Reteplase versus Alteplase for Acute Ischemic Stroke.

BACKGROUND: Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. METHODS: We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg) or intravenous alteplase (0.9 mg per kilogram of body weight; maximum dose, 90 mg). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. RESULTS: A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5% of the patients in the reteplase group and in 70.4% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P = 0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients (2.4%) in the reteplase group and in 14 of 699 (2.0%) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase (7.7% vs. 4.9%; risk ratio, 1.59; 95% CI, 1.00 to 2.51), as was the incidence of adverse events (91.6% vs. 82.4%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). CONCLUSIONS: Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.).

ORANGE interplays with TCP7 to regulate endoreduplication and leaf size.

Leaf size is a crucial agronomic trait directly affecting crop yield, which is mainly determined by coordinated cell proliferation, growth, and differentiation. Although endoreduplication is known to be correlated with the onset of cell differentiation and leaf size, the underlying molecular mechanisms are largely unclear. The DnaJ-like zinc finger domain-containing protein ORANGE (OR) was initially demonstrated to confer the massive accumulation of carotenoids in cauliflower curds. However, the cauliflower or mutant also possesses other phenotypes such as smaller curds, smaller leaves with elongated petioles, and delayed flowering. Here, we demonstrated that OR physically interacts with the transcription factor TCP7, which promotes endoreduplication by inducing the expression of the cell cycle gene CYCLIN D 1;1 (CYCD1;1). Overexpression of OR resulted in smaller rosette leaves, whereas the OR-silencing plants had larger rosette leaves than wild-type plants. Our microscopic observations and flow cytometry analysis revealed that the variation in leaf size was a result of different endoreduplication levels. Genetic analyses showed that OR functions antagonistically with TCP7 in regulating the endoreduplication levels in leaf cells. While the expression of OR is induced by TCP7, OR represses the transactivation activity of TCP7 by affecting its binding capability to the TCP-binding motif in the promoter region of CYCD1;1. Through this interaction, OR negatively regulates the expression of CYCD1;1 and reduces the nuclear ploidy level in rosette leaf cells. Our findings provide new insights into the regulatory network of leaf size and also reveal a regulatory circuit controlling endoreduplication in leaf cells.

Effect of Acupuncture for Methadone Reduction : A Randomized Clinical Trial.

BACKGROUND: Methadone maintenance treatment (MMT) is effective for managing opioid use disorder, but adverse effects mean that optimal therapy occurs with the lowest dose that controls opioid craving. OBJECTIVE: To assess the efficacy of acupuncture versus sham acupuncture on methadone dose reduction. DESIGN: Multicenter, 2-group, randomized, sham-controlled trial. (Chinese Clinical Trial Registry: ChiCTR2200058123). SETTING: 6 MMT clinics in China. PARTICIPANTS: Adults aged 65 years or younger with opioid use disorder who attended clinic daily and had been using MMT for at least 6 weeks. INTERVENTION: Acupuncture or sham acupuncture 3 times a week for 8 weeks. MEASUREMENTS: The 2 primary outcomes were the proportion of participants who achieved a reduction in methadone dose of 20% or more compared with baseline and opioid craving, which was measured by the change from baseline on a 100-mm visual analogue scale (VAS). RESULTS: Of 118 eligible participants, 60 were randomly assigned to acupuncture and 58 were randomly assigned to sham acupuncture (2 did not receive acupuncture). At week 8, more patients reduced their methadone dose 20% or more with acupuncture than with sham acupuncture (37 [62%] vs. 16 [29%]; risk difference, 32% [97.5% CI, 13% to 52%]; P < 0.001). In addition, acupuncture was more effective in decreasing opioid craving than sham acupuncture with a mean difference of -11.7 mm VAS (CI, -18.7 to -4.8 mm; P < 0.001). No serious adverse events occurred. There were no notable differences between study groups when participants were asked which type of acupuncture they received. LIMITATION: Fixed acupuncture protocol limited personalization and only 12 weeks of follow-up after stopping acupuncture. CONCLUSION: Eight weeks of acupuncture were superior to sham acupuncture in reducing methadone dose and decreasing opioid craving. PRIMARY FUNDING SOURCE: National Natural Science Foundation of China.

B-type natriuretic peptide levels predict long-term mortality in a large cohort of adults with congenital heart disease.

