Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke.

JOURNAL/nrgr/04.03/01300535-202503000-00029/figure1/v/2024-06-17T092413Z/r/image-tiff It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 µM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 µM) promoted nuclear translocation of ß-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the ß-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Impact of Dexmedetomidine on Hemodynamics, Plasma Catecholamine Levels, and Delirium Incidence Among Intubated Patients in the ICU--A Randomized Controlled Trial.

Objective: To investigate the impact of various sedative medications on hemodynamics and plasma levels of epinephrine (E) and norepinephrine (NE) in mechanically ventilated patients postoperatively in the intensive care unit (ICU). Methods: Ninety-seven patients admitted to the ICU undergoing postoperative mechanical ventilation with tracheal intubation and continuous analgesic sedation following general anesthesia were randomly assigned to either the observation group (dexmedetomidine) (n = 49) or the control group (propofol) (n = 48) in this randomized controlled trial. Upon transfer to the ICU, vital signs (heart rate [HR], respiratory rate [RR], mean arterial pressure [MAP]) were recorded prior to the initiation of the sedation treatment (T0), at one-hour post sedation (T1) and two hours following tracheal extubation (T2), plasma levels of epinephrine (E) and norepinephrine (NE) were measured at these time points. The incidence of delirium was recorded in both groups. Results: MAP between the two groups at both T0 and T1 At T2 plasma NE and HR were found to be lower in the observation group compared to the control group (P < 0.001). Among the patients receiving antihypertensive medication in the ICU, NE levels were significantly lower in the observation group compared to the control group (P = 0.019) Among the patients not receiving antihypertensive medication, both NE (P < 0.001) and MAP (P = 0.001) levels were lower in the observation group compared to the control group. The incidence of delirium in the observation group (dexmedetomidine) was not significantly different from that in the control group (propofol). Conclusion: With dexmedetomidine sedation, blood pressure fluctuated less, plasma catecholamine levels were lower, and sympathetic inhibition was stronger in patients before and after extubation. However, it did not significantly reduce the incidence of postoperative delirium.

Comparison of the safety and efficacy of laparoscopic single-incision triangulated umbilical surgery pyeloplasty with traditional three-hole surgery in a pediatric tertiary center.

OBJECTIVE: To report the application of laparoscopic single-incision triangulated umbilical surgery (SITUS) pyeloplasty in children with ureteropelvic junction obstruction (UPJO) and compare its feasibility and efficacy with traditional three-hole laparoscopic pyeloplasty. METHODS: Data from children with UPJO who underwent SITUS between July 2018 and August 2021 were included in this retrospective study and patients who were treated with traditional laparoscopic pyeloplasty were chosen for comparison. Thirty-two patients from SITUS group and 72 patients from traditional group were reviewed. The clinical characteristics, complications, and follow-up results were collected and compared. RESULTS: The preoperative demographic data and imaging parameters, including sex, surgical side, age, BMI, and preoperative anterior-posterior pelvic diameter (APD), showed no significant differences between the two groups. The median surgical time was 135 min (IQR: 119.75-160.5) in SITUS group, while 163.5 min (IQR: 141.25-187.5) in the traditional group (p = 0.0008). Two Clavien-Dindo III complications (6.25%) in SITUS group and 11 (15.3%) in the traditional group were recorded (p = 0.335). The success rate was 100% (32/32) in SITUS group and 94% (68/72) in the traditional group (p = 0.309). CONCLUSION: SITUS pyeloplasty is a feasible and effective laparo-endoscopic single-site (LESS) technique for pediatric patients with excellent cosmetic results comparable to the conventional laparoscopic pyeloplasty. More cases and longer follow-up periods are needed to determine the exact outcomes of the modified LESS technique.

CIEC: Cross-tissue Immune Cell Type Enrichment and Expression Map Visualization for Cancer.

