Superantigen-fused T cell engagers for tumor antigen-mediated robust T cell activation and tumor cell killing.

Inadequate T cell activation has severely limited the success of T cell engager (TCE) therapy, especially in solid tumors. Enhancing T cell activity while maintaining the tumor specificity of TCEs is the key to improving their clinical efficacy. However, currently, there needs to be more effective strategies in clinical practice. Here, we design novel superantigen-fused TCEs that display robust tumor antigen-mediated T cell activation effects. These innovative drugs are not only armed with the powerful T cell activation ability of superantigens but also retain the dependence of TCEs on tumor antigens, realizing the ingenious combination of the advantages of two existing drugs. Superantigen-fused TCEs have been preliminarily proven to have good (>30-fold more potent) and specific (>25-fold more potent) antitumor activity in vitro and in vivo. Surprisingly, they can also induce the activation of T cell chemotaxis signals, which may promote T cell infiltration and further provide an additional guarantee for improving TCE efficacy in solid tumors. Overall, this proof-of-concept provides a potential strategy for improving the clinical efficacy of TCEs.

Toward a coordinated understanding of hydro-biogeochemical root functions in tropical forests for application in vegetation models.

Tropical forest root characteristics and resource acquisition strategies are underrepresented in vegetation and global models, hampering the prediction of forest-climate feedbacks for these carbon-rich ecosystems. Lowland tropical forests often have globally unique combinations of high taxonomic and functional biodiversity, rainfall seasonality, and strongly weathered infertile soils, giving rise to distinct patterns in root traits and functions compared with higher latitude ecosystems. We provide a roadmap for integrating recent advances in our understanding of tropical forest belowground function into vegetation models, focusing on water and nutrient acquisition. We offer comparisons of recent advances in empirical and model understanding of root characteristics that represent important functional processes in tropical forests. We focus on: (1) fine-root strategies for soil resource exploration, (2) coupling and trade-offs in fine-root water vs nutrient acquisition, and (3) aboveground-belowground linkages in plant resource acquisition and use. We suggest avenues for representing these extremely diverse plant communities in computationally manageable and ecologically meaningful groups in models for linked aboveground-belowground hydro-nutrient functions. Tropical forests are undergoing warming, shifting rainfall regimes, and exacerbation of soil nutrient scarcity caused by elevated atmospheric CO2. The accurate model representation of tropical forest functions is crucial for understanding the interactions of this biome with the climate.

Las características de las raíces de los bosques tropicales y las estrategias de adquisición de recursos están subrepresentadas en modelos de vegetación, lo que dificulta la predicción del efecto de cambio de clima para estos ecosistemas ricos en carbono. Los bosques tropicales a menudo tienen combinaciones únicas a nivel mundial de alta biodiversidad taxonómica y funcional, estacionalidad de precipitación, y suelos infértiles, dando lugar a patrones distintos en los rasgos y funciones de las raíces en comparación con los ecosistemas de latitudes más altas. Integramos los avances recientes en nuestra comprensión de la función subterránea de los bosques tropicales en modelos de vegetación, centrándonos en la adquisición de agua y nutrientes. Ofrecemos comparaciones de avances recientes en la comprensión empírica y de modelos de las características de las raíces que representan procesos funcionales importantes en los bosques tropicales. Nos centramos en: (1) estrategias de raíces finas para adquisición de recursos del suelo, (2) acoplamiento y compensaciones entre adquisición del agua y de nutrientes, y (3) vínculos entre funciones sobre tierra y debajo del superficie en bosques tropicales. Sugerimos vías para representar estas comunidades de plantas extremadamente diversas en grupos computacionalmente manejables y ecológicamente significativos en modelos. Los bosques tropicales se están calentando, tienen cambios en los regímenes de lluvias, y tienen una exacerbación de la escasez de nutrientes del suelo causada por el elevado CO2 atmosférico. La representación precisa de las funciones de los bosques tropicales en modelos es crucial para comprender las interacciones de este bioma con el clima.

Operative treatment of isolated epiphyseal fracture of the distal fibula: 1 case report and literature review.

