LY333531 attenuates contraction of tumor necrosis factor-α-sensitized human airway smooth muscle cells.

Objective: Protein kinase C (PKC) has been implicated in the increased contraction of human airway smooth muscle cells (HASMCs) in asthma. Using the three-dimensional collagen gel contraction system, the study aimed to determine the effects of LY333531, a specific inhibitor of the PKC-ß isoform, on the contraction of tumor necrosis factor (TNF)-α-sensitized HASMCs.Methods: Cultured HASMCs were divided into five groups: the control group received no treatment, and the cells in the TNF-α group were sensitized with 10 ng/mL TNF-α for 48 hours, while TNF-α was administered to sensitize HASMCs in the presence of 0.1 µM, 0.2 µM, and 0.5 µM LY333531 for 48 hours in the 0.1LY, 0.2LY, and 0.5LY groups, respectively. Following this, HASMCs contraction were stimulated with 1 mM acetylcholine (ACh) for up to 24 h in each group and assessed using a three-dimensional collagen gel contraction assay. Furthermore, western blot and immunofluorescence analysis were performed.Results: The collagen gel contraction assay revealed that TNF-α increased the protein expression of phosphorylated PKC-ß2, CPI-17 and MLC, while exacerbating ACh-induced HASMCs contraction. LY333531 significantly attenuated HASMCs contraction and downregulated the protein expression of both p-CPI-17 and p-MLC.Conclusions: At least in part by regulating CPI-17 and MLC phosphorylation, LY333531 attenuates augmented contraction of TNF-α-sensitized HASMCs in a collagen gel contraction system.

CgSHIP2 negatively regulates the mRNA expressions of CgIL-17s in response to Vibrio splendidus stimulation in Crassostrea gigas.

SH2 domain containing inositol polyphosphate5-phosphatase-2 (SHIP2) is a member of the 5-phosphatase family, acting as a vital negative regulator of immune response in vertebrates. In the present study, a SHIP2 homologue (designed as CgSHIP2) was identified from Pacific oyster, Crassostrea gigas. There was a SH2 domain, an IPPc domain and a SAM domain in CgSHIP2. The mRNA transcripts of CgSHIP2 were widely expressed in all the tested tissues with the highest expression in haemolymph. The mRNA expressions of CgSHIP2 in haemocytes increased significantly at 6, 12, 48 and 72 h after Vibrio splendidus stimulation. The positive green signals of CgSHIP2 protein were mainly located in cytoplasm of haemocytes. After the expression of CgSHIP2 was inhibited by RNA interference, the mRNA transcripts of interleukin 17s (CgIL-17-1, CgIL-17-2, CgIL-17-3 and CgIL-17-6) in the haemocytes increased significantly at 24 h after V. splendidus stimulation, which were 8.15-fold (p < 0.001), 3.44-fold (p < 0.05), 2.15-fold (p < 0.01) and 4.63-fold (p < 0.05) compared with that in NC-RNAi group, respectively. Obvious branchial swelling and cilium shedding in gills were observed in CgSHIP2-RNAi group at 24 h after V. splendidus stimulation. The results suggested that CgSHIP2 played an important role in controlling inflammatory response induced by bacteria in oysters.

Application of nano-radiosensitizers in non-small cell lung cancer.

Radiotherapy stands as a cornerstone in the treatment of numerous malignant tumors, including non-small cell lung cancer. However, the critical challenge of amplifying the tumoricidal effectiveness of radiotherapy while minimizing collateral damage to healthy tissues remains an area of significant research interest. Radiosensitizers, by methods such as amplifying DNA damage and fostering the creation of free radicals, play a pivotal role in enhancing the destructive impact of radiotherapy on tumors. Over recent decades, nano-dimensional radiosensitizers have emerged as a notable advancement. Their mechanisms include cell cycle arrest in the G2/M phase, combating tumor hypoxia, and others, thereby enhancing the efficacy of radiotherapy. This review delves into the evolving landscape of nanomaterials used for radiosensitization in non-small cell lung cancer. It provides insights into the current research progress and critically examines the challenges and future prospects within this burgeoning field.

Novel Pyrazole-4-Carboxamide Derivatives Containing Oxime Ether Group as Potential SDHIs to Control Rhizoctonia solani.