Single-cell transcriptome sequencing technology has been applied to decode the cell types and functional states of immune cells, revealing their tissue-specific gene expression patterns and functions in cancer immunity. Comprehensive assessments of immune cells within and across tissues will provide us with a deeper understanding of the tumor immune system in general. Here, we present Cross-tissue Immune cell type or state Enrichment analysis of gene lists for Cancer (CIEC), the first web-based application that integrates database and enrichment analysis to estimate the cross-tissue immune cell type or state. CIEC version 1.0 consists of 480 samples covering primary tumor, adjacent normal tissue, lymph node, metastasis tissue, and peripheral blood from 323 cancer patients. By applying integrative analysis, we constructed an immune cell-type/state map for each context and adopted our previously developed Kyoto Encyclopedia of Genes and Genomes (KEGG) Orthology Based Annotation System (KOBAS) algorithm to estimate the enrichment for context-specific immune cell type/state. In addition, CIEC also provides an easy-to-use online interface for users to comprehensively analyze the immune cell characteristics mapped across multiple tissues, including expression map, correlation, similar genes detection, signature score, and expression comparison. We believe that CIEC will be a valuable resource for exploring the intrinsic characteristics of immune cells in cancer patients and for potentially guiding novel cancer-immune biomarker development and immunotherapy strategies. CIEC is freely accessible at http://ciec.gene.ac/.

Multi-omics analysis revealed the mechanism underlying flavonol biosynthesis during petal color formation in Camellia Nitidissima.

BACKGROUND: Camellia nitidissima is a rare, prized camellia species with golden-yellow flowers. It has a high ornamental, medicinal, and economic value. Previous studies have shown substantial flavonol accumulation in C. nitidissima petals during flower formation. However, the mechanisms underlying the golden flower formation in C. nitidissima remain largely unknown. RESULTS: We performed an integrative analysis of the transcriptome, proteome, and metabolome of the petals at five flower developmental stages to construct the regulatory network underlying golden flower formation in C. nitidissima. Metabolome analysis revealed the presence of 323 flavonoids, and two flavonols, quercetin glycosides and kaempferol glycosides, were highly accumulated in the golden petals. Transcriptome and proteome sequencing suggested that the flavonol biosynthesis-related genes and proteins upregulated and the anthocyanin and proanthocyanidin biosynthesis-related genes and proteins downregulated in the golden petal stage. Further investigation revealed the involvement of MYBs and bHLHs in flavonoid biosynthesis. Expression analysis showed that flavonol synthase 2 (CnFLS2) was highly expressed in the petals, and its expression positively correlated with flavonol content at all flower developmental stages. Transient overexpression of CnFLS2 in the petals increased flavonol content. Furthermore, correlation analysis showed that the jasmonate (JA) pathways positively correlated with flavonol biosynthesis, and exogenous methyl jasmonate (MeJA) treatment promoted CnFLS2 expression and flavonol accumulation. CONCLUSIONS: Our findings showed that the JA-CnFLS2 module regulates flavonol biosynthesis during golden petal formation in C. nitidissima.

Investigation of Human Milk as a Biological System in a Multicenter Mother-Infant Cohort: Protocol Design and Cohort Profile of the Phoenix Study.

Breastfeeding and human milk are the gold standard for infant feeding. Studying human milk with a systems biology approach in a large longitudinal cohort is needed to understand its complexity and health implications. The Phoenix study is a multicenter cohort study focusing on the interactions of maternal characteristics, human milk composition, infant feeding practices, and health outcomes of Chinese mothers and infants. A total of 779 mother-infant dyads were recruited from November 2021 to September 2022, and 769 mother-infant dyads were enrolled in the study. Scheduled home visits took place at 1, 4, 6, and 12 months postpartum, and 696 dyads (90.5% participants) completed the 12-month visit. At each visit, maternal and infant anthropometry was assessed. Questionnaires were administered to collect longitudinal information on maternal characteristics and lifestyle, infant feeding, and health. Digital diaries were used to record maternal dietary intake, infant feeding, and stool character. Human milk, maternal feces, infant feces, and infant saliva were collected. An external pharmaceutical-level quality assurance approach was implied to ensure the trial quality. Multi-omics techniques (including glycomics, lipidomics, proteomics, and microbiomics) and machine learning algorithms were integrated into the sample and data analysis. The protocol design of the Phoenix study provides a framework for prospective cohort studies of mother-infant dyads and will provide insights into the complex dynamics of human milk and its interplay with maternal and infant health outcomes in the Chinese population.

Dimethyl phthalate exposure induces cognitive impairment via COX2-mediated neuroinflammation.

