox proportional hazards regression model on univariate and multivariate analysis were used to analyze the data. RESULTS: Data from 79,214 patients who had undergone breast-conserving surgery were analyzed in this study, including those with breast cancer in the central region (n=3,128) and outside the central region (n=76,086). The DSS of central breast cancer patients and outside the central breast cancer patients was 58.1 months versus 58.0 months (P>0.05), respectively, while the OS of the 2 groups was 58.0 months versus 58.0 months (P>0.05), respectively. CONCLUSIONS: Breast cancer in the central region should not be contraindicated for breast conserving surgery and breast-conserving surgery can benefit a wider range of patients.

Protective Properties of the Extract of Chrysanthemum on Patients with Ischemic Stroke.

Investigation of the protective effect of chrysanthemum extract in ischemic strokes patients is among the challenging issues with the traditional hospital system in general and smart technology-based hospitals in particular. In this study, we have evaluated the protective effect of chrysanthemum extract on patients with ischemic stroke by detecting the severity of stroke, neuronal indexes, and oxidative stress biomarkers. For this purpose, forty-six patients with ischemic stroke were randomly divided into the control group (n = 30) and chrysanthemum group (n = 30). The control group received standard stroke treatment, and the chrysanthemum group was treated with chrysanthemum extract 400 mg/day (200 mg/day, twice/day) on the basis of standard treatment. The groups were compared the effect of saffron capsules using the National Institute of Health Stoke Scale (NIHSS), serum neuron specific enolase (NSE), S100, brain-derived neurotrophic factor (BDNF), malondialdehyde (MDA), Su-peroxide dismutase (SOD), and total antioxidant capacity (TAC ) levels, at the time of first day and fourth day after treatment. On the first day after treatment, there was no significant difference in the NIHSS score, serum NSE, S100, BDNF, MDA, SOD, and TAC levels between the chrysanthemum group and the control group (P > 0.05). On the fourth day after treatment, the NIHSS, serum NSE, S100, and MDA levels were significantly reduced in the chrysanthemum group compared to the control group, while the BDNF, SOD, and TAC levels were higher (P < 0.05). In addition, compared to the levels on the first day, the NIHSS, serum NSE, S100, and MDA levels were significantly reduced, and the BDNF, SOD, and TAC levels were increased in the chrysanthemum group on the fourth day (P < 0.05). Chrysanthemum extract has the effects of scavenging oxygen free radicals and antioxidation and has a neuroprotective effect on ischemic stroke patients.

Role of NADPH Oxidase-Induced Hypoxia-Induced Factor-1α Increase in Blood-Brain Barrier Disruption after 2-Hour Focal Ischemic Stroke in Rat.

We recently showed that inhibition of hypoxia-induced factor-1α (HIF-1α) decreased acute ischemic stroke-induced blood-brain barrier (BBB) damage. However, factors that induce the upregulation of HIF-1α expression remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase played a critical role in reperfusion-induced BBB damage after stroke. However, the role of NADPH oxidase in BBB injury during the acute ischemia stage remains unclear. This study is aimed at investigating the role of NADPH oxidase in BBB injury and the expression of HIF-1α after acute ischemic stroke. A sutured middle cerebral artery occlusion (MCAO) model was used to mimic ischemic stroke in rats. Our results show that the inhibition of NADPH oxidase by apocynin can significantly reduce the BBB damage caused by 2 h ischemic stroke accompanied by reducing the degradation of tight junction protein occludin. In addition, treatment with apocynin significantly decreased the upregulation of HIF-1α induced by 2 h MCAO. More importantly, apocynin could also inhibit the MMP-2 upregulation. Of note, HIF-1α was not colocalized with a bigger blood vessel. Taken together, our results showed that inhibition of NADPH oxidase-mediated HIF-1α upregulation reduced BBB damage accompanied by downregulating MMP-2 expression and occludin degradation after 2 h ischemia stroke. These results explored the mechanism of BBB damage after acute ischemic stroke and may help reduce the associated cerebral hemorrhage transformation after thrombolysis and endovascular treatment after ischemic stroke.

Precise high-throughput online near-infrared spectroscopy assay to determine key cell wall features associated with sugarcane bagasse digestibility.