BACKGROUND AND AIMS: Many adult patients with congenital heart disease (ACHD) are still afflicted by premature death. Previous reports suggested natriuretic peptides may identify ACHD patients with adverse outcome. The study investigated prognostic power of B-type natriuretic peptide (BNP) across the spectrum of ACHD in a large contemporary cohort. METHODS: The cohort included 3392 consecutive ACHD patients under long-term follow-up at a tertiary ACHD centre between 2006 and 2019. The primary study endpoint was all-cause mortality. RESULTS: A total of 11 974 BNP measurements were analysed. The median BNP at baseline was 47 (24-107) ng/L. During a median follow-up of 8.6 years (29 115 patient-years), 615 (18.1%) patients died. On univariable and multivariable analysis, baseline BNP [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.15-1.18 and HR 1.13, 95% CI 1.08-1.18, respectively] and temporal changes in BNP levels (HR 1.22, 95% CI 1.19-1.26 and HR 1.19, 95% CI 1.12-1.26, respectively) were predictive of mortality (P < .001 for both) independently of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. Patients within the highest quartile of baseline BNP (>107 ng/L) and those within the highest quartile of temporal BNP change (>35 ng/L) had significantly increased risk of death (HR 5.8, 95% CI 4.91-6.79, P < .001, and HR 3.6, 95% CI 2.93-4.40, P < .001, respectively). CONCLUSIONS: Baseline BNP and temporal BNP changes are both significantly associated with all-cause mortality in ACHD independent of congenital heart disease diagnosis, complexity, anatomic/haemodynamic features, and/or systolic systemic ventricular function. B-type natriuretic peptide levels represent an easy to obtain and inexpensive marker conveying prognostic information and should be used for the routine surveillance of patients with ACHD.

Artemisinin ameliorates cognitive decline by inhibiting hippocampal neuronal ferroptosis via Nrf2 activation in T2DM mice.

BACKGROUND: Neuronal ferroptosis plays a critical role in the pathogenesis of cognitive deficits. The present study explored whether artemisinin protected type 2 diabetes mellitus (T2DM) mice from cognitive impairments by attenuating neuronal ferroptosis in the hippocampal CA1 region. METHODS: STZ-induced T2DM mice were treated with artemisinin (40 mg/kg, i.p.), or cotreated with artemisinin and Nrf2 inhibitor MEL385 or ferroptosis inducer erastin for 4 weeks. Cognitive performance was determined by the Morris water maze and Y maze tests. Hippocampal ROS, MDA, GSH, and Fe2+ contents were detected by assay kits. Nrf2, p-Nrf2, HO-1, and GPX4 proteins in hippocampal CA1 were assessed by Western blotting. Hippocampal neuron injury and mitochondrial morphology were observed using H&E staining and a transmission electron microscope, respectively. RESULTS: Artemisinin reversed diabetic cognitive impairments, decreased the concentrations of ROS, MDA and Fe2+, and increased the levels of p-Nr2, HO-1, GPX4 and GSH. Moreover, artemisinin alleviated neuronal loss and ferroptosis in the hippocampal CA1 region. However, these neuroprotective effects of artemisinin were abolished by Nrf2 inhibitor ML385 and ferroptosis inducer erastin. CONCLUSION: Artemisinin effectively ameliorates neuropathological changes and learning and memory decline in T2DM mice; the underlying mechanism involves the activation of Nrf2 to inhibit neuronal ferroptosis in the hippocampus.

SARS-CoV-2 reinfection broadens the antibody responses and promotes the phenotypic differentiation of virus-specific memory T cells in adolescents.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants raises concerns regarding the effectiveness of immunity acquired from previous Omicron subvariants breakthrough infections (BTIs) or reinfections (RIs) against the current circulating Omicron subvariants. In this study, we prospectively investigate the dynamic changes of virus-specific antibody and T cell responses among 77 adolescents following Omicron BA.2.3 BTI with or without subsequent Omicron BA.5 RI. Notably, the neutralizing antibodies (NAbs) titers against various detected SARS-CoV-2 variants, especially the emerging Omicron CH.1.1, XBB.1.5, XBB.1.16, EG.5.1, and JN.1 subvariants, exhibited a significant decrease along the time. A lower level of IgG and NAbs titers post-BTI was found to be closely associated with subsequent RI. Elevated NAbs levels and shortened antigenic distances were observed following Omicron BA.5 RI. Robust T cell responses against both Omicron BA.2- and CH.1.1-spike peptides were observed at each point visited. The exposure to Omicron BA.5 promoted phenotypic differentiation of virus-specific memory T cells, even among the non-seroconversion adolescents. Therefore, updated vaccines are needed to provide effective protection against newly emerging SARS-CoV-2 variants among adolescents.