AIM: The present work explored the mechanism of dimethyl phthalate (DMP, the environmental contaminant) exposure in inducing cognitive impairment. METHODS: Targets and regulatory networks related to DMP-brain injury-cognitive impairment were analyzed through network pharmacology. DMP exposure was carried out to simulate DMP environmental uptake, whereas Morris water maze was performed for examining cognitive impairment. Additionally, inflammatory cytokine levels within tissues were measured. hematoxylin-eosin staining(H&E) and Nissl staining was conducted to examine brain tissue injury, while Western blot was carried out for identifying protein levels. After applying.Small interfering RNA(siRNA-COX2) and celecoxib-COX2 inhibitors separately, we analyzed impacts of DMP. Besides, in vitro experiments were performed to analyze impacts of DMP on microglial activation. RESULTS: As suggested by network pharmacology,Cyclooxygenase-2-PTGS2 (COX2) showed significant relation to DMP, and it exerted its effect via COX2. Following DMP exposure, mice experienced obvious cognitive impairment and brain damage, besides, microglial cells were activated, and inflammatory cytokines were up-regulated. Applying siRNA-COX2 and celecoxib-COX2 suppressed DMP's impact and mitigated mouse cognitive impairment. Based on in vitro analysis, DMP led to microglial activation and neuroinflammation. CONCLUSION: DMP exposure causes neuroinflammation via the COX2-regulated microglial activation, thus leading to cognitive impairment. COX2 may serve as the key action target of DMP.

Calcium silicate cements endowing bioactivity and sustaining mechanical strength of low-heat-releasing and fast-curing magnesium phosphate cements.

It is known that magnesium phosphate cements (MPCs) show appreciable mechanical strength and biocompatibility, but the hydration reaction processes often lead to intense heat release while the hydration products present weak resistance to mechanical decay and low bioactivity. Herein we developed an MPC-based system, which was low-heat-releasing and fast-curing in this study, by compounding with self-curing calcium silicate cements (CSCs). The MPC composed of magnesium oxide (MgO), potassium dihydrogen phosphate (KH2PO4), disodium hydrogen phosphate (Na2HPO4), magnesium hydrogen phosphate trihydrate (MgHPO4·3H2O) and chitosan were weakly basic, which would be more stable in vivo. The physicochemical properties indicated that the addition of CSCs could increase the final setting time while decrease the heat release. Meanwhile, the CSCs could endow MPC substrate with apatite re-mineralization reactivity, especially, which add 25 wt.% CSCs showed the most significant apatite deposition. What's more, the mechanical evolution in buffer demonstrated CSCs could enhance and sustain the mechanical strength during degradation, and the internal constructs of cement implants could still be reconstructed by µCT analysis in rabbit femoral bone defect model in vivo. Particularly, appropriate CSCs adjusted the biodegradation and promoted new bone tissue regeneration in vivo. Totally, the MPC/CSCs composite system endows bioactivity and sustains mechanical strength of the MPC, which may be promising for expending the clinical applications of MPC-based bone cements.

Phosphoproteomic analysis reveals CDK5-Mediated phosphorylation of MTDH inhibits protein synthesis in microglia.

CDK5 plays a crucial role in maintaining normal central nervous system (CNS) development and synaptic function, while microglia are the primary immune cells present in the CNS and play vital physiological roles in CNS development, immune surveillance, and regulation of synaptic plasticity. Despite this, our understanding of both the substrate proteins and functional mechanisms of CDK5 in microglia remains limited. To address this, we utilized CRISPR-Cas9 knockout of Cdk5 in BV2 cells and conducted quantitative phosphoproteomics analysis to systematically screen potential CDK5 substrates in microglia. Our findings identified 335 phosphorylation sites on 234 proteins as potential CDK5 substrates in microglia based on the reported sequence motif. Through in vitro kinase assay and intracellular inhibition and knockout of CDK5 experiments, we confirmed that ER proteins MTDH (protein LYRIC) and Calnexin are novel substrate proteins of CDK5. Moreover, we demonstrated for the first time a critical mechanism for regulating protein synthesis in microglia, that the phosphorylation of S565 site on MTDH, a key protein mediating cell growth, by CDK5 inhibits protein synthesis. Our data provide valuable insights for the discovery of new substrate proteins of CDK5 and the in-depth investigation of the function and mechanism of CDK5 in microglia.

