Inactivation of Malic Enzyme 1 in Endothelial Cells Alleviates Pulmonary Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive cardiopulmonary disease with a high mortality rate. Although growing evidence has revealed the importance of dysregulated energetic metabolism in the pathogenesis of PH, the underlying cellular and molecular mechanisms are not fully understood. In this study, we focused on ME1 (malic enzyme 1), a key enzyme linking glycolysis to the tricarboxylic acid cycle. We aimed to determine the role and mechanistic action of ME1 in PH. METHODS: Global and endothelial-specific ME1 knockout mice were used to investigate the role of ME1 in hypoxia- and SU5416/hypoxia (SuHx)-induced PH. Small hairpin RNA and ME1 enzymatic inhibitor (ME1*) were used to study the mechanism of ME1 in pulmonary artery endothelial cells. Downstream key metabolic pathways and mediators of ME1 were identified by metabolomics analysis in vivo and ME1-mediated energetic alterations were examined by Seahorse metabolic analysis in vitro. The pharmacological effect of ME1* on PH treatment was evaluated in PH animal models induced by SuHx. RESULTS: We found that ME1 protein level and enzymatic activity were highly elevated in lung tissues of patients and mice with PH, primarily in vascular endothelial cells. Global knockout of ME1 protected mice from developing hypoxia- or SuHx-induced PH. Endothelial-specific ME1 deletion similarly attenuated pulmonary vascular remodeling and PH development in mice, suggesting a critical role of endothelial ME1 in PH. Mechanistic studies revealed that ME1 inhibition promoted downstream adenosine production and activated A2AR-mediated adenosine signaling, which leads to an increase in nitric oxide generation and a decrease in proinflammatory molecule expression in endothelial cells. ME1 inhibition activated adenosine production in an ATP-dependent manner through regulating malate-aspartate NADH (nicotinamide adenine dinucleotide plus hydrogen) shuttle and thereby balancing oxidative phosphorylation and glycolysis. Pharmacological inactivation of ME1 attenuated the progression of PH in both preventive and therapeutic settings by promoting adenosine production in vivo. CONCLUSIONS: Our findings indicate that ME1 upregulation in endothelial cells plays a causative role in PH development by negatively regulating adenosine production and subsequently dysregulating endothelial functions. Our findings also suggest that ME1 may represent as a novel pharmacological target for upregulating protective adenosine signaling in PH therapy.

Enhancing anticancer treatment: Development of cRGD-Conjugated F-OH-Evo prodrugs for targeted delivery.

Small molecule drugs sourced from natural products are pivotal for novel therapeutic discoveries. However, their clinical deployment is often impeded by non-specific activity and severe adverse effects. This study focused on 3-fluoro-10-hydroxy-Evodiamine (F-OH-Evo), a potent derivative of Evodiamine, whose development is curtailed due to suboptimal tumor selectivity and heightened cytotoxicity. By harnessing the remarkable stability, specificity, and αvß3 integrin affinity of c(RGDFK), a novel prodrug by conjugating F-OH-Evo with cRGD was synthesized. This innovative prodrug substantially enhanced the tumor-specific targeting of F-OH-Evo and improved the anti-tumor activities. Among them, compound 3c demonstrated the best selective inhibitory activity toward U87 cancer cells in vitro. It selectively enterd U87 cells by binding to αvß3 integrin, releasing the parent molecule under the dual response of ROS and GSH to exert inhibitory activity on topo I. The results highlight the potential of cRGD-conjugated prodrugs in targeted cancer therapy. This approach signifies a significant advancement in developing safer and more effective chemotherapy drugs, emphasizing the role of prodrug strategies in overcoming the limitations of traditional cancer treatments.

The effectiveness of digital psychosocial interventions on psychological distress, depression, anxiety, and health-related quality of life in patients with gynaecological cancer: a systematic review and meta-analysis.

PURPOSE: Patients with gynaecological cancer often experience psychological issues due to multiple stressors. Psychological disturbances have debilitating effects on patients with gynaecological cancer. In recent decades, digital psychosocial interventions have rapidly advanced and been incorporated into mental health interventions. Digital psychosocial interventions could provide patients with several benefits over traditional in-person interventions, including convenience, anonymity, flexible scheduling, and geographic mobility. The aim of this systematic review was to synthesize the effectiveness of digital psychosocial intervention in reducing psychological distress, depression, and anxiety and improving health-related quality of life in patients with gynaecological cancer. METHODS: Three-step extensive search was performed on 22 December 2022 from nine bibliographic databases, trial registries and grey literature. Experimental studies involving patients with gynaecological cancer utilizing digital psychosocial interventions for the improvement of mental health outcomes were included. Meta-analysis was conducted using RevMan 5.4 software. Heterogeneity was analysed by Cochran's Q test and I2. Subgroup analyses were attempted to evaluate relative effect sizes of subgroup features. RESULTS: Meta-analysis of nine studies revealed small effect size in reduction of depression post-intervention (d = 0.24, 95% CI - 0.46 to - 0.02) and medium effect size in reduction of psychological distress post-intervention (d = 0.51, 95% CI - 0.81 to - 0.21) and follow-up (d = 0.65, 95% CI - 1.25 to - 0.05) compared to the control group. The effects of digital psychosocial interventions on anxiety and health-related quality of life were not statistically significant. CONCLUSIONS: Digital psychosocial interventions probably reduced psychological distress and slightly reduced depression amongst patients with gynaecological cancer compared to the control group, which can be integrated into clinical practice. Additional trials with rigorous methodology and bigger sample sizes are needed to validate findings. TRIAL REGISTRATION: PROSPERO (CRD42023389502).