A structural variation in the promoter of the leucoanthocyanidin reductase gene AaLAR1 enhances freezing tolerance by modulating proanthocyanidin accumulation in kiwifruit (Actinidia arguta).

Proanthocyanidins (PAs) are important metabolites that enhance freezing tolerance of plants. Actinidia arguta, especially freezing-tolerant germplasms, accumulate abundant PAs in dormant shoots and thereby enhance freezing tolerance, but the underlying mechanism is unknown. In this study, we used two A. arguta with contrasting cold-resistant phenotypes, KL and RB, to explore the mechanisms in response to cold tolerance. We determined that a leucoanthocyanidin reductase gene (AaLAR1) was more highly expressed in freezing-tolerant KL than in freezing-sensitive RB. Moreover, overexpressing AaLAR1 in kiwifruit promoted PAs biosynthesis and enhanced cold tolerance. The AaLAR1 promoters of various A. arguta germplasms differ due to the presence of a 60-bp deletion in cold-tolerant genotypes that forms a functional binding site for MYC-type transcription factor. Yeast one-hybrid and two-hybrid, dual-luciferase reporter, bimolecular fluorescence complementation and coimmunoprecipitation assays indicated that the AaMYC2a binds to the MYC-core cis-element in the AaLAR1 promoter with the assistance of AaMYB5a, thereby promoting PAs accumulation in the shoots of cold-tolerant kiwifruit. We conclude that the variation in the AaLAR1 promoter and the AaMYC2a-AaMYB5a-AaLAR1 module shape freezing tolerance in A. arguta. The identification of a key structural variation in the AaLAR1 promoter offers a new target for resistance breeding of kiwifruit.

Hypoxaemia risk in pediatric flexible bronchoscopy for foreign body removal: a retrospective study.

BACKGROUND: Hypoxemia represents the most prevalent adverse event during flexible bronchoscopy procedures aimed at foreign body retrieval in pediatric patients; if not expeditiously managed, it carries the potential for cardiac or respiratory arrest. The specific risk factors contributing to the occurrence of hypoxemia during foreign body FB removal via bronchoscopy have yet to be definitively established. METHODS: This retrospective study included a cohort of 266 pediatric subjects from January 1, 2015, to December 31, 2022, who underwent flexible bronchoscopy for the purpose of FB extraction. In this cohort, the supraglottic airway was used to connect the anesthesia apparatus during the removal procedure. RESULTS: In total, 45 of the pediatric patients (16.9%) experienced episodes of hypoxemia during the FB removal procedure. Multivariate analysis revealed that the following factors were significantly associated with the occurrence of hypoxemia: an operation time exceeding 60 min (odds ratio [OR] 8.55; 95% confidence interval [CI] 3.82-19.13), a maximum diameter exceeding 7 mm (OR 5.03; 95% CI, 2.24-11.29), and the presence of radiological evidence indicating pneumonia (OR 2.69; 95% CI, 1.27-5.69). CONCLUSION: During flexible bronchoscopy procedures aimed at FB removal in pediatric patients, there is an increased susceptibility to hypoxemia. Factors including extended operation duration, larger FB dimensions, and radiographic evidence suggestive of pneumonia significantly contribute to a heightened risk of hypoxemia.

A Robust Interacting Multi-Model Multi-Bernoulli Mixture Filter for Maneuvering Multitarget Tracking under Glint Noise.

In practical radar systems, changes in the target aspect toward the radar will result in glint noise disturbances in the measurement data. The glint noise has heavy-tailed characteristics and cannot be perfectly modeled by the Gaussian distribution widely used in conventional tracking algorithms. In this article, we investigate the challenging problem of tracking a time-varying number of maneuvering targets in the context of glint noise with unknown statistics. By assuming a set of models for the possible motion modes of each single-target hypothesis and leveraging the multivariate Laplace distribution to model measurement noise, we propose a robust interacting multi-model multi-Bernoulli mixture filter based on the variational Bayesian method. Within this filter, the unknown noise statistics are adaptively learned while filtering and the predictive likelihood is approximately calculated by means of the variational lower bound. The effectiveness and superiority of our proposed filter is verified via computer simulations.