Pediatric ankle injuries are common; ankle epiphyseal fractures are also common in children. But isolated distal epiphyseal fibular fractures of the distal fibula are clinically rare. We describe one unusual case of an adolescent with a completely displaced Salter-Harris type II distal fibular epiphyseal fracture. The attempt of closed reduction failed, and the patient required open reduction and internal fixation. The localized periosteum and the superior peroneal retinaculum were avulsed from the distal fibular metaphysis, with the peroneal tendons underneath exposed but no obvious subluxation. To the best of our knowledge, this combination of injuries has not been previously reported.

Aluminum phytotoxicity in acidic environments: A comprehensive review of plant tolerance and adaptation strategies.

Aluminum (Al), a non-essential metal for plant growth, exerts significant phytotoxic effects, particularly on root growth. Anthropogenic activities would intensify Al's toxic effects by releasing Al3+ into the soil solution, especially in acidic soils with a pH lower than 5.5 and rich mineral content. The severity of Al-induced phytotoxicity varies based on factors such as Al concentration, ionic form, plant species, and growth stages. Al toxicity leads to inhibited root and shoot growth, reduced plant biomass, disrupted water uptake causing nutritional imbalance, and adverse alterations in physiological, biochemical, and molecular processes. These effects collectively lead to diminished plant yield and quality, along with reduced soil fertility. Plants employ various mechanisms to counter Al toxicity under stress conditions, including sequestering Al in vacuoles, exuding organic acids (OAs) like citrate, oxalate, and malate from root tip cells to form Al-complexes, activating antioxidative enzymes, and overexpressing Al-stress regulatory genes. Recent advancements focus on enhancing the exudation of OAs to prevent Al from entering the plant, and developing Al-tolerant varieties. Gene transporter families, such as ATP-Binding Cassette (ABC), Aluminum-activated Malate Transporter (ALMT), Natural resistance-associated macrophage protein (Nramp), Multidrug and Toxic compounds Extrusion (MATE), and aquaporin, play a crucial role in regulating Al toxicity. This comprehensive review examined recent progress in understanding the cytotoxic impact of Al on plants at the cellular and molecular levels. Diverse strategies developed by both plants and scientists to mitigate Al-induced phytotoxicity were discussed. Furthermore, the review explored recent genomic developments, identifying candidate genes responsible for OAs exudation, and delved into genome-mediated breeding initiatives, isolating transgenic and advanced breeding lines to cultivate Al-tolerant plants.

Astragaloside IV targeting autophagy of T cells improves inflammation of asthma.

Astragaloside IV (AST) has been confirmed to have antiasthmatic effects. However, the underline mechanism is unclear. The study aimed to explore the treatment mechanism of AST based on autophagy of memory T cells. AST treatment significantly decreased the number of T effector cells in asthma mice blood and the nude mice that received AST-treated TCMs had relieved inflammation compared with the untreated group; meanwhile, we found that AST significantly decreased the autophagy level and inhibited OX40/OX40L signal pathway of lymphocytes. The results highlighted that AST regulated autophagy to inhibit differentiation of effector T-cell phenotype.

[Morphological and biochemical characterization during seed development of Notopterygium incisum].

This study aimed to examine the morphological, physiological, and biochemical alterations occurring in Notopterygium incisum seeds throughout their developmental stages, with the objective of establishing a theoretical foundation for the cultivation of superior quality seeds. The experimental materials utilized in this study were the seeds of N. incisum at various stages of development following anthesis. Through the employment of morphological observation and plant physiology techniques, the external morphology, nutrients, enzyme activity, and endogenous hormones of the seeds were assessed. The results revealed a transition in seed coat color from light green to brown during the growth and development of N. incisum seeds. Additionally, as the seeds matured, a decrease in water content was observed. Conversely, starch content exhibited a progressive increase, while sucrose content displayed fluctuations. At 7 days after anthesis, the soluble sugar content attained its highest level of 4.52 mg·g~(-1), whereas the soluble protein content reached its maximum of 6.00 mg·g~(-1) at 14 days after anthesis and its minimum of 4.94 mg·g~(-1) at 42 days after anthesis. The activity of superoxide dismutase(SOD) exhibited an initial increase, followed by a decrease, and eventually reached a stable state. Conversely, the activities of catalase(CAT) and peroxidase(POD) demonstrated a decrease initially, followed by an increase, and then another decrease. The levels of the four endogenous hormones, namely gibberellin(GA_3), zeatin riboside(ZR), auxin(IAA), and abscisic acid(ABA), in the seeds displayed significant variations, with IAA and ABA exhibiting considerably higher levels compared to the other hormones. The levels of plant growth-promoting hormones, represented by IAA, generally displayed a pattern of initial increase followed by a subsequent decrease during seed development, while the plant growth-inhibiting hormone ABA showed the opposite trend. The findings indicate that the alterations in nutrient composition, antioxidant enzyme activity, and endogenous hormone levels vary throughout the maturation process of N. incisum seeds. These observations hold relevance for the cultivation of N. incisum seeds.

