Untreated Group Research Articles

Resolvin E1 and Inhibition of BLT2 Signaling Attenuate the Inflammatory Response and Improve One-Lung Ventilation-Induced Lung Injury

ABSTRACT Introduction One-lung ventilation (OLV) is a prevalently used technique to sustain intraoperative pulmonary function. Resolvin E1 (RvE1), a specialized pro-resolving lipid mediator, accelerates the resolution of inflammation in the lungs. However, its therapeutic effects on OLV-induced lung injury remain unclear. Methods We initially developed an OLV rat model and treated it with RvE1. Subsequently, we assessed the wet/dry ratio of the lung tissue, performed hematoxylin and eosin staining, and calculated the ratio of polymorphonuclear cells to white blood cells in the bronchoalveolar lavage fluid. Additionally, we assessed apoptosis, inflammatory factor levels, and lung permeability in the rat lung tissues in the RvE1 treated and untreated groups and explored the molecular mechanisms mediated by RvE1. Results Our results indicated that RvE1 alleviated lung injury and inflammation and improved lung tissue apoptosis and permeability in OLV rats. Moreover, RvE1 suppressed the expression of the BLT1/2 signaling pathway and its ligands. The use of BLT2 and BLT1 inhibitors (LY255283 and U-75302, respectively) enhanced RvE1’s anti-inflammatory effects and reduced lung injury. Furthermore, synergistic treatment with the BLT2 inhibitor and RvE1 provided grater benefits by more effectively inhibiting the NF-kB, p38 MAPK, and ERK pathways. Discussion RvE1 and the inhibition of BLT2 signalling reduce the inflammatory response and mitigate OLV-induced lung injury. These findings suggest a novel therapeutic pathway for managing OLV-related complications.

A PSMA-targeted Tri-specific Killer Engager enhances NK cell cytotoxicity against prostate cancer.

Natural killer (NK) cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with co-activation may enhance NK cell function in mCRPC. We describe a Tri-specific Killer Engager (TriKE) construct that engages with the activating receptor CD16 on NK cells, prostate-specific membrane antigen (PSMA) on mCRPC cells, and has an interleukin (IL)-15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation and cytokine production of NK cells derived from healthy donors or prostate cancer patients. Bystander killing of PSMA-negative was also achieved with PSMA TriKE treatment when co-cultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment (TME), NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or MDSCs maintained their potent function while IL-15 treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared to IL-15 and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their anti-tumor potential in prostate cancer, especially in the setting of a hostile TME.

The impact of preoperative treatment on mismatch repair protein and HER2 expression in colorectal cancer: an analysis of paired samples.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality, highlighting the necessity for multifaceted treatment strategies, including preoperative treatment (PT), which can enhance surgical outcomes and provide prognostic insights. This study aims to clarify the impact of PT-induced changes in mismatch repair (MMR) and human epidermal growth factor receptor 2 (HER2) expression, potentially informing tailored treatment strategies and improving clinical outcomes for CRC patients. This retrospective study analyzed 120 paired samples from CRC patients who underwent preoperative treatment, comparing pre- and post-treatment specimens. A control group of 60 untreated surgical specimens was also included. Immunohistochemistry assessed MMR proteins (MSH6, MSH2, MLH1, PMS2) and HER2 expression. MSI status was determined in samples with low MMR expression. Compared to pre-treatment samples, post-treatment samples exhibited lower levels of MSH6, MSH2, and total MMR expression, along with higher levels of HER2 expression. However, when compared to the untreated control group, there were no significant differences in the expression of MSH6, total MMR, and HER2. All samples that exhibited weak MMR expression and those that shifted to deficient mismatch repair (dMMR) status following treatment had stable microsatellite status. No clear clinicopathological characteristics or prognostic factors were found to be associated with changes in MMR and HER2 expression, except for the use of fluorouracil or capecitabine, which was related to changes in total MMR scores. ypTNM stage and TRG scores were identified as independent factors affecting disease progression in our study. PT is associated with a reduction in MMR expression, notably for the MSH2 protein, while it does not appear to influence HER2 expression.

Evolving COVID-19 Landscape: Assessing the Effectiveness and Safety Profile of Nirmatrelvir/Ritonavir in Adolescents

This study evaluates nirmatrelvir/ritonavir (Paxlovid) in preventing severe coronavirus disease 2019 in adolescents (12–18). Conducted from January 2022 to July 2023, it compared hospital admissions and healthcare visits within 30 days post-treatment. Results showed similar follow-up rates between treated and untreated groups, with slightly more adverse effects in the nirmatrelvir/ritonavir group. Further research is needed to confirm its efficacy in this population.