A Sparse Recovery Algorithm for Suppressing Multiple Linear Frequency Modulation Interference in the Synthetic Aperture Radar Image Domain.

In synthetic aperture radar (SAR) signal processing, compared with the raw data of level-0, level-1 SAR images are more readily accessible and available in larger quantities. However, an amount of level-1 images are affected by radio frequency interference (RFI), which typically originates from Linear Frequency Modulation (LFM) signals emitted by ground-based radars. Existing research on interference suppression in level-1 data has primarily focused on two methods: transforming SAR images into simulated echo data for interference suppression, or focusing interference in the frequency domain and applying notching filters to reduce interference energy. However, these methods overlook the effective utilization of the interference parameters or are confined to suppressing only one type of LFM interference at a time. In certain SAR images, multiple types of LFM interference manifest bright radiation artifacts that exhibit varying lengths along the range direction while remaining constant in the azimuth direction. It is necessary to suppress multiple LFM interference on SAR images when original echo data are unavailable. This article proposes a joint sparse recovery algorithm for interference suppression in the SAR image domain. In the SAR image domain, two-dimensional LFM interference typically exhibits differences in parameters such as frequency modulation rate and pulse width in the range direction, while maintaining consistency in the azimuth direction. Based on this observation, this article constructs a series of focusing operators for LFM interference in SAR images. These operators enable the sparse representation of dispersed LFM interference. Subsequently, an optimization model is developed that can effectively suppress multi-LFM interference and reduce image loss with the assistance of a regularization term in the image domain. Simulation experiments conducted in various scenarios validate the superior performance of the proposed method.

[Effect of modified holmium laser enucleation of the prostate on postoperative urinary control and sexual function in elderly patients with benign prostatic hyperplasia].

OBJECTIVE: To investigate the impact of retaining part of the urethral mucosa on postoperative urinary control, erectile function, and ejaculatory function in patients undergoing holmium laser enucleation of the prostate (HoLEP) surgery. METHODS: A retrospective analysis was conducted on 176 benign prostatic hyperplasia (BPH) patients who underwent surgical treatment at our hospital from January 2019 to January 2022, including 80 cases of modified HoLEP surgery and 96 cases of standard HoLEP surgery. Preoperative and postoperative clinical data were collected and analyzed. RESULTS: At 3 months postoperatively, both groups showed significant improvement in maximum flow rate (Qmax), International Prostate Symptom Score (IPSS) , residual urine volume (RUV) , and quality of life (QOL) compared to pre-treatment values, with statistically significant differences (P<0.05) . There was a significant difference in QOL scores between the experimental and control groups (P<0.05) . At 3 months postoperatively, the incidence of urinary incontinence was significantly lower in the experimental group compared to the control group (P<0.05) . At 6 months postoperatively, both groups showed a significant increase in International Index of Erectile Function-5 (IIEF-5) scores compared to preoperative values (P<0.05) , with no significant difference between the two groups. The incidence of retrograde ejaculation in the experimental group was significantly lower than that in the control group (P<0.05) . CONCLUSIONS: Retaining part of the urethral mucosa in HoLEP surgery can effectively treat BPH, providing significant advantages in terms of urinary control and playing a positive role in overall postoperative sexual function recovery.

Chinese clients' experiences throughout family therapy for school-refusing adolescents: A multiperspectival interpretative phenomenological analysis.

OBJECTIVE: This study aimed to explore Chinese clients' experiences with family dynamic change throughout family therapy for school refusal and the interventions adolescents and their parents identified as useful during family therapy. METHODS: A multiperspective interpretative phenomenology analysis (IPA) was adopted. Thirty-two participants from 11 Chinese families with school-refusing adolescents were recruited after completing family therapy at the hospitals. Semistructured interviews were conducted with the families, and the transcripts were analyzed. RESULTS: Four main superordinate themes emerged: reshaping healthy family boundaries, building a harmonious family atmosphere, learning to cooperate and fight against stress, and achieving individual growth. CONCLUSION: Our analysis suggested that changes in school-refusing adolescents through family therapy consisted of multilevel factors. These factors influence the reversal of adolescents' school refusal. Some targeted interventions for Chinese adolescents who refuse school are discussed and suggested.

Single nucleotide and copy number variants of cancer driver genes inform drug response in multiple cancers.