Utilization of natural alleles for heat adaptability QTLs at the flowering stage in rice.

BACKGROUND: Heat stress threatens rice yield and quality at flowering stage. In this study, average relative seed setting rate under heat stress (RHSR) and genotypes of 284 varieties were used for a genome-wide association study. RESULTS: We identified eight and six QTLs distributed on chromosomes 1, 3, 4, 5, 7 and 12 in the full population and indica, respectively. qHTT4.2 was detected in both the full population and indica as an overlapping QTL. RHSR was positively correlated with the accumulation of heat-tolerant superior alleles (SA), and indica accession contained at least two heat-tolerant SA with average RHSR greater than 43%, meeting the needs of stable production and heat-tolerant QTLs were offer yield basic for chalkiness degree, amylose content, gel consistency and gelatinization temperature. Chalkiness degree, amylose content, and gelatinization temperature under heat stress increased with accumulation of heat-tolerant SA. Gel consistency under heat stress decreased with polymerization of heat-tolerant SA. The study revealed qHTT4.2 as a stable heat-tolerant QTL that can be used for breeding that was detected in the full population and indica. And the grain quality of qHTT4.2-haplotype1 (Hap1) with chalk5, wx, and alk was better than that of qHTT4.2-Hap1 with CHALK5, WX, and ALK. Twelve putative candidate genes were identified for qHTT4.2 that enhance RHSR based on gene expression data and these genes were validated in two groups. Candidate genes LOC_Os04g52830 and LOC_Os04g52870 were induced by high temperature. CONCLUSIONS: Our findings identify strong heat-tolerant cultivars and heat-tolerant QTLs with great potential value to improve rice tolerance to heat stress, and suggest a strategy for the breeding of yield-balance-quality heat-tolerant crop varieties.

IL-8-induced CXCR2 down-regulation in circulating monocytes in hepatocellular carcinoma is partially dependent on MAGL.

BACKGROUND: CXC-chemokine receptor 2 (CXCR2) expression was found to be down-regulated on circulating monocytes of cancer patients. Here, we analyze the percentage of CD14+CXCR2+ monocyte subsets in hepatocellular carcinoma (HCC) patients, and investigate the mechanisms that regulate CXCR2 surface expression on monocytes and its biological function. METHODS: Flow cytometry was used to analyze the proportion of the CD14+CXCR2+ subset from the total circulating monocytes of HCC patients. Interleukin 8 (IL-8) levels were measured from serum and ascites, and their correlation with the CD14+CXCR2+ monocyte subset proportion was calculated. THP-1 cells were cultured in vitro and treated with recombinant human IL-8 and CXCR2 surface expression was analyzed. CXCR2 was knocked down to examine how it affects the antitumor activity of monocytes. Finally, a monoacylglycerol lipase (MAGL) inhibitor was added to analyze its effect on CXCR2 expression. RESULTS: A decrease in the proportion of the CD14+CXCR2+ monocyte subset was observed in HCC patients compared with healthy controls. CXCR2+ monocyte subset proportion was associated with the AFP value, TNM stage, and liver function. Overexpression of IL-8 was observed in the serum and ascites of HCC patients, and negatively correlated with CXCR2+ monocyte proportion. IL-8 decreased CXCR2 expression in THP-1 cells, contributing to decreased antitumor activity toward HCC cells. MAGL expression in THP-1 cells was up-regulated after IL-8 treatment, and the MAGL inhibitor partially reversed the effects of IL-8 on CXCR2 expression. CONCLUSIONS: Overexpression of IL-8 drives CXCR2 down-regulation on circulating monocytes of HCC patients, which could be partially reversed by a MAGL inhibitor.