Protective effects of YCHD on the autoimmune hepatitis mice model induced by Ad-CYP2D6 through modulating the Th1/Treg ratio and intestinal flora

BackgroundAutoimmune hepatitis (AIH) is a chronic liver inflammatory disease mediated by autoimmune reactions, the pathogenesis of AIH is probably related to the imbalance of intestinal flora. Yinchenhao decoction (YCHD) has been used to relieve AIH. However, the mechanisms underpinning YCHD’s hepatoprotective effects with the gut microbito have not been fully revealed.ObjectiveTo explore the potential mechanism of YCHD in treating AIH based on changes in the intestinal flora and Th1/Treg ratio in the spleen and hepatic hilar lymph nodes.MethodsThe AIH mice model induced by the adenovirus vectors that overexpress human cytochrome P450 family 2 subfamily D member 6 (Ad-CYP2D6) was established (untreated group). One week after the Ad-CYP2D6 injection, the AIH model mice were treated by administering YCHD by gavage for 14 days (YCHD-treated group). The therapeutic efficacy of YCHD on AIH was evaluated by detecting the histopathological changes of the liver, serum transaminases (ALT and AST), inflammatory factors (TNF-α,IL-17 and IFN-γ), and autoantibodies (including LKM-1 and LC-1). The ratio of Th1 to Treg within the spleen and hepatic hilar lymph nodes of the mice was detected by flow cytometry. The changes in the species and abundance of intestinal flora and intestinal flora metabolites were analyzed via 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC/MS) to reveal the protective mechanism of YCHD on liver injury.ResultYCHD decreased the transaminase activity (AST and ALT), the content of autoantibodies (LC-1 and LKM-1), and the serum TNF-α, IL-12, and IL-17 levels in AIH mice. The degree of inflammatory infiltration in the YCHD-treated group was significantly less than that in the untreated group. YCHD can effectively reverse the abundance and diversity of intestinal flora in AIH mice and affect the release of short-chain fatty acids (SCFAs), especially butyric acid. Moreover, the flow cytometry results showed that YCHD could also decline the ratio of Th1/Treg, which probably be induced by SCFAs via the G protein-coupled receptor (GPR).ConclusionYCHD may affect the release of SCFAs by regulating the intestinal microbiota, thereby affecting the differentiation of Th1 and Treg, and achieving the effect of alleviating liver damage.

Comparative Analysis of Modern 3D-Printed Hybrid Resin-Ceramic Materials for Indirect Restorations: An In Vitro Study

The study investigated the impact of aging on surface roughness, color stability, and biocompatibility of hybrid resin-ceramic materials. A total of 225 specimens were produced from three three-dimensional (3D)-printed (HarzLabs Dental Sand Pro (HL), BEGO VarseoSmile Crown plus (BV), Voco V-Print c&b temp (VV)) and one milled material (Voco Grandio Blocs (VG)). Specimens were grouped into untreated, polished, and glazed surfaces. 5000 thermal cycles simulated aging. Surface roughness and color stability were analyzed, and surface topography was observed using scanning electron microscopy (SEM). Biocompatibility was evaluated with L929 cells. Surface roughness differed significantly between untreated and other groups, with no changes before and after artificial aging. Untreated milled samples were significantly smoother than 3D-printed ones. SEM analysis revealed roughest surfaces in untreated 3D-printed specimens. Polished and glazed specimens were smoother than untreated ones. Color values showed significant differences between untreated and treated/aged groups. No material showed cytotoxicity. In summary, untreated VG was smoother than 3D-printed materials, but polishing and glazing reduced roughness to levels comparable to VG. Surface treatments induced color changes, with glazing causing more changes than polishing. Aging affected color stability and biocompatibility but not surface roughness. All materials showed acceptable color changes and good biocompatibility.