BACKGROUND: Sugarcane is one of the most crucial energy crops that produces high yields of sugar and lignocellulose. The cellulose crystallinity index (CrI) and lignin are the two kinds of key cell wall features that account for lignocellulose saccharification. Therefore, high-throughput screening of sugarcane germplasm with excellent cell wall features is considered a promising strategy to enhance bagasse digestibility. Recently, there has been research to explore near-infrared spectroscopy (NIRS) assays for the characterization of the corresponding wall features. However, due to the technical barriers of the offline strategy, it is difficult to apply for high-throughput real-time analyses. This study was therefore initiated to develop a high-throughput online NIRS assay to rapidly detect cellulose crystallinity, lignin content, and their related proportions in sugarcane, aiming to provide an efficient and feasible method for sugarcane cell wall feature evaluation. RESULTS: A total of 838 different sugarcane genotypes were collected at different growth stages during 2018 and 2019. A continuous variation distribution of the near-infrared spectrum was observed among these collections. Due to the very large diversity of CrI and lignin contents detected in the collected sugarcane samples, seven high-quality calibration models were developed through online NIRS calibration. All of the generated equations displayed coefficient of determination (R2) values greater than 0.8 and high ratio performance deviation (RPD) values of over 2.0 in calibration, internal cross-validation, and external validation. Remarkably, the equations for CrI and total lignin content exhibited RPD values as high as 2.56 and 2.55, respectively, indicating their excellent prediction capacity. An offline NIRS assay was also performed. Comparable calibration was observed between the offline and online NIRS analyses, suggesting that both strategies would be applicable to estimate cell wall characteristics. Nevertheless, as online NIRS assays offer tremendous advantages for large-scale real-time screening applications, it could be implied that they are a better option for high-throughput cell wall feature prediction. CONCLUSIONS: This study, as an initial attempt, explored an online NIRS assay for the high-throughput assessment of key cell wall features in terms of CrI, lignin content, and their proportion in sugarcane. Consistent and precise calibration results were obtained with NIRS modeling, insinuating this strategy as a reliable approach for the large-scale screening of promising sugarcane germplasm for cell wall structure improvement and beyond.

The efficacy and safety of probiotics for prevention of chemoradiotherapy-induced diarrhea in people with abdominal and pelvic cancer: A systematic review and meta-analysis based on 23 randomized studies.

BACKGROUND AND AIMS: We evaluated the efficacy and safety of probiotics for prevention of chemoradiotherapy-induced diarrhea in patients with abdominal or pelvic cancer. METHODS: We searched the Cochrane Library, PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and VIP databases up to August 2019. We also hand searched the citation lists of included studies and previous systematic reviews identified to identify further relevant trials. The primary outcome was the incidence of chemoradiotherapy-induced diarrhea of all grades. The secondary outcomes were improvement of antidiarrheal medication use, stool form (Bristol scale), response rate, and adverse events (AEs). Diarrhea was graded according to the Common Toxicity Criteria system. Two reviewers assessed trial quality and extracted data independently. The included studies were analyzed using Review Manager ver. 5.2. RESULTS: Twenty-three randomized, placebo-controlled studies (N = 2570 participants) were included in the efficacy assessment. The incidence of all diarrhea (risk ratio [RR] 0.16; 95% confidence interval [CI] 0.51-0.73), grade ≥ 3 diarrhea (RR 0.36; 95% CI 0.18-0.72), and grade ≥ 2 diarrhea (RR 0.65; 95% CI 0.54-0.78), but not that of grade ≤ 2 diarrhea (RR 1.07; 95% CI 0.95-1.21), was significantly reduced in the probiotics compared to the placebo groups. No significant increase in the incidence of AEs was found in the probiotics group, although four studies reported a variety of AEs. CONCLUSIONS: Probiotics prevented chemoradiotherapy-induced diarrhea, particularly high-grade diarrhea. Probiotics rarely cause AEs.

miR-30b protects nigrostriatal dopaminergic neurons from MPP(+)-induced neurotoxicity via SNCA.

OBJECTIVE: To explore the function of miR-30b in pathogenesis of Parkinson's disease (PD) and its underlying molecular mechanism. MATERIALS AND METHODS: We used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPP(+)) as a tool for constructing the PD cell model, using miR-30b mimics or inhibitors to manipulate miR-30b level for an experimental model of acquisition. The cell viability of SH-SY5Y was detected by CCK, and luciferase was used to screen the binding of target genes. The protein levels of SNCA were measured by Western blot. Then, we investigate the changes in pro- and anti-apoptotic markers with or without miR-30b treatment. RESULTS: There was a significant low expression of MiR-30b in MPP(+)-induced cells. SH-SY5Y cell viability was rescued by MiR-30b overexpression. Luciferase experiments showed that MiR-30b may bind to the 3'-UTR side of SNCA and inhibited its expression. By Western blot, the SNCA level was markedly decreased by miR-30b. miR-30b attenuated the upregulation of Bax and the depletion of Bcl-2 induced by MPP(+).