In the search for novel succinate dehydrogenase inhibitor (SDHI) fungicides to control Rhizoctonia solani, thirty-five novel pyrazole-4-carboxamides bearing either an oxime ether or an oxime ester group were designed and prepared based on the strategy of molecular hybridization, and their antifungal activities against five plant pathogenic fungi were also investigated. The results indicated that the majority of the compounds containing oxime ether demonstrated outstanding in vitro antifungal activity against R. solani, and some compounds also displayed pronounced antifungal activities against Sclerotinia sclerotiorum and Botrytis cinerea. Particularly, compound 5e exhibited the most promising antifungal activity against R. solani with an EC50 value of 0.039 µg/mL, which was about 20-fold better than that of boscalid (EC50 = 0.799 µg/mL) and 4-fold more potent than fluxapyroxad (EC50 = 0.131 µg/mL). Moreover, the results of the detached leaf assay showed that compound 5e could suppress the growth of R. solani in rice leaves with significant protective efficacies (86.8%) at 100 µg/mL, superior to boscalid (68.1%) and fluxapyroxad (80.6%), indicating promising application prospects. In addition, the succinate dehydrogenase (SDH) enzymatic inhibition assay revealed that compound 5e generated remarkable SDH inhibition (IC50 = 2.04 µM), which was obviously more potent than those of boscalid (IC50 = 7.92 µM) and fluxapyroxad (IC50 = 6.15 µM). Furthermore, SEM analysis showed that compound 5e caused a remarkable disruption to the characteristic structure and morphology of R. solani hyphae, resulting in significant damage. The molecular docking analysis demonstrated that compound 5e could fit into the identical binding pocket of SDH through hydrogen bond interactions as well as fluxapyroxad, indicating that they had a similar antifungal mechanism. The density functional theory and electrostatic potential calculations provided useful information regarding electron distribution and electron transfer, which contributed to understanding the structural features and antifungal mechanism of the lead compound. These findings suggested that compound 5e could be a promising candidate for SDHI fungicides to control R. solani, warranting further investigation.

The experiences of children and adolescents with cancer returning to school: A qualitative meta-synthesis.

BACKGROUND: Returning to school can be challenging for children and adolescents with cancer who have been absent for a long time. As there is little known about the return to school experience of children and adolescents with cancer, this meta-synthesis aimed to describe the experiences of children and adolescent cancer patients as they return to school. METHODS: Seven English databases and three Chinese databases were searched from inception to March 14, 2023. The Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI) was used to appraise study quality. Data were synthesized using the Thomas and Harden thematic and content analysis method. RESULTS: Twelve qualitative studies met the inclusion criteria and were analyzed into meta-synthesis. Data synthesis led to constructing four analytical themes and twelve sub-themes. The four major themes constructed were:benefits to school re-entry, barriers to school re-entry, motivators to school re-entry and the adaptation process after returning to school. CONCLUSION: Children and adolescents with cancer were willing to return to education and can adapt to school life over time. But they were faced with challenges, including physical, psychological, and social barriers. Appropriate measures need to be taken to reduce those barriers. IMPLICATIONS TO PRACTICE: Findings can be used to inform future research and interventions to support a successful return to education for children and adolescents with cancer. Healthcare providers should address the needs of children and adolescents at different stages and actively work with schools, hospitals and families to help childhood cancer survivors successfully return to school.

Relationship Between Microstructural Alterations and Cognitive Decline After Whole-Brain Radiation Therapy for Brain Metastases: An Exploratory Whole-Brain MR Analysis Based on Neurite Orientation Dispersion and Density Imaging.

BACKGROUND: Cognitive impairment frequently occurs in patients with brain metastases (BM) after whole-brain radiotherapy (WBRT). It is crucial to explore the underlying mechanisms of cognitive impairment in BM patients receiving WBRT. PURPOSE: To detect brain microstructural alterations in patients after WBRT by neurite orientation dispersion and density imaging (NODDI), and evaluate the performance of microstructural alterations in predicting cognitive impairment. STUDY TYPE: Prospective. POPULATION: Twenty-six patients (seven female; mean age, 60.9 years). FIELD STRENGTH/SEQUENCE: 3-T, multi-shell diffusion-weighted single-shot echo-planar sequence. Three-dimensional magnetization-prepared rapid acquisition with gradient echo sequence. ASSESSMENT: Mini-mental state examination (MMSE) evaluations were conducted prior to, following, 1 and 3 months after WBRT. The diffusion data were collected twice, 1 week before and 1 week after WBRT. NODDI analysis was conducted to assess microstructural alterations in whole brain (orientation dispersion index, neurite density index, volume fraction of isotropic water molecules). Reliable change indices (RCI) of MMSE were used to measure cognitive decline. The performance of support vector machine models based on NODDI parameters and clinical features (prednisone usage, tumor volume, etc.) in predicting MMSE-RCI was evaluated. STATISTICAL TESTS: Paired t-test to assess alterations of NODDI measures and MMSE during follow-up. Statistical significance level of P-value <0.05. RESULTS: Significantly decreased MMSE score was found at 3 months after WBRT. After WBRT, corpus callosum, medial prefrontal cortex, limbic lobe, occipital lobe, parietal lobe, putamen, globus pallidus lentiform, and thalamus demonstrated damage in NODDI parameters. The predicted MMSE-RCI based on NODDI features was significantly associated with the measured MMSE-RCI at 1 month (R = 0.573; P = 0.003) and 3 months (R = 0.687; P < 0.0001) after WBRT. DATA CONCLUSION: Microstructural alterations in several brain regions including the middle prefrontal and limbic cortexes were observed in patients with BM following WBRT, which may contribute to subsequent cognitive decline. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Self-assembled flagella protein nanofibers induce enhanced mucosal immunity.