Nonselective beta blockade enhances gut microbiome diversity in a rodent model of trauma, hemorrhage, and chronic stress

BACKGROUND Traumatic injury leads to gut dysbiosis with changes in microbiome diversity and conversion toward a “pathobiome” signature characterized by a selective overabundance of pathogenic bacteria. The use of non-selective beta antagonism in trauma patients has been established as a useful adjunct to reduce systemic inflammation. We sought to investigate whether beta-adrenergic blockade following trauma would prevent the conversion of microbiome to a “pathobiome” phenotype. METHODS Sprague-Dawley rats (n = 6–8/group) were subjected to routine daily handling (naïve), lung contusion with hemorrhagic shock (LCHS), or LCHS with daily chronic stress (LCHS/CS), each with or without administration of intraperitoneal propranolol (BB) (10 mg/kg/day). Fecal microbiome was measured on Days 0, 7, and 14 using high-throughput 16S rRNA sequencing and QIIME2 bioinformatics analyses. Alpha- and beta-diversity and microbiome composition were assessed with significance defined as *p < 0.05. RESULTS Use of propranolol following LCHS or LCHS/CS demonstrated a significant increase in the number of bacterial species (Chao1 index), as well as overall richness and evenness (Shannon index) compared with their untreated counterparts at Day 7. By Day 14, these differences were no longer apparent between BB and untreated groups subjected to LCHS/CS. There was an abundance of commensal bacteria such as Oscillospiraceae and Clostridia in LCHS and LCHS/CS treated with BB after 7 days which persisted at 14 days. CONCLUSION These findings suggest a role for beta-antagonism in altering the diversity of the gut microbiome and the need for further studies to elucidate the cellular and molecular mechanisms underlying this intriguing connection of microbiome with trauma and beta-blockade.

Kaempferol Remodels Liver Monocyte Populations and Treats Hepatic Fibrosis in Mice by Modulating Intestinal Flora and Metabolic Reprogramming.

Changes in gut flora are associated with liver fibrosis. The interactions of host with intestinal flora are still unknown, with little research investigating such interactions with comprehensive multi-omics data. The present work analyzed and integrated large-scale multi-omics transcriptomics, microbiome, metabolome, and single-cell RNA-sequencing datasets from Kaempferol-treated and untreated control groups by advanced bioinformatics methods. This study concludes that kaempferol dose-dependently improved serum markers (like AST, ALT, TBil, Alb, and PT) and suppressed fibrosis markers (including HA, PC III, LN, α-SMA, and Collagen I), while kaempferol also increased body weight. Mechanistically, kaempferol improved the metabolic levels of intestinal flora dysbiosis and associated lipids. This was achieved by increasing the abundance of g__Robinsoniella, g__Erysipelotrichaceae_UCG-003, g__Coriobacteriaceae_UCG-002, and 5-Methylcytidine, all-trans-5,6- Epoxyretinoic acid, LPI (18:0), LPI (20:4), etc. to achieve this. Kaemferol exerts anti-inflammatory and immune-enhancing effects by down-regulating the Th17/IL-17 signaling pathway in PDGF-induced LX2 cells. In addition, kaempferol administration remarkably elevated CD4 + T and CD8 + T cellular proportions, thereby activating immune cells for protecting the body and controlling inflammatory conditions. The combined interaction of multiple data may explain how Kaempferol modulates the intestinal flora thereby remodeling the hepatocyte population and alleviating liver fibrosis.

Correlation between antihypertensive drugs and cerebral hemodynamic parameters: insights from observational findings using transcranial Doppler.

Antihypertensives (AHD) can influence cerebral autoregulation (CA) and attenuate hypertrophic concentric remodelling of arterioles. The aim of this study was to examine the associations between AHD, CA and structural and functional properties of cerebral arteries. In this observational, cross-sectional study 115 volunteers were divided in group 1 (non-hypertensive) [n = 30]; group 2 (hypertensive with systolic blood pressure [SBP] < 140 and diastolic blood pressure [DBP] < 90 mmHg) [n = 54]; group 3 (hypertensive with SBP ≥ 140 or DBP ≥ 90 mmHg) [n = 31] and simultaneous measurements of systemic blood pressure (BP) and middle cerebral artery blood flow velocity (CBFV) were obtained from digital plethysmography and transcranial Doppler. Beat-to-beat, critical closing pressure (CrCP), resistance-area product (RAP) and autoregulation index (ARI) values were extracted by linear regression analysis of instantaneous BP and CBFV waveforms using computerised analysis. Pulsatility index (PI) was calculated and CO2 reactivity was assessed by the breath-holding test. Despite their higher RAP (1.7 [±0.7], p < 0.001) compared to groups 1 and 2, uncontrolled hypertensive using diuretics (p = 0.047) and α2-agonists (p = 0.009) had significantly lower PI. Impaired CO2 reactivity was common between the two hypertensive groups (p = 0.008), however ARI, CrCP and CBFV did not differ between them and non-hypertensive individuals and also did not correlate with any AHD used. Unlike the RAP, PI does not seem to reflect the real cerebrovascular resistence resulting from chronic arterial remodelling. Despite impaired CO2 reactivity, hypertensivehavearterial tonus and CA comparable to non-hypertensive. Experimental studies involving an untreated hypertensive control group are required to robustly make definitive conclusions about these questions.