Due to the heterogeneity of cancer, precision medicine has been a major challenge for cancer treatment. Determining medication regimens based on patient genotypes has become a research hotspot in cancer genomics. In this study, we aim to identify key biomarkers for targeted therapies based on single nucleotide variants (SNVs) and copy number variants (CNVs) of genes. The experiment is carried out on 7 cancers on the Encyclopedia of Cancer Cell Lines (CCLE) dataset. Considering the high mutability of driver genes which result in abundant mutated samples, the effect of data sparsity can be eliminated to a large extent. Therefore, we focus on discovering the relationship between driver mutation patterns and three measures of drug response, namely area under the curve (AUC), half maximal effective concentration (EC50), and log2-fold change (LFC). First, multiple statistical methods are applied to assess the significance of difference in drug response between sample groups. Next, for each driver gene, we analyze the extent to which its mutations can affect drug response. Based on the results of multiple hypothesis tests and correlation analyses, our main findings include the validation of several known drug response biomarkers such as BRAF, NRAS, MAP2K1, MAP2K2, and CDKN2A, as well as genes with huge potential to infer drug responses. It is worth emphasizing that we identify a list of genes including SALL4, B2M, BAP1, CCDC6, ERBB4, FOXA1, GRIN2A, and PTPRT, whose impact on drug response spans multiple cancers and should be prioritized as key biomarkers for targeted therapies. Furthermore, based on the statistical p-values and correlation coefficients, we construct gene-drug sensitivity maps for cancer drug recommendation. In this work, we show that driver mutation patterns could be used to tailor therapeutics for precision medicine.

Mechanical Stretch-Induced ATP Release from Osteocytes Promotes Osteogenesis of Bone Marrow Mesenchymal Stem Cells.

BACKGROUND: Mandibular distraction osteogenesis (MDO) is a highly effective method for bone regeneration, commonly employed in treating craniofacial defects and deformities. Osteocytes sense mechanical forces in the pericellular space, relay external stimuli to biochemical changes, and send signals to other effector cells, including bone marrow mesenchymal stem cells (BM-MSCs), to regulate bone resorption and formation. Piezo1 potentially affects the secretion signal molecules of bone cells under mechanical stretch. The primary aim of this study was to enhance our comprehension of the molecular biology underlying this therapeutic approach and to identify specific signaling molecules that facilitate bone formation in response to stretch forces. METHODS: Mechanical stretching was applied to negative controls and Piezo1 knockdown osteocyte-like MLO-Y4 cells. Alkaline phosphatase and Alizarin Red S staining were used to survey the osteogenic potential of BM-MSCs. The production and secretion content of adenosine triphosphate (ATP) was measured using ATP content determination analysis. Pathway-related and osteo-specific genes and proteins were evaluated using real-time polymerase chain reaction (RT-PCR), Western blots, and immunofluorescence. Mitochondrial organization was examined with a transmission electron microscope. RESULTS: The conditioned medium of stretch-exposed MLO-Y4s significantly upregulated osteogenesis-related indicators of BM-MSCs (p < 0.001). The upregulation of BM-MSC osteogenesis was associated with ATP release from osteocytes. Mechanically induced calcium transfer and transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation mediated by Piezo1 could promote mitochondrial fission and ATP release. Osteocytes detected stretch forces through Piezo1, triggering calcium influx, TAZ nuclear translocation, and ATP production. CONCLUSIONS: The stretch stimulation of Piezo1 induces calcium influx, which in turn promotes calcium-related TAZ nuclear translocation, changes in mitochondrial dynamics, and the release of ATP in osteocytes. This signaling cascade leads to an up-regulation in the osteogenic capacity of BM-MSCs. Mitochondrial energy metabolism of mechanosensitive protein Piezo1-dependent and ATP release may provide a new effective intervention method for mechanically related bone remodeling.

Reteplase versus alteplase for acute ischaemic stroke within 4.5 hours (RAISE): rationale and design of a multicentre, prospective, randomised, open-label, blinded-endpoint, controlled phase 3 non-inferiority trial.