Rapidly molded sodium alginate/soy protein adhesive hydrogel with 808-nm laser inhibition of infected wounds.

Infected wounds produce pus and heal slowly. To address this issue, we developed a rapid-setting SP/SA@BP-C hydrogel by combining sodium alginate (SA) and soy protein (SP) with black phosphorus (BP) grafted with clarithromycin (Cla) and incorporating Ca2+ for chelation. This hydrogel dressing exhibits excellent photothermal (PT) and photodynamic (PD) bacteriostatic effects without biotoxicity, making it suitable for treating infected wounds. Characterization confirmed its successful fabrication, and the bacteriostatic effect demonstrated over 99 % efficacy through the synergistic effects of PT, PD, and Cla. Cellular studies indicated nontoxicity and a promoting effect on cell proliferation (121.6 %). In the mouse-infected wound model, the hydrogel led to complete healing in 12 days, with good recovery of the skin's superficial dermal layer and appendages. Consequently, SP/SA@BP-C is a natural hydrogel dressing with promising properties.

Dipeptide metabolite, glutamyl-glutamate mediates microbe-host interaction to boost spermatogenesis.

The decrease in sperm count and infertility is a global issue that remains unresolved. By screening environmental bacterial isolates, we have found that a novel lactic acid bacterium, Lactiplantibacillus plantarum SNI3, increased testis size, testosterone levels, sperm count, sexual activity and fertility in mice that have consumed the bacteria for four weeks. The abundance of L. plantarum in the colon microbiome was positively associated with sperm count. Fecal microbiota transplantation (FMT) from L. plantarum SNI3-dosed mice improved testicular functions in microbiome-attenuated recipient animals. To identify mediators that confer pro-reproductive effects on the host, untargeted in situ mass spectrometry metabolomics was performed on testis samples of L. plantarum SNI3-treated and control mice. Enrichment pathway analysis revealed several perturbed metabolic pathways in the testis of treated mice. Within the testis, a dipeptide, glutamyl-glutamate (GluGlu) was the most upregulated metabolite following L. plantarum SNI3 administration. To validate the pro-reproductive feature of GluGlu, systemic and local injections of the dipeptide have been performed. γ-GluGlu increased sperm count but had no effect on testosterone. These findings highlight the role of γ-GluGlu in mediating spermatogenetic effects of L. plantarum on the male mouse host and -following relevant human clinical trials- may provide future tools for treating certain forms of male infertility.

Self-Polymerized Tough and High-Entanglement Zwitterionic Functional Hydrogels.

Zwitterionic hydrogels exhibit great potential in biomedical applications due to their antifouling properties and biocompatibility. However, the single-network structure of pure zwitterionic hydrogels leads to a low toughness and strength, limiting their application in biomedical fields. In this work, a high entanglement sulfobetaine methacrylate-dopamine hydrogel (SBMA-DA-PE) with low cross-linker content and high monomer concentration is prepared by using a dopamine oxidative radical polymerization method. Compared to a regular zwitterionic hydrogel, the SBMA-DA-PE hydrogel exhibits a 5-fold increase in tensile fracture stress and a 10-fold increase in compressive fracture stress. The SBMA-DA-PE hydrogel possesses excellent mechanical properties (the maximum compressive stress ≥4.85 MPa, the maximum compressive strain ≥90%). Besides, the non-covalent interactions between catechol or ortho-quinones within the SBMA-DA-PE hydrogel, combined with strong intermolecular electrostatic interactions, endow the SBMA-DA-PE hydrogel with great self-healing capabilities and fatigue resistance. The SBMA-DA-PE hydrogel demonstrates low swellability and possesses good antifouling properties. Furthermore, the good printability and conductivity of the tough SBMA-DA-PE hydrogel endows it with new possibilities for developing biological 3D scaffolds and electronic devices. Overall, this work provides new insights into the preparation of zwitterionic hydrogels with high mechanical strength and multi-functionality for biomedical applications.

Multifunctional Sensors for Successive Detection of Endogenous ONOO- and Mitochondrial Viscosity: Discriminating Normal to Cancer Models.