EXTH-01. EFFICACY OF PERAMPANEL AGAINST GLIOBLASTOMA CELLS

Abstract We investigated the antitumor effect of perampanel, which is the AMPA-type glutamate receptor antagonist widely used as an antiepileptic drug in Japan, on glioblastoma cells both in vitro and vivo. Commercially available glioblastoma cell lines (A-172, AM-38, T98G, U-138MG, U-251MG and YH-13) and newly established glioblastoma cell line 0125-DGC were used in the experiments. First, the antitumor effect of perampanel was evaluated by cell counting assay. The number of surviving cells after administrating drugs (perampanel, carbamazepine, sodium valproate, levetiracetam, and temozolomide) was counted. The cell proliferation inhibitory effect was observed in all cell lines after administration of perampanel and temozolomide. The antitumor effect was greater when perampanel and temozolomide were used together than when they were used alone. Next, we investigated the mechanism of the antitumor effect of perampanel on glioblastoma cells using FACS, western blotting, RT-PCR, and transwell assay. The expression levels of apoptosis-related proteins and mRNAs on glioblastoma cells were increased after administration of perampanel. Furthermore, perampanel demonstrated the inhibitory effect on the migration of glioblastoma cells. Finally, we evaluated the antitumor effect of perampanel in vivo. U-87MG cells were transplanted into the brains of immunodeficient mice, and these mice were treated by perampanel and/or temozolomide. The transplanted mice were divided into an untreated control group, a perampanel treatment group, a temozolomide treatment group, and a combination treatment group. As a result, survival times were significantly prolonged in all treatment groups compared to the untreated control group. Notably, survival times in the combination therapy group was significantly longer than in the monotherapy group. These results revealed that perampanel exhibits antitumor effects on glioblastoma cells by inducing apoptosis and suppressing cell migration ability. Furthermore, perampanel may enhance the antitumor effect of temozolomide for glioblastoma when it used as combination therapy.

TMIC-72. MECHANISMS TO ENHANCE IMMUNOTHERAPY EFFICACY IN A RAT MODEL OF MEDULLOBLASTOMA

Abstract Medulloblastoma is the most common malignant brain tumor in children. Current treatments are limited by irreversible CNS damage, particularly in high-risk subgroups. Innate immune cells constitute a significant portion of the brain tumor microenvironment, nurturing tumor growth and suppressing key defense mechanisms. Leveraging the innate immune system for improved clinical outcomes remains unrealized. We aimed to determine if Baicalein (Bac), a known tumoricidal M1 macrophage potentiator, improves efficacy in medulloblastoma models. Nude rats (N=10) were implanted with MB002 medulloblastoma intracerebellar patient-derived non-WNT/non-SHH, group 3 xenografts. Baseline T2 and gadolinium-enhanced MRI (Gd-MRI) T1 estimated pre-therapy tumor volumes. Single fraction 2Gy irradiation to the tumor-bearing hemisphere with 20mg/kg temozolomide (CRT) combined with Bac 100mg/kg PO QD daily x8 (N= 3) was administered. CRT alone (N= 3) and no treatment (N= 4) served as controls. Seven days post-therapy, Gd-MRI and histology established tumor volume and CD68 and CD163 expression (T-test; p≤ 0.05). MRI demonstrated the therapeutic effect of Bac+CRT compared to CRT only (P&amp;lt; 0.01) and untreated controls (P= 0.01). This was confirmed via histology volumes; untreated group (P&amp;lt; 0.01) and a trend toward significance vs. CRT only (P= 0.22). The normal brain demonstrated a near significant increase in CD68 expression in the Bac+CRT compared to CRT and control (P&amp;lt; 0.06). A near statistically significant decrease in CD163 expression was observed at the tumor margin for Bac+CRT compared to CRT only (P&amp;lt; 0.06). Likewise when comparing CRT to untreated control (P&amp;lt; 0.05). Preliminary data suggests Bac+CRT uniquely induces an innate immune response within the brain that expresses features of M1 polarization, resulting in effective tumoricidal efficacy in preclinical medulloblastoma models. Current studies are evaluating the mechanisms of efficacious innate immune targeted therapies in larger sample sizes with the eventual goal of clinical translation.