BACKGROUND AND PURPOSE: Reteplase is the third generation of alternative thrombolytic agent. We hypothesis that reteplase will be non-inferior to alteplase in achieving excellent functional outcome at 90 days among eligible patients with acute ischaemic stroke. METHODS AND DESIGN: Reteplase versus alteplase for acute ischaemic stroke within 4.5 hours (RAISE) trial is a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE), controlled phase 3 non-inferiority trial. A total of 1412 eligible patients will be randomly assigned to receive either reteplase at a dose of 18 mg+ 18 mg or alteplase 0.9 mg/kg at a ratio of 1:1. An independent data monitoring committee will review the trail's progress and safety data. STUDY OUTCOMES: The primary efficacy outcome of this study is proportion of individuals attaining an excellent functional outcome, defined as modified Rankin Scale (mRS) 0-1 at 90 days. The secondary efficacy outcomes encompass favourable functional outcome defined as mRS 0-2, major neurological improvement on the National Institutes of Health Stroke Scale, ordinal distribution of mRS and Barthel Index score of at least 95 points at 90 days. The primary safety outcomes are symptomatic intracranial haemorrhage at 36 hours within 90 days. DISCUSSION: The RAISE trial will provide crucial insights into the selection of thrombolytic agents for stroke thrombolysis. TRIAL REGISTRATION NUMBER: NCT05295173.

Gynura procumbens and selected metabolites: Amelioration of depressive-like behaviors in mice and risperidone-induced hyperprolactinemia in rats.

Gynura procumbens (Lour.) Merr., utilized in traditional Chinese medicine, is known for its liver-protective, liver-soothing, and depression-alleviating properties. This research examines the antidepressant and anti-hyperprolactinemia potentials of an ethanol extract from G. procumbens stems (EEGS) and specific metabolites. To model depression and hyperprolactinemia, chronic unpredictable mild stress (CUMS) was induced in mice and risperidone was administered to rats, respectively. Treatments involved administering low (5 mg/kg), medium (25 mg/kg), and high (125 mg/kg) doses of EEGS and certain metabolites to both models. Behavioral assessments were conducted in the CUMS-induced mice, while the CA3 neuronal damage in mice and histopathological alterations in rat mammary glands were evaluated using Nissl and Hematoxylin & Eosin staining techniques, respectively. EEGS decreased immobility times in the forced swimming and tail suspension tests in mice, enhancing their exploration of the central zone. It elevated the serum levels of 5-hydroxytryptamine, norepinephrine, estradiol, luteinizing hormone (LH), and testosterone in mice. Moreover, EEGS restored the neuronal cell arrangement in the CA3 area, reduced interleukin-1beta mRNA production, and increased the expression of interleukin-10 and beta-catenin mRNA. In the context of risperidone-induced hyperprolactinemia, EEGS lowered blood prolactin levels, reduced the dimensions of rat nipples, and enhanced LH, progesterone, and dopamine levels, alongside mitigating mammary hyperplasia. Among the EEGS selected metabolites, the combined effect of chlorogenic acid and trans-p-coumaric acid was found to be more effective than the action of each compound in isolation. Collectively, the findings indicate that EEGS and its selected metabolites offer promising antidepressant benefits while counteracting hyperprolactinemia.

Rationale and design of Treatment of Acute Ischaemic Stroke with Edaravone Dexborneol II (TASTE-2): a multicentre randomised controlled trial.

BACKGROUND: Edaravone dexborneol is believed to be a novel cytoprotective drug, demonstrating a synergistic combination of antioxidative and anti-inflammatory properties in animal models. The Treatment of Acute Ischaemic Stroke with Edaravone Dexborneol (TASTE) trial demonstrated its superior efficacy over edaravone alone for acute ischaemic stroke (AIS) patients. However, its efficacy in individuals undergoing endovascular therapy (EVT) remains uncertain. AIM: To clarify the rationale and design of the TASTE II (TASTE-2) trial. DESIGN: The TASTE-2 is a multicentre, double-blind, randomised, placebo-controlled trial designed to evaluate the efficacy and safety of edaravone dexborneol in patients with AIS and large-vessel occlusion in the anterior circulation. The eligible participants, presenting with a National Institute of Health Stroke Scale score between 6 and 25 (range 0-42, with larger values suggesting severe neurological dysfunction) and an Alberta Stroke Program Early Computed Tomography Score ranging from 6 to 10 (range 0-10, with smaller values suggesting larger infarction) within the initial 24 hours after symptom onset, will be randomly allocated to either the edaravone dexborneol group or the placebo group in equal proportions prior to thrombectomy. The treatment will be continuously administered for a duration of 10-14 days. A follow-up period of 90 days will be implemented for all participants. STUDY OUTCOMES: The primary efficacy outcome is defined as achieving favourable functional independence, measured by a modified Rankin Scale of 0-2 at 90 days. The primary safety outcome focuses on the incidence of serious adverse events. DISCUSSION: The TASTE-2 trial will provide evidence to determine whether the administration of edaravone dexborneol in AIS patients undergoing EVT could yield significant improvements in neurological function.