Abnormal microstructure of corpus callosum in children with primary nocturnal enuresis: a DTI study.

Primary nocturnal enuresis (PNE) is a common childhood disorder with abnormal sleep or arousal. The corpus callosum (CC) continues to develop into adulthood and plays an important role in sleep arousal. This study aimed to evaluate the microstructure of the CC in children with PNE. Diffusion tensor imaging (DTI) indices were extracted throughout the CC and its seven subregions were compared between the children with PNE and healthy children (HC). The correlation between abnormal DTI indices of the CC and cognitive condition was also tested. Compared to HC, decreased fiber number (NF) (F = 8.492, PFDR = 0.032) and fractional anisotropy (FA) value (F = 8.442, PFDR = 0.040) were found in the posterior midbody of the CC, increased RD was found in the posterior midbody (F = 6.888, PFDR = 0.040) and isthmus (F = 7.967, PFDR = 0.040) in children with PNE. The reduction of FA value was more obvious in boys than girls with PNE. In children with PNE, there was a significant positive correlation between the NF of the posterior midbody and full IQ (r = 0.322, P = 0.025) and between the FA value and the general knowledge memory (r = 0.293, P = 0.043). This study provides imaging evidence for abnormalities in the microstructure of the CC in children with PNE, especially in male PNE, which might affect the children's cognitive performance.

Eosinophils protect against pulmonary hypertension through 14-HDHA and 17-HDHA.

BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease featuring pulmonary vessel remodelling and perivascular inflammation. The effect, if any, of eosinophils (EOS) on the development of PH remains unclear. METHODS: EOS infiltration and chemotaxis were investigated in peripheral blood and lung tissues from pulmonary arterial hypertension (PAH) patients without allergic history and from sugen/hypoxia-induced PH mice. The role of EOS deficiency in PH development was investigated using GATA1-deletion (ΔdblGATA) mice and anti-interleukin 5 antibody-treated mice and rats. Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was conducted to identify the critical oxylipin molecule(s) produced by EOS. Culture supernatants and lysates of EOS were collected to explore the mechanisms in co-culture cell experiments. RESULTS: There was a lower percentage of EOS in peripheral blood but higher infiltration in lung tissues from PAH patients and PH mice. PAH/PH lungs showed increased EOS-related chemokine expression, mainly C-C motif chemokine ligand 11 derived from adventitial fibroblasts. EOS deficiency aggravated PH in rodents, accompanied by increased neutrophil and monocyte/macrophage infiltration. EOS highly expressed arachidonate 15-lipoxygenase (ALOX15). 14-hydroxy docosahexaenoic acid (14-HDHA) and 17-HDHA were critical downstream oxylipins produced by EOS, which showed anti-inflammatory effects on recruitment of neutrophils and monocytes/macrophages through N-formyl peptide receptor 2. They also repressed pulmonary artery smooth muscle cell (PASMC) proliferation by activating peroxisome proliferator-activated receptor γ and blunting Stat3 phosphorylation. CONCLUSIONS: In PH development without external stimuli, peripheral blood exhibits a low EOS level. EOS play a protective role by suppressing perivascular inflammation and maintaining PASMC homeostasis via 14/17-HDHA.

Dauricine alleviates cognitive impairment in Alzheimer's disease mice induced by D-galactose and AlCl3 via the Ca2+/CaM pathway.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Dysregulation of intracellular Ca2+ homeostasis plays a critical role in the pathological development of AD. Dauricine (DAU) is a bisbenzylisoquinoline alkaloid isolated from Menispermum dauricum DC., which can prevent the influx of extracellular Ca2+ and inhibit the release of Ca2+ from the endoplasmic reticulum. DAU has a potential for anti-AD. However, it is unclear whether DAU can exert its anti-AD effect in vivo by regulating the Ca2+ related signaling pathways. Here, we investigated the effect and mechanism of DAU on D-galactose and AlCl3 combined-induced AD mice based on the Ca2+/CaM pathway. The results showed that DAU (1 mg/kg and 10 mg/kg for 30 days) treatment attenuated learning and memory deficits and improved the nesting ability of AD mice. The HE staining assay showed that DAU could inhibit the histopathological alterations and attenuate neuronal damage in the hippocampus and cortex of AD mice. Studies on the mechanism indicated that DAU decreased the phosphorylation of CaMKII and Tau and reduced the formation of NFTs in the hippocampus and cortex. DAU treatment also reduced the abnormally high expression of APP, BACE1, and Aß1-42, which inhibited the deposition of Aß plaques. Moreover, DAU could decrease Ca2+ levels and inhibit elevated CaM protein expression in the hippocampus and cortex of AD mice. The molecular docking results showed that DAU may have a high affinity with CaM or BACE1. DAU has a beneficial impact on pathological changes in AD mice induced by D-galactose and AlCl3 and may act by negative regulation of the Ca2+/CaM pathway and its downstream molecules such as CaMKII and BACE1.