Peptidomic Analysis of Potential Bioactive Peptides in Mare Milk Under Different Heat Treatment Conditions

Active peptides in mare milk have unique biological activities, but how the bioactive protein in mare’s milk changes under the influence of temperature has not been fully studied. Therefore, in this study, the differential expression of bioactive peptides potentially present in horse milk under different heat treatment conditions was investigated for the first time using peptidomic and bioinformatic techniques. We collected a total of 15 samples. In this study, we divided the samples into five groups, specifically, 65 °C, 30 min; 72 °C, 15 min; 83 °C; 10 min; 95 °C, 5 min; and an untreated group as a control, which involved four different temperature treatments, in order to understand changes in bioactive peptides and to identify the sequence of bioactive peptides. In the experiment, a total of 2341 active peptides were identified. The amino acid composition of the potential active peptides remained stable across different temperatures, but their abundance varied with temperature. In all, 23 peptides from 20 different proteins were identified, with the highest number of active peptides identified at 72 °C. Through database searches, we found that a majority of these peptides were within β-lactoglobulin and immunoglobulin domain proteins, which are known for their potential biological activities. These findings provide a theoretical foundation for the development of peptides with different bioactivities as potential functional foods.

Biochemical Studies of Averrhoa carambola Ethanol Leaf and Fruit Extracts on Alloxan-induced Diabetic Rats

The use of herbal medicines has always been an option to treat diseases such as diabetes cancer and other ailments. This study aimed to evaluate the effect of Averrhoa carambola leaf and its fruit ethanol extracts on biochemical parameters and histopathology features. Forty five albino rats were assigned into 9 groups of 5 rats each. Except for the normal control group, others were induced to be diabetic by a single intraperitoneal injection of alloxan. Group 1 (normal control) and Group 2 (diabetic untreated) received water. Group 3 received 2.5mg/kg glibenclamide, Groups 4-9 received graded doses (250mg/kg, 500mg/kg and 750mg/kg) of leaf and fruit extracts of Averrhoa carambola. Treatment lasted 14days. At the end of the treatment, blood samples and organ (pancreas) were collected from the animals for biochemical and histopathological evaluation. Treatment of alloxan-induced diabetic rats significantly (p&lt;0.05) reduced the glucose concentration across all treated groups. Following induction of diabetic mellitus, the serum activities of liver enzymes (Alanine amino transferase, Aspartate aminotransferase and Alkaline phosphatase), low-density lipoprotein cholesterol (LDL-C) and triglyceride were significantly (p&lt;0.05) elevated in diabetic untreated group with corresponding reduction in serum protein, albumin and high-density lipoprotein cholesterol (HDL-C) compared to the normal control and treated groups. However, the fruit extracts exhibited a high increase in urea and creatinine levels especially at dose of 750mg/kg body weight when compared with the leaf though not significantly higher than the diabetic untreated group. From histopathology studies, the groups treated with the leaf extract of Averrhoa carambola showed greater structural improvement and an increase in pancreatic islet cells. Therefore this study showed that although ethanol extracts of Averrhoa carambola leaf and fruit have antidiabetic properties, the leaf extract possesses more antidiabetic effect.

Harmine promotes odontoblastic differentiation of dental pulp stem cells

Introduction Dental pulp stem cells (DPSCs) have the potential to differentiate into various types of tissues including tooth, adipose, cartilage, muscle, nerve, and also possess regenerative properties. Harmine, a beta-carboline alkaloid, has been shown to have antitumor activities and promote bone formation through the differentiation of osteoblasts. The aim of this study was to investigate the effect of harmine on the differentiation of DPSCs into odontoblast cells. Materials and methods DPSCs were obtained from Iran’s National Genetic Reserve Center and cultured under standard stem cell culture conditions. The cells were differentiated in culture medium with and without harmine, and cell viability was evaluated using MTT assay at different harmine concentrations. Moreover, differentiation of cells was measured using Alizarin Red staining, and the expression of Runx2, DSPP, and DMP1 genes was evaluated using western blotting and real-time PCR. Results Harmine increased the survival rate of DPSCs in a time-­dependent manner, but higher doses (above 80 μM) had a toxic effect. On day 14, Alizarin Red staining showed increased differentiation of odontoblasts in the harmine-treated groups compared to the untreated groups. Furthermore, harmine increased the expression of Runx2, DSPP, and DMP1 genes and proteins. Conclusion These findings suggest that harmine has a significant impact on the differentiation and proliferation of odontoblasts in DPSCs, likely due to its various properties and role in healing various diseases. Therefore, harmine could serve as a potential therapeutic agent for promoting dental tissue regeneration using DPSCs.