Diagnosing cancer in its early stages can play an important role in prolonging the lifespan of patients, which demands the use of powerful tools to detect biomarkers accurately. However, since most fluorescent probes described for cancer diagnosis are limited to recognizing a single molecule, achieving the high accuracy criteria remains difficult. Here, sensor 1 is constructed for the sequential detection of D, ONOO-, and viscosity. Initially, sensor 1 detected D and underwent an intramolecular charge transfer mechanism, resulting in the formation of 2 and fluorescence quenching at 587 nm. Subsequently, the intermediate (2) monitored ONOO- and reproduced sensor 1 reversibly with fluorescence enhancement at 496 nm, showing concentration-related quantitative analysis. Similar sensing processes were observed in monitoring ONOO- and viscosity by synthetically developed sensor 2. The proposed mechanisms of sensors 1 and 2 are verified through various characterizations (1H NMR, HR-MS, and HPLC) and DFT calculations. Investigations on endogenous ONOO- and mitochondrial viscosity in cancer (HeLa) and normal (NCM460) cells were conducted to distinguish cancerous cells from normal cells. We anticipated that sensor 2 could effectively serve as a reliable bioanalytical reagent for cancer diagnosis at an earlier stage through sequential detection of two cancer markers, ONOO- and mitochondrial viscosity, in living cells. Importantly, sensor 2 has been employed for imaging ONOO- in normal and liver injury mouse models and tissues, achieving outstanding results.

[Multi-time Scale Variation of Atmospheric Ammonia Concentration and Dry Deposition in a Paddy Rice Region in Subtropical China].

Meteorological factors and anthropogenic activities significantly affect atmospheric ammonia （NH3） concentration and its dry deposition. Former studies have examined the spatial and temporal variability in atmospheric NH3 concentrations at monthly scales. However, the characteristics of atmospheric concentrations at finer time scales such as hourly and daily scales and the influencing factors remain unclear. In this study, atmospheric NH3 concentration and related meteorological factors were continuously monitored online for one year in a double cropping rice region in subtropical China, and atmospheric NH3 concentration and its meteorological influencing factors as well as dry deposition were analyzed at different time scales （hourly, daily, and monthly）. The main results were as follows： The annual average daily concentration of NH3 in the rice area varied from 0.01 to 58.0 µg·m-3 （in N, same below）, and the annual average concentration was 5.3 µg·m-3. On the hourly scale, the 24-hour dynamics of atmospheric NH3 concentration showed a unimodal pattern, and the time of the NH3 peak appearance in different seasons was different； the time of the peak that appeared in winter lagged behind that in the other seasons. From the perspective of daily scale, NH3 concentration was mainly affected by fertilization in the paddy fields, peaking at 1-3 days after fertilization and then gradually decreasing. On the monthly scale, NH3 concentration peaked at 12.8 µg·m-3 in July and was the lowest in October at 1.6 µg·m-3. On the hourly scale, NH3 concentration varied seasonally due to the influences of meteorological factors, mainly as follows： NH3 concentration showed significant positive correlations with air temperature and solar radiation in all four seasons and with wind speed in spring and summer, whereas it showed significant negative correlations with relative humidity except in winter. On the daily scale, NH3 concentration showed a significant positive correlation with air temperature, rainfall, and solar radiation, whereas it showed a significant negative correlation with relative humidity. On the monthly scale, no significant correlation existed between each meteorological factor and NH3 concentration. The annual dry deposition flux （in N） calculated from the hourly average NH3 concentration was 8.5 kg·ï¼ˆhm2·a）-1, which was 11.6% higher than the annual flux calculated from the daily average and 12.4% higher than the annual flux calculated from the monthly average. In summary, there were significant daily and seasonal variations in atmospheric NH3 concentration in the paddy rice region in subtropical China, and conducting hourly-scale observations of NH3 concentration can help to reveal the multi-time scale variations in NH3 concentration and to quantify NH3 dry deposition more accurately.

Acousto-Drag Photovoltaic Effect by Piezoelectric Integration of Two-Dimensional Semiconductors.