Flood risk assessment by using an interpretative structural modeling based Bayesian network approach (ISM-BN): An urban-level analysis of Shenzhen, China.

With increasingly uncertain environmental conditions under global change, it is rather important for water security management to evaluate the flood risk, which is influenced by the compound effect of severe weather events and strong anthropogenic activities. In this paper, a risk assessment model in the framework of Bayesian network (BN) was proposed through incorporating with the Interpretative Structural Modeling method (ISM), which would produce an integrated ISM-BN model for reliable flood assessments. The ISM is employed to identify the relations among multiple risk factors, and then helps to configure the BN structure to conduct a risk inference. The established model was further demonstrated in Shenzhen city of China to perform an urban-level risk analysis of the flood disaster, and the Enhanced Water Index (EWI) was introduced to derive model parameters for training and verification. The obtained results of risk assessment lead to an accuracy of 76% with the Area Under ROC Curve (AUC) of 0.82, and spatial distribution of risk levels also showed a satisfactory performance. In addition, it was found that the maximum daily rainfall among ten risk factors play a key part in flood occurrence, while the elevation and storm frequency are also sensitive indicators for the study area. Besides, the spatial flood risk map generated under various design rainfall scenarios would contribute to identifying potential areas that are worth paying particular attention. Thus, the developed assessment model would be a useful tool for supporting flood risk governance to achieve reliable urban water security.

[Systematic review and Meta-analysis of Biling Weitong Granules in treatment of stomach ache disorder].

This study aimed to evaluate the efficacy and safety of Biling Weitong Granules in the treatment of stomach ache disorder. Randomized controlled trial(RCT) of Biling Weitong Granules in the treatment of digestive diseases with stomach ache disorder as the primary symptom was retrieved from Chinese and English electronic databases and trial registration platforms from database inception to June 10, 2022. Two investigators conducted literature screening and data extraction according to the screening criteria. The Cochrane risk-of-bias tool(v 2.0) was used to assess the risk of bias in the included studies. Analyses were performed using RevMan 5.4 and R 4.2.2, with summary estimates measured using fixed or random effects models. The primary outcome indicators were the visual analogue scale(VAS) scores and stomach ache disorder symptom scores. The secondary outcome indicators were clinical recovery rate, Helicobacter pylori(Hp) eradication rate, and adverse reaction/events. Twenty-seven RCTs were included with a sample size of 2 902 cases. Meta-analysis showed that compared with conventional western medicine treatments or placebo, Biling Weitong Granules could improve VAS scores(SMD=-1.90, 95%CI[-2.18,-1.61], P<0.000 01), stomach ache disorder symptom scores(SMD=-1.26, 95%CI[-1.71,-0.82], P<0.000 01), the clinical recovery rate(RR=1.85, 95%CI[1.66, 2.08], P<0.000 01), and Hp eradication rate(RR=1.28, 95%CI[1.20, 1.37], P<0.000 01). Safety evaluation revealed that the main adverse events in the Biling Weitong Granules included nausea and vomiting, rash, diarrhea, loss of appetite, and bitter mouth, and no serious adverse events were reported. Egger's test showed no statistical significance, indicating no publication bias. The results showed that Biling Weitong Granules in the treatment of digestive system diseases with stomach ache disorder as the primary symptom could improve the VAS scores and stomach ache disorder symptom scores of patients, relieve stomach ache disorder, and improve the clinical recovery rate and Hp eradication rate, with good safety and no serious adverse reactions. However, the quality of the original studies was low with certain limitations. Future studies should use unified and standardized detection methods and evaluation criteria of outcome indicators, pay attention to the rigor of study design and implementation, and highlight the clinical safety of the medicine to provide more reliable clinical evidence support for clinical application.