Long-Term Adverse Effects and Complications After Prostate Cancer Treatment

Due to the often indolent nature of prostate cancer (PCA), treatment decisions must weigh the risks and benefits of cancer control with those of treatment-associated morbidities. To characterize long-term treatment-related adverse effects and complications in patients treated for PCA compared to a general population of older males. This cohort study used a novel approach linking data from 2 large PCA prevention clinical trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin-E Cancer Prevention Trial) with Medicare claims records. This analysis included patients with PCA who had been treated with prostatectomy or radiotherapy compared with an untreated control group. Multivariable Cox regression was used, with a time-varying covariate for the occurrence of PCA treatment, adjusted for age, race, and year of time-at-risk initiation, and stratified by study and intervention arm. Data analyses were performed from September 21, 2022, to March 18, 2024. Prostatectomy and radiotherapy occurring after a PCA diagnosis, identified from trial data or Medicare claims records. Ten potential PCA treatment-related complications identified from Medicare claims data. The study sample comprised 29 196 participants (mean [SD] age at time-at-risk initiation, 68.7 [4.8] years). Of these, 3946 participants had PCA, among whom 655 were treated with prostatectomy and 1056 with radiotherapy. The 12-year hazard risk of urinary or sexual complications was 7.23 times greater for those with prostatectomy (95% CI, 5.96-8.78; P < .001) and 2.76 times greater for radiotherapy (95% CI, 2.26-3.37; P < .001) compared to untreated participants. Moreover, among participants treated with radiotherapy, there was a nearly 3-fold greater hazard risk of bladder cancer than in the untreated (hazard ratio [HR], 2.78; 95% CI, 1.92-4.02; P < .001), as well as an approximately 100-fold increased hazard risk of radiation-specific outcomes including radiation cystitis (HR, 131.47; 95% CI, 52.48-329.35; P < .001) and radiation proctitis (HR, 87.91; 95% CI, 48.12-160.61; P < .001). The incidence per 1000 person-years of any 1 of the 10 treatment-related complications was 124.26 for prostatectomy, 62.15 for radiotherapy, and 23.61 for untreated participants. This cohort study found that, even after accounting for age-related symptoms and disease, PCA treatment was associated with higher rates of complications in the 12 years after treatment. Given the uncertain benefit of PCA treatment for most patients, these findings highlight the importance of patient counseling before PCA screening and treatment and provide a rationale for pursuing opportunities for cancer prevention.

Development of paroxetine loaded nanotransferosomal gel for intranasal delivery with enhanced antidepressant activity in rats

The aim of this study was to develop paroxetine (PXT) loaded nanotransferosomal gel (PXT-NTFG) for intranasal brain delivery. The process involved fabricating PXT-NTFs (paroxetine-loaded nanotransferosomes) through a thin film hydration method and optimizing them based on parameters such as particle size (PS), zeta potential (ZP), polydispersity index (PDI), and entrapment efficiency (EE). The optimized PXT-NTFs exhibited uniform morphology with a PS of 158.30 ± 2.73 nm, low PDI (0.142 ± 0.072), high ZP (21.00 ± 0.75 mV), and excellent EE (88.09 ± 3.40 %). Characterization through various techniques confirmed the incorporation of PXT into the nanotransferosomes and its conversion to amorphous state. Moreover, PXT-NTFG was formulated with suitable viscosity and mucoadhesive properties. In vitro release studies demonstrated sustained drug release from PXT-NTFG at different pH levels as compared to PXT-NTFs and NTF dispersion. Similarly, ex vivo experiments showed 4 folds enhanced drug permeation from PXT-NTFG when compared with PXT conventional gel. Stability studies indicated that the optimized PXT-NTFs remained stable for four months at 4°C and 25°C. Additionally, improved behavioral outcomes, increased neuronal survival rates, and upregulated brain-derived neurotrophic factor (BDNF) expression was observed in lipopolysaccharide (LPS) induced depressed Sprague-Dawley rats after treatment with PXT-NTFG as compared to PXT-dispersion treated and untreated LPS-control groups. Notably, the formulation led to a significant reduction in brain and plasma TNF-α levels. In conclusion, intranasal PXT-NTFG is a promising formulation with sustained drug release, improved brain targeting and enhanced antidepressant activity.