Nanofibers are potential vaccines or adjuvants for vaccination at the mucosal interface. However, how their lengths affect the mucosal immunity is not well understood. Using length-tunable flagella (self-assembled from a protein termed flagellin) as model protein nanofibers, we studied the mechanisms of their interaction with mucosal interface to induce immune responses length-dependently. Briefly, through tuning flagellin assembly, length-controlled protein nanofibers were prepared. The shorter nanofibers exhibited more pronounced toll-like receptor 5 (TLR5) and inflammasomes activation accompanied by pyroptosis, as a result of cellular uptake, lysosomal damage, and mitochondrial reactive oxygen species generation. Accordingly, the shorter nanofibers elevated the IgA level in mucosal secretions and enhanced the serum IgG level in ovalbumin-based intranasal vaccinations. These mucosal and systematic antibody responses were correlated with the mucus penetration capacity of the nanofibers. Intranasal administration of vaccines (human papillomavirus type 16 peptides) adjuvanted with shorter nanofibers significantly elicited cytotoxic T lymphocyte responses, strongly inhibiting tumor growth and improving survival rates in a TC-1 cervical cancer model. This work suggests that length-dependent immune responses of nanofibers can be elucidated for designing nanofibrous vaccines and adjuvants for both infectious diseases and cancer.

The Psychological Adaptation Process in Chinese Parent Caregivers of Pediatric Leukemia Patients: A Qualitative Analysis.

BACKGROUND: Psychological stresses caused by caring for pediatric leukemia patients can affect their parent caregivers' health. How these stressors are successfully managed determines how well these caregivers adapt to the illness situation over time. Previous studies suggest that caregivers will adapt gradually to the adverse consequences of caring for their child with a long-term illness. However, studies of the psychological adaptation process of family caregivers of children with leukemia are limited. OBJECTIVE: The aim of this study was to study the psychological adaptation process of the parent caregivers of pediatric leukemia patients. METHODS: In this qualitative study, we interviewed 32 caregivers of children with leukemia in China. Data were collected through semistructured interviews and analyzed using the content analysis method. RESULTS: The psychological adaptation process in caregivers of pediatric leukemia patients seems to involve 5 stages: initial devastation, accumulation of hope, fluctuation in feelings, integration, and psychological adaptation. Significant emotional changes were observed at each stage. CONCLUSIONS: This study identified commonalities in the psychological adaptation process experienced by caregivers of children with leukemia in the Chinese social and cultural context. It also characterized the different emotions that the caregivers had in the 5 stages of adaptation. In addition, our research identified the possible psychological interventions at different stages. IMPLICATIONS FOR PRACTICE: The study described the adaptation process of Chinese parents of children with leukemia. The findings of this study will help nurses identify main coping resources, controllable intervention factors, and the timing of intervention for these caregivers of children with leukemia.

Binding Peptide-Promoted Biofunctionalization of Graphene Paper with Hydroxyapatite for Stimulating Osteogenic Differentiation of Mesenchymal Stem Cells.