Evaluation of Clinical Outcome and Risk Factors for Recurrence after Pelvic Reconstruction of Pelvic Organ Prolapse with Implanted Mesh or Biological Grafts: A Single-Blind Randomized Trial.

BACKGROUND: There are few studies on the relative factors related to postoperative recurrence. OBJECTIVES: To compare the outcomes of pelvic floor reconstruction involving Herniamesh mesh and biological grafts and to investigate the correlative factors of postoperative recurrence. METHOD: Two hundred and thirty-two patients were randomly divided into 2 groups: Herniamesh mesh group (117) and biological graft group (115). Follow-ups for 6 months and 1 year after the surgery. The primary outcomes were recurrence, perioperative complications. Secondary outcome was a questionnaire about the life habits associated with relapse. RESULTS: The recurrence rate at 6 months or 1 year did not differ substantially between the 2 groups (p = 0.787 and 0.968, respectively). Adverse events occurred with significantly different frequencies over 1 year (p = 0.005). Twelve factors were investigated and analyzed by logistic regression analysis. It showed that recurrence had a strong association with a long-term vegetarian diet (OR 0.283, 95% CI 0.117-0.683), long-term soybean product diet (OR 8.010, 95% CI 2.514-25.523), and vaginal intercourse (OR 5.154, 95% CI 1.461-18.184). CONCLUSIONS: The surgical recurrence rate for the mesh was similar to biological grafts at short-term follow-up. Eating soy products often and vaginal intercourse after surgery can reduce recurrence.

Dl-NBP (Dl-3-N-Butylphthalide) Treatment Promotes Neurological Functional Recovery Accompanied by the Upregulation of White Matter Integrity and HIF-1α/VEGF/Notch/Dll4 Expression.

Dl-3-n-butylphthalide (dl-NBP) was approved by the FDA of China for the treatment of acute ischemic stroke. Dl-NBP has been shown to promote neurological functional recovery and enhance white matter integrity using an endothelin-1-induced focal permanent cerebral ischemia model, which could mimic those patients who have no opportunity to receive either tissue plasminogen activator (tPA) thrombolysis or endovascular therapy. However, it is not clear whether dl-NBP could promote neurological functional recovery in a focal transient cerebral ischemia model, which could mimic those patients who have the opportunity to receive either tPA thrombolysis or endovascular therapy. In this study, using a model of middle cerebral artery occlusion in mice, we aim to explore the effect of two-week dl-NBP treatment on neurological functional recovery after ischemic stroke as well as its underlying mechanism. Our results showed that dl-NBP treatment promoted functional recovery assessed by neurological scores and an adhesive remove test, and this improved the integrity of white matter after 60-min ischemia and 14-day reperfusion. In addition, dl-NBP increased the number of RECA-1 positive vessels and enhanced the expression of the tight junction protein occludin. More importantly, dl-NBP also promoted the expression of hypoxia-induced factor-1α, the vascular endothelial growth factor, Notch, and delta-like ligand 4. In conclusion, our study provides evidence that dl-NBP treatment could also promote functional recovery after focal transient ischemia stroke, and this recovery is associated with upregulated white matter integrity, microvessels, and the tight junction protein occludin. Our results suggested that, in future, dl-NBP may also be applied in clinic to promote functional recovery during the later phase of focal transient ischemic stroke.

Inhibition of HIF-1α Reduced Blood Brain Barrier Damage by Regulating MMP-2 and VEGF During Acute Cerebral Ischemia.