Establishment of a mouse model of ovarian oxidative stress induced by hydrogen peroxide

IntroductionOxidative stress, resulting from environmental changes, significantly affects female fertility. Developing a mouse model to study oxidative stress lays the groundwork for research into human reproductive health and livestock fertility.Materials and methodsIn this study, we established and evaluated an oxidative stress model by administering hydrogen peroxide (H2O2) to mice. ICR mice of similar age (7–8 weeks old) and average body weight (31.58 ± 1.12 g) were randomly assigned to four groups (A, B, C, and D). Group A served as the control and was injected with a saline solution, while groups B, C, and D received saline solutions containing 0.75%, 1.50%, and 3.0% H2O2, respectively, over one week. We measured the body weights of all mice before and after the experimental period.Results and discussionOur findings showed that the average body weight of mice in groups A and B increased, while groups C and D experienced weight loss. Group C showed a significantly lower average weight gain compared to groups A and B, and group D exhibited an even more pronounced reduction in weight gain. Although group D had a high mortality rate, there was no significant difference in mortality rates among groups B, C, and D. Serum malondialdehyde (MDA) content increased with higher concentrations of H2O2, with a significant difference noted between groups C and A. Catalase (CAT) activity in group B was significantly higher than in group A, while superoxide dismutase (SOD) activity in group C was notably elevated compared to groups A and B. Conversely, glutathione peroxidase (GSH-Px) activity in group C was significantly lower than in both group A and group B. Hematoxylin and eosin (HE) staining revealed changes in ovarian morphology and follicle dynamics. The percentage of atretic follicles in group C was significantly higher than in the control group, and group D had a significantly lower total number of healthy follicles compared to the untreated group. Increased H2O2 content resulted in a reduction of ovary size and an irregular appearance in group D.ConclusionBased on our findings, treatment with 1.50% H2O2 effectively established an oxidative stress model in mice within 1 week. This model serves as a valuable reference for future clinical studies on oxidative stress and reproductive disorders in female animals and humans.

Seed and foliar application of nano-selenium improves sesame triacylglycerols and oil yield via photosynthetic pigment and enzymatic and chemical antioxidant enhancement revealed by spectrophotometric, UHPLC-analysis and chemometric modeling

The current study aimed to investigate the effects of plant-mediated selenium nanoparticles (SeNPs) on plant growth, photosynthetic pigments, antioxidant activity, and the triacylglycerol profile of sesame (Sesamum indicum L.). The green synthesis of SeNPs was achieved using garlic extract, resulting in spherical nanoparticles with an average size range of 70–75 nm. Three SeNP treatments (T3, 30 ppm; T4, 40 ppm; and T5, 50 ppm) were applied through seed and foliar spray on six sesame varieties (V1, TS-5; V2, TH-6; V3, Til-18; V4, Niab Millennium; V5, Niab Pearl; and V6, NS-16). All enzymatic antioxidant parameters showed an increase in the treated groups, such as SOD (74.4% in V1 at T4), POD (43% in V5 at T5), APX (62% in V1 at T3), and GPX (31.56% in V3 at T4). CAT showed the highest percentage improvement in T5 for V1, V2, V4, and V5, while V3 and V4 exhibited the highest values at T4. Likewise, seed antioxidant parameters also showed increase in antioxidant activity, highest total phenolic content (6.06 mg GAE/g) was found at T5 treatment with percent increase of 27.41%, but the highest percent increase was found to be at T4 treatments in V1 with increase of 46.83%. Percent oil yield was also noted to be higher as highest percent (60%) oil yield was obtained at T4 treatment in V3. Ultra High Performance Mass-Spectrometry (UHPLC-MS) analysis and chemometric modeling suggested a total of 10 triacylglycerol (TG) biomarkers separating untreated groups, with higher relative abundance values at T4 and T5 treatments compared to control. PCA and correlation analysis showed clustering of untreated groups from T4 and T5, which suggests that these two treatments result in higher accumulation of oil. A generalized linear model with ANOVA showed a highly significant impact of treatments on all the growth and oil parameters, with significance involvement of varieties. The interaction between variety and treatment showed no significant effect on the growth and oil biomarkers of sesame. However, it can be concluded that the T4 and T5 treatments (40 ppm and 50 ppm) of SeNPs, applied through seed and foliar methods, have a strong influence on the overall growth and oil yield of sesame. This warrants further transcriptomic and molecular analysis to gain deeper insight into the mechanisms of action of SeNPs.

Enhanced Biodegradation of Silk Fibroin Hydrogel for Preventing Postoperative Adhesion.