Testosterone Exacerbates the Formation of Liver Cancer Induced by Environmental N-Nitrosamines Exposure: Potential Mechanisms and Implications for Human Health.

Background: Humans are frequently exposed to N-nitrosamines through various sources, including diet, cigarette smoking, contaminated water, the atmosphere, and endogenous nitrosation. Exposure to these carcinogens may also contribute to the gender-specific incidence of liver cancer, which is significantly higher in males than in females, possibly due to the influence of endogenous hormones such as testosterone. However, the effect of testosterone on N-nitrosamine-induced liver cancer and its underlying mechanism remains unclear. Purpose: To investigate the effect of testosterone on the development of liver cancer induced by N-nitrosamines exposure. Patients and Methods: Histopathological and immunohistochemical staining techniques were employed to analyze the expression levels and nuclear localizations of key signaling molecules, including androgen receptor (AR), ß-catenin, and HMGB1, in both tumor and non-tumor regions of liver samples obtained from human patients and mice. Results: The findings demonstrated a strong correlation between AR and ß-catenin in the nuclear region of tumor areas. AR also showed a significant correlation with HMGB1 in the cytoplasmic region of non-tumor areas in both human and mice samples. The study further analyzed the expression levels and patterns of these three proteins during the progression of liver tumors. Conclusion: This study confirms that AR has the ability to modulate the expression levels and patterns of ß-catenin and HMGB1 in vivo, thereby exacerbating the progression of liver cancer induced by environmental N-nitrosamines exposure. Importantly, the effect of testosterone on the formation of liver cancer induced by environmental N-nitrosamine exposure intensifies this progression. These findings have important implications for drug safety in clinical practice and emphasize the significance of reducing N-nitrosamines exposure through conscious choices regarding diet and lifestyle to ensure environmental safety.

Li-Hong Tang alleviates dextran sodium sulfate-induced colitis by regulating NRF2/HO-1 signaling pathway and gut microbiota.

Introduction: Ulcerative colitis (UC) is marked by recurring inflammation. Existing treatments are ineffective and may have toxic side effects. Thus, new therapeutic agents are urgently needed. We studied the botanical formula "Li-Hong Tang (LHT)", which contains two main ingredients, Salvia plebeia R. Br and Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba. In this study, we aimed to identify the effects of LHT on UC and explore its potential mechanism. Methods: LHT was analyzed using a mass spectrometer (MS). DSS at a dose of 2.5% was utilized to develop UC in mice. The administered groups received low, medium, and high dosages (0.32 g/kg, 0.64 g/kg, and 1.28 g/kg) of LHT and the positive medication, sulfasalazine (0.2 g/kg), respectively. Body weight, disease activity index (DAI) score, colon length, spleen index, serum myeloperoxidase (MPO), nitric oxide (NO), superoxide dismutase (SOD) and inflammatory factor concentrations were monitored. The expression of NRF2 and HO-1 in colonic tissues was evaluated by immunohistochemistry. 16S rDNA sequencing was employed to investigate alterations in the gut microbiota of the mice, aiming to elucidate the extent of LHT's impact. Results: LHT may ameliorate DSS-induced colitis in mice by lowering inflammation, reducing oxidative stress, restoring the intestinal barrier, and influencing the NRF2/HO-1 pathway. Moreover, LHT treatment exhibited a regulatory effect on the gut microbiota, characterized by elevated levels of Patescibacteria, Verrucomicrobiota, Candidatus_Saccharimonas, Lactobacillus, and Ligilactobacillus levels while decreasing Oscillibacter and Colidextribacter levels. Further study indicated that MPO, NO, and inflammatory factors were positively correlated with Oscillibacter, Colidextribacter, Escherichia-Shigella, Anaerostines, and negatively with Lactobacillus, Clostridiales_unclassified, Candidatus_Saccharimonas, and Patescibacteria. Furthermore, colony network analysis revealed that Lactobacillus was negatively associated with Oscillibacter and Colidextribacter, whereas Oscillibacter was positively related to Colidextribacter. Conclusion: LHT protects against DSS-induced mice by inhibiting the inflammatory response, oxidative stress, and mucosal injury. The protective role may involve regulating the NRF2/HO-1 signaling pathway and gut microbiota.