Graphene paper (GP), a macroscopic self-supporting material, has exceptional flexibility and preserves the excellent physical and chemical properties of graphene nanomaterials. But its applications in regenerative medicine remain to be further explored. Here, we biologically functionalized GP with hydroxyapatite (HA) nanorods by the use of GP-binding peptides as an affinity linker. This strategy solved two daunting challenges for regenerative medicine applications of GP: the lack of good hydrophilicity for supporting cell growth and the difficulty in forming composites by binding with nanobiomaterials. Briefly, we first screened a high-affinity GP-binding peptide (TWWNPRLVYFDY) by the phage display technique. Then we chemically conjugated the GP-binding peptide to the synthetic HA nanorods. The GP-binding peptide on the resultant HA nanorods enabled them to be bound and assembled onto the GP substrate with high affinity, forming a GP-peptide-HA composite with significantly improved hydrophilicity of GP. The composite promoted the attachment and proliferation of mesenchymal stem cells (MSCs), demonstrating its outstanding biocompatibility. Due to the unique compositions of the composite, it was also found to induce osteogenic differentiation of MSCs in vitro in the absence of other inducers in the medium, by verifying the expression of the osteogenic markers including collagen-1, bone morphogenetic proteins 2, runx-related transcription factor 2, osteocalcin, and alkaline phosphatase. Our work suggests that the GP-binding peptide can be used to link inorganic nanoparticles onto GP to facilitate the biomedical applications of GP.

[Expression and significance of Ki-67, PI3K and Beclin1 in oral squamous cell carcinoma].

PURPOSE: To detect the expression and significance of Ki-67, PI3K and Beclin1 in oral squamous cell carcinoma (OSCC). METHODS: Thirty patients with OSCC admitted to Nanjing Stomatology Hospital from January 2017 to December 2018 were selected. All specimens were harvested and treated with immunohistochemical staining. The expressions of Ki-67, PI3K and Beclin 1 were detected. Pearson's correlation was used to analyze the correlation among TMSG-1, Ki-67 and Pgp1.The data were analyzed with SPSS 20.0 software package. RESULTS: The positive rates of Ki-67 and PI3K in OSCC tissues were significantly higher than those in adjacent tissues, and the positive rates of Beclin1 were significantly lower than those in adjacent tissues (P<0.05). The positive expression rates of Ki-67, PI3K and Beclin1 in highly differentiated OSCC were significantly higher than those in moderately differentiated and poorly differentiated OSCC (P<0.05). The positive expression rates of Ki-67 and PI3K in OSCC with lymph node metastasis were significantly higher than those in OSCC without lymph node metastasis. The positive expression rates of Beclin1 in OSCC with lymph node metastasis were significantly lower than those in OSCC without lymph node metastasis (P<0.05). The positive expression rates of Ki-67, PI3K and Beclin1 in stageⅠ+Ⅱ and Ⅲ+Ⅳ OSCC were not significantly different (P>0.05). Ki-67 was positively correlated with PI3K (r=0.391, P=0.032), Ki-67 was negatively correlated with Beclin1 (r=-0.525, P=0.02), and Beclin1 was negatively correlated with PI3K(r=-0.367, P=0.045). CONCLUSIONS: Ki-67, PI3K and Beclin1 are correlated with lymph node metastasis and pathological staging. They may be involved in the occurrence and development of OSCC.

Mechanical stress promotes biological functions of C2C12 myoblasts by activating PI3K/AKT/mTOR signaling pathway.

The PI3K/AKT signaling pathway regulates cell proliferation and differentiation in multiple types of cells. The present study aimed to investigate the effects of mechanical stress on C2C12 cell proliferation and to explore the associated mechanisms. A cyclic mechanical stress model of C2C12 myoblasts was established. Reverse transcription­quantitative PCR and western blotting assay were used to examine the PI3K signaling pathways involved in the progress of cell differentiation. Cell counting kit­8 (CCK­8) assay was used to evaluate the proliferation of C2C12 cells. Flow cytometry was employed to evaluate apoptosis following mechanical stress. The results demonstrated that mechanical stress activated the PI3K signaling pathway in C2C12 myoblasts. Mechanical stress significantly promoted phosphorylation (p­) of AKT and expression of mammalian target of rapamycin (mTOR) compared with the normal group. Mechanical stress significantly promoted 4E­binding protein 1 (4EBP1) expression in C2C12 cells compared with the normal group. The PI3K specific inhibitor LY294002 significantly decreased 4EBP1 expression and reduced p­AKT and p­mTOR expression compared with the mechanical stress group. Mechanical stress promoted C2C12 cell proliferation. Apoptosis of C2C12 significantly decreased in the mechanical stress group compared with the normal group. Cyclin D levels significantly increased in the mechanical stress group compared with the normal group. In conclusion, mechanical stress promoted biological functions of C2C12 cells by activating the PI3K/AKT signaling pathway. These results may contribute to a better understanding of the effects of mechanical stress on cells.