An absorbable adhesion barrier is a medical device that prevents postoperative adhesion and matches its biodegradation time with the regeneration period of its target tissues, which is important for antiadhesion effects. Physical hydrogels of Bombyx mori silk fibroin (SF) proteins are degradable in vivo. However, their biodegradation time is too long to exert antiadhesion effects. To shorten the biodegradation time of the SF hydrogels, we decreased the molecular weight (MW) of the SF proteins by alkaline treatment and prepared low-MW (LMW) SF hydrogels. The hydrogels contained less β-sheet crystalline and more amorphous structures than conventional, high-MW (HMW) SF hydrogels. Because of the potential loosened SF molecular structures in the hydrogel networks, the LMW SF hydrogels showed enhanced biodegradation (i.e., shorter in vitro enzymatic biodegradation time and faster in vivo biodegradation rate) as well as a lower affinity for plasma proteins and fibroblasts, which are involved in postoperative adhesion formation. An antiadhesion test using a rat abdominal adhesion model demonstrated that the LMW SF hydrogel applied to the abraded cecum was almost completely degraded within two weeks postimplantation, with a significantly lower adhesion severity score than that in the untreated model rat group. Conversely, the HMW SF hydrogel remained between the cecum and abdominal wall, with the same adhesion severity as that of the untreated model rat group. Therefore, we concluded that the antiadhesion effects of SF hydrogels were induced by enhanced biodegradation. The results of this study indicate the potential of LMW SF hydrogels as absorbable adhesion barriers.

Analysis of Pregnancy Outcomes in Patients Exhibiting Recurrent Miscarriage With Concurrent Low-Titer Antiphospholipid Antibodies.

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombotic events and adverse pregnancy outcomes, often associated with elevated antiphospholipid antibodies (aPLs). The 2023 ACR/EULAR criteria for APS necessitate persistent medium to high titers of aPLs for laboratory confirmation. However, the impact of persistently low-titer aPLs in recurrent miscarriage (RM) patients remains controversial. This study aims to analyze the effect of treatment on pregnancy outcomes and maternal-fetal complications in patients with low-titer aPLs. The study encompassed 252 pregnancies in 237 RM patients tested for aPLs at the Third Hospital of Guangzhou Medical University from January 2018 to July 2022. Patients were divided into two groups based on aPLs titers: 86 with low-titer aPLs (92 pregnancies) and 151 aPLs-negative (160 pregnancies). Of the low-titer group, 71 received treatment, while 21 and all aPLs-negative patients did not. Seventy-one treated patients with low-titer aPLs were divided into two groups. Group A (n = 15) received a standard treatment regimen that included low-dose aspirin (LDA) and low-molecular-weight heparin (LMWH). In contrast, Group B (n = 56) received a multidrug regimen, which included hydroxychloroquine (HCQ) and/or glucocorticoids (GC) and/or intravenous immunoglobulin (IVIG) in addition to the standard treatment of LDA and LMWH. Pregnancy outcomes and maternal-fetal complications were subsequently compared. The highest positivity rates were for aCL-IgM (76.2% in the untreated low-titer aPLs group and 81.7% in the treated low-titer aPLs group), followed by aβ2GPI-IgM (23.8% in the untreated low-titer aPL group and 11.4% in the treated low-titer aPLs group), and LA (5.6% in the untreated low-titer aPLs group and 3.3% in the treated low-titer aPLs group). Single antibody positivity was 90.5% in the untreated low-titer aPL group and 87.3% in the treated low-titer aPLs group, with double positivity at 9.5% in the untreated low-titer aPLs group and 12.7% in the treated low-titer aPLs group. No triple positivity was detected. The treated low-titer aPLs group had more previous miscarriages (p < 0.05) and a higher ANA positivity rate (p < 0.05) than the aPLs-negative group. Additionally, the treated low-titer aPLs group had lower complement levels than the aPLs-negative group. Immunoglobulin IgM levels were higher in both the untreated and treated low-titer aPL groups compared to the aPLs-negative group (p < 0.05). Post treatment, the live birth rate in the low-titer group significantly exceeded that of the untreated group (67.6%vs. 33.3%; p = 0.005). The miscarriage rate was notably lower in untreated low-titer patients compared to aPLs-negative patients (32.4%vs. 66.7%; p = 0.005). No significant differences were observed in maternal or fetal complications between the groups. In the standard treatment group (Group A), there were 8 (53.3%) live births, whereas the multidrug treatment group (Group B) had 40 (71.4%) live births, a significantly higher rate than in the standard treatment group, although the difference lacked statistical significance. The study indicates that untreated RM patients with low-titer positive aPLs have a higher recurrence of miscarriage compared to the aPLs-negative RM group. However, recurrence significantly decreases following appropriate intervention, suggesting the benefits of treatment for RM patients with low-titer aPLs.