Light-to-electricity conversion is crucial for energy harvesting and photodetection, requiring efficient electron-hole pair separation to prevent recombination. Traditional junction-based mechanisms using built-in electric fields fail in nonbarrier regions. Homogeneous material harvesting under a photovoltaic effect is appealing but is only realized in noncentrosymmetric systems via a bulk photovoltaic effect. Here we report the realization of a photovoltaic effect by employing surface acoustic waves (SAWs) to generate zero-bias photocurrent in the conventional layered semiconductor MoSe2. SAWs induce periodic modulation to electronic bands and drag the photoexcited pairs toward the traveling direction. The photocurrent is extracted from a local barrier. The separation of generation and extraction processes suppresses recombination and yields a large nonlocal photoresponse. We distinguish the acousto-electric drag and electron-hole pair separation effect by fabricating devices of different configurations. The acousto-drag photovoltaic effect, enabled by piezoelectric integration, offers an efficient light-to-electricity conversion method, independent of semiconductor crystal symmetry.

Hypnotic Use and the Risk of Cardiovascular Diseases in Insomnia Patients.

AIMS: We aimed to examine the association between hypnotic agents and cardiovascular outcomes in general individuals with insomnia. METHODS: In a propensity score matched cohort of UK Biobank (UKB) participants with insomnia, Cox proportional hazard model was used to estimate the association between regular use of hypnotic agents and predetermined cardiovascular outcomes including incident coronary heart diseases (CHD), heart failure (HF), stroke, and cardiovascular death. Inverse probability of treatment weighting, competing risk models, and shared frailty models were further performed during sensitivity analysis. Drug-target Mendelian randomization (MR) analyses were employed for further evaluation of the association between therapeutic targets of hypnotics and cardiovascular diseases. RESULTS: During a median follow-up of 14.3 years, the matched cohort documented a total of 929 CHD cases, 360 HF cases, 262 stroke cases, and 180 cardiovascular deaths. No significant association was detected between Z-meds and CHD, stroke, and cardiovascular mortality. Benzodiazepine use was significantly associated with the increased risk of CHD, HF, and cardiovascular mortality. The inverse probability of treatment weighting, competing risk models, and shared frailty models didn't alter the above associations. Moreover, drug-target MR analyses corroborated the safety of Z-meds in the general population regarding cardiovascular health. CONCLUSIONS: Our findings suggested the heterogeneous associations between different categories of hypnotics and incident cardiovascular events in individuals with insomnia. Both observational and genetic evidence raised safety concerns regarding the cardiovascular impact of benzodiazepines. No cardiovascular hazard of Z-meds was discovered in the UKB population with insomnia.

In the general population with insomnia, we uncovered the heterogeneous associations between different categories of hypnotics and incident cardiovascular events incorporating results from a propensity score matched cohort study of UK Biobank participants and drug-target Mendelian randomization analyses.Benzodiazepine was significantly associated with the increased risk of coronary heart disease, heart failure, and cardiovascular mortality.No adverse evidence regarding the cardiovascular safety of Z-meds was found in both observational and Mendelian randomization analyses.

NRF2-HIF2α Signaling Attenuates Endothelial Cell Senescence and Maintains Intercellular Junctions in Diabetes.

In the context of diabetes, endothelial cells frequently exhibit compromised intercellular junctions and accelerated cellular senescence simultaneously. The precise mechanisms underlying these issues and the identification of effective treatments remain largely undefined. Our findings reveal that human umbilical vein endothelial cells (HUVECs) can counteract senescence and uphold the integrity of intercellular junctions under mildly to moderately elevated glucose levels (10 mM and 15 mM) via two primary mechanisms: i) The acetylation of NRF2 at lysine residues K56, K68, and K52 prevents its ubiquitination, enhancing the transcription of antioxidant genes GST, SOD1, and GPX1. This activity diminishes cytoplasmic oxidative stress, thereby mitigating endothelial cell senescence. ii) The interaction between the Neh2 domain of NRF2 and the PAS-B domain of HIF-2α within the nucleus curtails the attachment of HIF-2α to the NOX4/p22phox promoter. This action lessens oxidative stress near the cell membrane, maintaining intercellular junctions by safeguarding the disulfide bonds in occludin and E-cadherin from disruption. However, these protective strategies prove insufficient under severe hyperglycemic conditions (25 mM). Further investigation has identified Oltipraz, an activator of NRF2, as also promoting the degradation of HIF-2α. Through its simultaneous modulation of NRF2 and HIF-2α, Oltipraz significantly reduces cellular senescence and prevents the deterioration of intercellular junctions in HUVECs subjected to high glucose concentrations (25 mM). Our research positions Oltipraz as a promising therapeutic candidate for mitigating diabetes-induced vascular endothelial damage, potentially offering benefits against diabetes-related atherosclerosis and valvular calcification.