Catalytic σ-Bond Annulation with Ambiphilic Organohalides Enabled by ß-X Elimination.

We describe a catalytic cascade sequence involving directed C(sp3 )-H activation followed by ß-heteroatom elimination to generate a PdII (π-alkene) intermediate that then undergoes redox-neutral annulation with an ambiphilic aryl halide to access 5- and 6-membered (hetero)cycles. Various alkyl C(sp3 )-oxygen, nitrogen, and sulfur bonds can be selectively activated, and the annulation proceeds with high diastereoselectivity. The method enables modification of amino acids with good retention of enantiomeric excess, as well as σ-bond ring-opening/ring-closing transfiguration of low-strain heterocycles. Despite its mechanistic complexity, the method employs simple conditions and is operationally straightforward to perform.

Similar Midterm Clinical Outcomes and Aortic Remodeling in Bifurcated and Straight Aortic Stent Grafts Used to Treat Isolated Abdominal Aortic Dissection.

PURPOSE: The optimal treatment for isolated abdominal aortic dissection (IAAD) is currently unknown. We compared the effects of straight and bifurcated aortic stent grafts on postoperative aortic remodeling in patients with IAAD. MATERIALS AND METHODS: From February 2012 to December 2019, 57 patients with IAAD were treated using endovascular methods, including either a bifurcated or a straight aortic stent graft. The clinical features, risk factors, computed tomography angiograms, midterm follow-up results, and aortic remodeling of these patients were reviewed and analyzed. RESULTS: In total, 44 (77%) patients were treated with a bifurcated graft and 13 (23%) patients were treated with a straight graft. Patients treated with straight grafts had fewer common iliac arteries involved (38% vs 73%, p=0.023), the dissection length was shorter (76.3 ± 40.0 vs 116.2 ± 56.7 mm, p=0.011), and the preoperative aortic diameter (26.0 ± 5.6 vs 35.2 ± 12.1 mm) and the false lumen diameter (13.1 ± 5.2 vs 21.2 ± 11.3 mm) were smaller. During the procedure, there were 3 (5.3%) type I endoleaks, 1 (1.8%) surgical conversion and 1 (1.8%) partial renal artery coverage without perioperative mortality. Patients with straight grafts had shorter operative time (96.5 ± 24.4 vs 144.2 ± 49.0 minutes, p<0.0001). The median follow-up duration was 37.6 ± 21.0 (range = 3-89) months with 1 (1.8%) aortic-related death. Type A aortic dissection occurred in 1 (1.8%) patient. New descending aortic dissection occurred in 3 (5.3%) patients, and 1 patient advanced to type A aortic dissection 3 months later. Two (3.5%) patients had limb occlusion. There was no significant difference in aortic remodeling, survival, and freedom from all adverse events between the 2 treatment strategies. CONCLUSIONS: Endovascular treatment provides a safe, minimally invasive treatment for IAAD in midterm follow-up. Compression of the true lumen at the aortic bifurcation is the main concern after treatment with a bifurcated graft. Straight grafts are an excellent alternative for some patients, with the benefit of reduced procedural time, effective aortic remodeling, and excellent clinical prognosis. More experience is needed to offer clear recommendations for making treatment decisions as well as determine long-term effectiveness and durability.

Changes of serum miR-221 and miR-145 levels with papillary thyroid carcinoma and their relationship with invasive activity.