Increase of blood brain barrier (BBB) permeability after acute ischemia stroke is a predictor to intracerebral hemorrhage transformation (HT) for tissue plasminogen activator (tPA) thrombolysis and post-endovascular treatment. Previous studies showed that 2-h ischemia induced damage of BBB integrity and matrix metalloproteinase-2 (MMP-2) made major contribution to this disruption. A recent study showed that blocking ß2-adrenergic receptor (ß2-AR) alleviated ischemia-induced BBB injury by reducing hypoxia-inducible factor-1 alpha (HIF-1α) level. In this study, we sought to investigate the interaction of HIF-1α with MMP-2 and vascular endothelial growth factor (VEGF) in BBB injury after acute ischemia stroke. Rat suture middle cerebral artery occlusion (MCAO) model was used to mimic ischemia condition. Our results showed that ischemia produced BBB damage and MMP-2/9 upregulation was colocalized with Rhodamine-dextran leakage. Pretreatment with YC-1, a HIF-1α inhibitor, alleviated 2-h ischemia-induced BBB injury significantly accompanied by decrease of MMP-2 upregulation. In addition, YC-1 also prevented VEGF-induced BBB damage. Of note, VEGF was shown to be colocalized with neurons but not astrocytes. Taken together, BBB damage was reduced by inhibition of interaction of HIF-1α with MMP-2 and VEGF during acute cerebral ischemia. These findings provide mechanisms underlying BBB damage after acute ischemia stroke and may help reduce thrombolysis- and post-endovascular treatment-related cerebral hemorrhage.

Efficient Upper-Excited State Fluorescence in an Organic Hyperbolic Metamaterial.

Upper-excited state emission is not usually observed from molecules owing to competition with much faster nonradiative relaxation pathways; however, it can be made more efficient by modifying the photonic density of states to enhance the radiative decay rate. Here, we show that embedding the small molecule zinc tetraphenylporphyrin (ZnTPP) in a hyperbolic metamaterial enables an ∼18-fold increase in fluorescence intensity from the second singlet excited state ( S2) relative to that from the lowest singlet excited state ( S1). By varying the number of periods in the HMM stack, we are able to systematically tune the ZnTPP fluorescence spectrum from red (dominated by emission from S1) to blue (dominated by emission from S2) with an instrument-limited decay lifetime <10 ps. Our results are consistent with a broadband Purcell enhancement in the radiative rate of both transitions predicted via transfer matrix modeling and point to a general opportunity to harness upper-excited states for spectrally tunable, ultrafast fluorescence via radiative decay engineering.

PCAF-mediated acetylation of Lin28B increases let-7 biogenesis in lung adenocarcinoma H1299 cells.

BACKGROUND: Lin28B and its paralog Lin28A are small RNA binding proteins that have similar inhibitory effects, although they target separate steps in the maturation of let-7 miRNAs in mammalian cells. Because Lin28B participates in the promotion and development of tumors mostly by blocking the let-7 tumor suppressor family members, we sought to explore the associated mechanisms to gain insights into how Lin28B might be decreased in human cancer cells to increase let-7 levels and reverse malignancy. RESULTS: We demonstrated that the histone acetyltransferase PCAF, via its cold shock domain, directly interacts with and subsequently acetylates Lin28B in lung adenocarcinoma-derived H1299 cells. RT-qPCR assays showed that both let-7a-1 and let-7g were increased in PCAF-transfected H1299 cells. Lin28B is acetylated by ectopic PCAF and translocates from the nucleus to the cytoplasm in H1299 cells. CONCLUSIONS: The effects of acetylated Lin28B on let-7a-1 and let-7g are similar to that of stable knockdown of Lin28B in H1299 cells. The new role of PCAF in mediating Lin28B acetylation and the specific release of its target microRNAs in H1299 cells may shed light on the potential application of let-7 in the clinical treatment of lung cancer patients.

CRIF1 enhances p53 activity via the chromatin remodeler SNF5 in the HCT116 colon cancer cell lines.

CR6-interacting factor 1 (CRIF1) is ubiquitously expressed in human tissues. CRIF1 was first identified as a Gadd45γ (also known as CR6)-interacting protein, and it was also identified in a human colon cancer cell line stably transformed with p53. These results suggested that CRIF1 functions in the nucleus with p53 and Gadd45 family proteins in the suppression of cell growth and tumor development. Here, we found that CRIF1 could be recruited to a specific region in the promoter of the p53 gene, eliciting an increase in the mRNA and protein levels of p53 as well as p53 functional target genes. These functions required CRIF1 to interact with SNF5. CRIF1 was further recruited to the upstream promoter region of the p53 gene to suppress cell cycle progression in HCT116 cells. To our knowledge, this is the first evidence indicating that SNF5 is indispensable for CRIF1-enhanced p53 activity and its function in the suppression of cell cycle arrest in human cancer cells.