Targeted agents plus CHOP compared with CHOP as the first-line treatment for newly diagnosed patients with peripheral T-cell lymphoma (GUIDANCE-03): an open-label, multicentre phase 2 clinical trial.

Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p = 0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).

Magnetically actuated cisplatin-loaded nanoparticle collectives enhance drug penetration for potentiated ovarian cancer chemotherapy.

Chemotherapy is the main clinical treatment for ovarian cancer, but still faces challenges of low drug targeting efficiency and insufficient drug permeability. Drug-loaded nanoparticle collectives, which are actuated by magnetic field, could be targeted to a designated location and achieve targeted drug delivery. In this work, we report a strategy that utilizes magnetic mesoporous silica nanoparticles loaded with cis-diaminodichloroplatinum (Fe3O4@SiO2-CDDP) for targeted delivery of chemotherapeutic drugs and enhances penetration into deep tumors. The Fe3O4@SiO2-CDDP collectives actively moved to the target tumor site, and this movement was regulated by a magnetic actuation system. Under the action of a torque-force hybrid magnetic field (TFMF), Fe3O4@SiO2-CDDP could further penetrate into the interior of tumors and achieve pH-responsive drug release in the tumor environment. The feasibility of this strategy was verified in three-dimensional cell spheres in vitro and in a tumor-bearing mouse model in vivo. This magnetically actuated nanoparticle collectives enhanced drug penetration strategy provides a new paradigm for targeted drug delivery and potentiated tumor therapy.

[Comparison of the posterior hemipelvectomy of the greater trochanter approach with the standard Kocher-Langenbeck approach in the treatment of posterior acetabulum wall fractures].

OBJECTIVE: To compare the clinical efficacy of the posterior hemipelvectomy of the greater trochanter approach with the standard Kocher-Langenbeck(K-L) approach in the treatment of posterior acetabulum wall fractures and to explore a more optimal approach for the treatment of posterior acetabulum wall fractures. METHODS: Total of 26 patients with posterior acetabulum wall fractures were retrospectively analysed and divided into two groups:the posterior hemipelvectomy of the greater trochanter group (test group) and the standard K-L approach group (control group). In the test group, there were 24 patients including 16 males and 8 females with an average age of (42.00±4.52) years old, the time of injury to surgery was (6.75±1.15) d. In the control group, there were 23 patients including 16 males and 7 females with an average age of (41.00±5.82) years old, the time of injury to surgery was (7.09±1.20) days. The total hospital stay, length of incision, operation time, intraoperative bleeding, postoperative drainage, discharge, fracture reduction quality (Matta criteria), hip abduction muscle strength, hip function (Merle d'Aubigne-Postel score), postoperative complications and the incidence of ectopic ossification were compared. RESULTS: All cases were followed up for 6 months. There was no significant difference in incision length, intraoperative bleeding and postoperative drainage between two groups(P>0.05). However, the operation time of the test group was shorter than that of the control group (P<0.05). There was no statistically significant difference in fracture reduction and hip function between two groups (P>0.05). The hip abduction muscle strength of test group was better than that of control group(P<0.05). In addition, there was no significant difference in the incidence of postoperative complications and heterotopic ossification between two groups(P>0.05). CONCLUSION: Compared with the standard K-L approach, the posterior hemipelvectomy of the greater trochanter approach can shorten the operative time, has better recovery of the postoperative hip abduction muscle strength, exposes the view of the fracture involving the more comminuted posterior acetabulum wall or the fracture of the roof of the socket, improved the rate of fracture anatomical repositioning, provides a new idea for the clinical treatment of posterior acetabulum wall fractures, and allows patients to perform functional exercises at an early stage.