This study aimed to investigate the expression of miR-221 and miR-145 in papillary thyroid carcinoma, and the effect of miR-221 and miR-145 on the invasion ability of thyroid cancer cells and its mechanism. For this purpose, 120 patients with thyroid nodules were divided into the observation group (PTC) of 43 cases and the control group (benign nodules) of 42 cases according to postoperative pathological diagnosis. Total RNA was extracted from serum samples of all patients, and the expression levels of miRNA-145 and miR-221 were detected by fluorescence quantitative PCR. The expression of two kinds of miRNAs in the groups was compared, and their correlation was analyzed. The results showed that the expression of miRNA-145 in thyroid cancer tissues was lower than that in paired adjacent normal tissues (P < 0.001). The expression of miRNA-221 in thyroid cancer tissues was higher than that in paired adjacent normal tissues (P < 0.001). The proliferation and migration ability of miRNA-145 cells were significantly decreased (P < 0.01). The expression of miRNA-221 was up-regulated, and the proliferation and migration ability of cells was significantly enhanced (P < 0.05). High expression of miRNA-145 can inhibit cell proliferation and migration and promote apoptosis, while high expression of miRNA-221 will promote cell proliferation and migration and enhance the invasion ability of cancer cells. In general, the expression of miRNA-22l in serum of PTC patients is significantly up-regulated, while the expression level of miR-145 is down-regulated, which can be used as effective indicators to judge the biological activity of the tumor, and the combined detection of the two can significantly enhance the diagnostic value of PTC. Upregulation of miR-145 inhibits PTC cell proliferation; arrests cell cycle and promotes apoptosis miR-145 may play an important role as a tumor suppressor gene.

Osthole Suppresses Knee Osteoarthritis Development by Enhancing Autophagy Activated via the AMPK/ULK1 Pathway.

Knee osteoarthritis (KOA) is an increasingly prevalent heterogeneous disease characterized by cartilage erosion and inflammation. As the main chemical constituent of Angelicae Pubescentis Radix (APR), an anti-inflammatory herbal medicine, the potential biological effects and underlying mechanism of osthole on chondrocytes and KOA progression remain elusive. In this study, the potential effect and mechanism of osthole on KOA were investigated in vitro and in vivo. We found that osthole inhibited IL-1ß-induced apoptosis and cartilage matrix degeneration by activating autophagy in rat chondrocytes. In addition, osthole could activate autophagy through phosphorylation of AMPK/ULK1, and AMPK serves as a positive upstream regulator of ULK1. Furthermore, KOA rats treated with osthole showed phosphorylation of the AMPK/ULK1 pathway and autophagy activation, as well as cartilage protection. Collectively, the AMPK/ULK1 signaling pathway can be activated by osthole to enhance autophagy, thereby suppressing KOA development. Osthole may be a novel and effective therapeutic agent for the clinical treatment of KOA.

Louki Zupa decoction attenuates the airway inflammation in acute asthma mice induced by ovalbumin through IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway.

CONTEXT: Asthma is a common respiratory system disease. Louki Zupa decoction (LKZP), a traditional Chinese medicine, presents a promising efficacy against lung diseases. OBJECTIVE: To investigate the pathogenic mechanism of asthma and reveal the intervention mechanism of LKZP. MATERIALS AND METHODS: Forty-eight female Balb/c mice were randomly divided into 6 groups: normal control group (NC), ovalbumin (OVA)/saline asthma model group, OVA/LL group, OVA/LM group, OVA/LH group and OVA/DEX group (n = 8 per group). The asthmatic mice were modelled through intraperitoneal injecting and neutralizing OVA. LKZP decoction was administrated by gavage at the challenge stage for seven consecutive days (2.1, 4.2 and 8.4 g/kg/day). We investigated the change in lung function, airway inflammation, mucus secretion and TH-1/TH-2-related cytokines. We further verify the activated status of the IL-33/ST2/NF-κB/GSK3ß/mTOR signalling pathway. RESULTS: LKZP was proved to improve asthmatic symptoms, as evidenced by the down-regulated airway resistance by 36%, 58% and 53% (p < 0.01, p < 0.001 vs. OVA/saline group), up-regulated lung compliance by 102%, 114% and 111%, decreased airway inflammation and mucus secretion by 33%, 40% and 33% (p < 0.001 vs. OVA/saline group). Moreover, the content of cytokines in BALF related to airway allergy (such as IgE) and T helper 1/T helper 2 cells (like IL-2, IL-4, IL-5, IL-13, TNF-α and IFN-γ), were also markedly reduced by 13-65% on LKZP intervention groups compared with model group. Mechanistic research revealed that the IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway was activated in the OVA/saline group and LKZP significantly down-regulated this pathway. DISCUSSION AND CONCLUSION: LKZP improves lung function, airway inflammation, mucus secretion and correct immune imbalance by intervening with the IL-33/ST2-NF-κB/GSK3ß/mTOR signalling pathway, presenting a promising therapeutic choice for asthma.

Gender Differences in the Score and Influencing Factors of Social Participation among Chinese Elderly.

This study measured the social participation score of the Chinese elderly, described its decayed trajectory based on birth cohort, and analyzed the gender differences of factors that affected the social participation of the elderly based on MIMIC model by groups. Results showed that age, economic status, and living status were the influencing factors with significant gender differences on social participation level of Chinese elderly. At any age, the social participation of Chinese elderly women was lower than that of elderly men, and this gap widened with age. Social participation of older women was more vulnerable to economic conditions. Living with children had a significant negative impact on the social participation of elderly women. There was no significant gender difference in the influence of marital status and educational level on the social participation of the elderly.

Allicin can suppress the activity of vascular endothelial cells probably by regulating JAK2/STAT3 pathway.

Whether allicin can suppress the angiogenesis via inhibiting the activity of vascular endothelial cells (VECs) in preventing epidural hypertrophic scars remains unknown. VECs were treated by allicin at a gradient of concentrations. Cell activity was measured by CCK-8 assay, scratch assay and flow cytometry. Reverse-transcription PCR and Western Blot were used to measure the expression levels of relevant genes and proteins. After treated with allicin at concentrations of 0, 25, 50 and 100 mg/L, the viability of VECs significantly decreased at 24 h (p < 0.001*) and 48 h (p < 0.001*), and migration rate significantly decreased in scratch assay (p = 0.017*) and in Transwell assay (p = 0.021*). As the concentrations of allicin increased, the apoptosis rate of VECs rose up (p = 0.018*). There was no significant difference on cell numbers at S phase (p = 0.25), but cell numbers at G1 phase decreased (p = 0.039*) and at G2 phase increased (p = 0.047*). With the increase of allicin concentrations, the ability of tube formation for VECs significantly decreased (p < 0.001*). Comparing with control group, the expression of PCNA and BCL-2 decreased (p < 0.001*), while the expression of BAX increased significantly (p < 0.001*). Regarding to JAK2/STAT3 pathway, the expression levels of JAK3 and STAT3 decreased significantly with the increase of allicin concentrations (p < 0.001*). Allicin can suppress the activity of VECs probably by regulating JAK2/STAT3 pathway.

Baicalin ameliorates cigarette smoke-induced airway inflammation in rats by modulating HDAC2/NF-κB/PAI-1 signalling.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease distinguished by airway remodelling and progressive inflammation. PAI-1 is an important regulator of fibrosis. Recent studies have shown that PAI-1 seems to be involved in COPD progression. Elevated levels of PAI-1 have been found in the lungs of patients with acute inflammation. PAI-1 has been shown to regulate the levels of proinflammatory cytokines in the lungs, such as tumour necrosis factor (TNF)-α and interleukin (IL)-6, indicating that PAI-1 may play a fundamental role during inflammation. In the present study, we investigated the anti-inflammatory role of baicalin, the main active component of Scutellaria baicalensis, against cigarette smoke (extract) (CS/CSE)-induced airway inflammation in vivo and in vitro. For the in vivo study, SD rats were exposed to CS for 1 h/day, 6 days/week, for 24 weeks and treated with baicalin (40, 80 and 160 mg/kg) or budesonide (0.2 mg/kg). For this study, HBE cells were pretreated with baicalin (10, 20, 40 µM) or dexamethasone (10-7 M) and then exposed to CSE. We found that baicalin treatment could ameliorate CS-induced airway inflammatory infiltration in rats and decrease PAI-1 expression. The ELISA results showed that baicalin significantly inhibited the levels of TNF-α and IL-1ß in CS/CSE-exposed rats and cells. Mechanistic studies showed that baicalin enhanced histone deacetylase 2 (HDAC2) protein expression and inhibited the expression of NF-κB and its downstream target PAI-1, and these effects were reversed by the HDAC2 inhibitor CAY-10683. In conclusion, baicalin ameliorated CS-induced airway inflammation in rats, and these effects were partially attributed to the modulation of HDAC2/NF-κB/PAI-1 signalling.

Naringin alleviates H2O2-induced apoptosis via the PI3K/Akt pathway in rat nucleus pulposus-derived mesenchymal stem cells.

Purpose: To investigate the protective effect of naringin (Nar) on H2O2-induced apoptosis of nucleus pulposus-derived mesenchymal stem cells (NPMSC) and the potential mechanism in this process. Methods: Rat NPMSC were cultured in MSC culture medium or culture medium with different concentrations of H2O2. Nar or the combination of Nar and LY294002 was added into the culture medium to investigate the effects of Nar. Cell viability was evaluated by cell counting kit-8 (CCK-8) assay. The apoptosis rate was determined using Annexin V/PI dual staining and terminal deoxynucleotide transferase-mediated dUTP nick end labeling (TUNEL) assays. Additionally, the levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. ATP level in NPMSC was analyzed via ATP detection kit. Mitochondrial ultrastructure change was observed through transmission electron microscope (TEM). Levels of apoptosis-associated molecules (cleaved caspase-3, Bax and Bcl-2) were evaluated via RT-PCR and western blot, respectively. Results: The cells isolated from NP met the criteria for MSC. H2O2 significantly promoted NPMSC apoptosis in a dose and time-dependent manner. Nar showed no cytotoxicity effect on NPMSC up to a concentration of 100 µM for 24 h. Nar exhibited protective effects against H2O2-induced NPMSC apoptosis including apoptosis rate, expressions of proapoptosis and antiapoptosis related genes and protein. Nar could also alleviate H2O2-induced mitochondrial dysfunction of increased mitochondrial ROS production, reduced MMP, decreased intracellular ATP and mitochondrial ultrastructure change. However, these protected effects were inhibited after LY294002 treatment. Conclusions: Our results demonstrated that Nar efficiently attenuated H2O2-induced NPMSC apoptosis and mitochondrial dysfunction. The activation of ROS-mediated PI3K/Akt pathway may be the potential mechanism in this process.

Post-contrast acute kidney injury in a hospitalized population: short-, mid-, and long-term outcome and risk factors for adverse events.

OBJECTIVES: To investigate the prognosis including major adverse kidney events within 30 days (MAKE30) and 90-day and 1-year adverse outcome in hospitalized patients with post-contrast acute kidney injury (PC-AKI) to identify high-risk factors. METHODS: This retrospective observational study included 288 PC-AKI patients selected from 277,898 patients admitted to hospitals from January 2015 to December 2015. PC-AKI was defined according to the 2018 guideline of European Society of Urogenital Radiology. Multivariable Cox regression and logistic regression analyses were used to analyze main outcome and risk factors. RESULTS: PC-AKI patients with AKI stage ≥ 2 had much higher incidence of MAKE30 than those with AKI stage 1 (RR = 7.027, 95% CI 4.918-10.039). Persistent renal dysfunction, heart failure, central nervous system failure, baseline eGFR < 60 mL/min/1.73 m2, oliguria or anuria, blood urea nitrogen ≥ 7.14 mmol/L, respiratory failure, and shock were independent risk factors of 90-day or 1-year adverse prognosis (p < 0.05). Compared with transient renal dysfunction, PC-AKI patients with persistent renal dysfunction had a higher all-cause mortality rate (RR = 3.768, 95% CI 1.612-8.810; RR = 4.106, 95% CI 1.765-9.551) as well as combined endpoints of death, chronic kidney disease, or end-stage renal disease (OR = 3.685, 95% CI 1.628-8.340; OR = 5.209, 95% CI 1.730-15.681) within 90 days or 1 year. CONCLUSIONS: PC-AKI is not always a transient, benign creatininopathy, but can result in adverse outcome. AKI stage is independently correlated to MAKE30 and persistent renal dysfunction may exaggerate the risk of long-term adverse events. KEY POINTS: • PC-AKI can result in adverse outcome such as persistent renal dysfunction, dialysis, chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. • AKI stage is independently correlated to MAKE30. • Persistent renal dysfunction may exaggerate the risk of long-term adverse events.