Hsa_circ_0080608 Attenuates Lung Cancer Progression by Functioning as a Competitive Endogenous RNA to Regulate the miR-661/ADRA1A Pathway.

Circular RNAs (circRNAs) participate in the progression of human cancers and have been broadly elucidated. Here, we aimed to elucidate the roles and functional mechanisms of hsa_circ_0080608 (circ_0080608) in lung cancer. Quantitative real-time PCR (qPCR) was performed to assess the mRNA expression levels of circ_0080608, miR-661, and adrenoceptor alpha 1A (ADRA1A). Western blotting was performed to measure ADRA1A protein levels. CCK-8, colony formation, and Transwell assays were performed to determine the effect of circ_0080608 on cell proliferation and migration. Animal models were used to assess how circ_0080608 influences tumor progression in vivo. The binding relationships of miR-661's with circ_0080608 and ADRA1A was confirmed using dual-luciferase reporter and RIP assays. Circ_0080608 exhibited relatively low expression in lung cancer samples and cells. Lung cancer cells overexpressing circ_0080608 exhibited reduced migratory and proliferative abilities. Additionally, circ_0080608 binds to miR-661 and operates as a competing endogenous RNA (ceRNA) and shares a miR-661 binding site with the 3' UTR of ADRA1A. Furthermore, circ_0080608 inversely regulates miR-661 expression, consequently restraining the aggressive behavior of lung cancer cells. Lung cancer cells overexpressing ADRA1A also exhibit repressed migratory and proliferative abilities. However, reintroduction of miR-661 led to a decline in ADRA1A expression, thereby attenuating the functional effects of ADRA1A. Circ_0080608 impedes lung cancer progression by regulating the miR-661/ADRA1A pathway. Our findings provide new insights into the progression of lung cancer.

A lightweight hierarchical convolution network for brain tumor segmentation.

BACKGROUND: Brain tumor segmentation plays a significant role in clinical treatment and surgical planning. Recently, several deep convolutional networks have been proposed for brain tumor segmentation and have achieved impressive performance. However, most state-of-the-art models use 3D convolution networks, which require high computational costs. This makes it difficult to apply these models to medical equipment in the future. Additionally, due to the large diversity of the brain tumor and uncertain boundaries between sub-regions, some models cannot well-segment multiple tumors in the brain at the same time. RESULTS: In this paper, we proposed a lightweight hierarchical convolution network, called LHC-Net. Our network uses a multi-scale strategy which the common 3D convolution is replaced by the hierarchical convolution with residual-like connections. It improves the ability of multi-scale feature extraction and greatly reduces parameters and computation resources. On the BraTS2020 dataset, LHC-Net achieves the Dice scores of 76.38%, 90.01% and 83.32% for ET, WT and TC, respectively, which is better than that of 3D U-Net with 73.50%, 89.42% and 81.92%. Especially on the multi-tumor set, our model shows significant performance improvement. In addition, LHC-Net has 1.65M parameters and 35.58G FLOPs, which is two times fewer parameters and three times less computation compared with 3D U-Net. CONCLUSION: Our proposed method achieves automatic segmentation of tumor sub-regions from four-modal brain MRI images. LHC-Net achieves competitive segmentation performance with fewer parameters and less computation than the state-of-the-art models. It means that our model can be applied under limited medical computing resources. By using the multi-scale strategy on channels, LHC-Net can well-segment multiple tumors in the patient's brain. It has great potential for application to other multi-scale segmentation tasks.

Epidemiological study of HPV infection in 40,693 women in Putian: a population study based on screening for high-risk HPV infection.

BACKGROUND: The infection rate of human papillomavirus (HPV) is high in the coastal regions of China. However, the infection rate among high-risk genotypes of women in Putian City is unknown. Therefore, this study aimed to analyse the epidemiology of high-risk HPV infection among women in Putian and provide a reference for the diagnosis, treatment and vaccination of cervical cancer in this region. METHODS: The data used were obtained from the Chinese government's public health program ("Cervical and Breast Cancer Screening Project"). A total of 40,693 female cervical cell exfoliation samples screened for high-risk HPV at the Affiliated Hospital of Putian University from July 2020 to December 2021 were enrolled. DNA was extracted using a fully automatic extractor. Then, 14 high-risk genotypes of HPV were detected by polymerase chain reaction. The characteristics of HPV infection, distribution of high-risk genotypes, infection types and thinprep cytologic test (TCT) classification at different age groups were analysed. RESULTS: Among the 40,693 samples, 3899 were infected with HPV, with an infection rate of 9.6%. Accordingly, HPV infection rates gradually increased with age, and statistically significant differences were observed among age groups (χ2 = 74.03, P < 0.01). The infection rates of high-risk HPV52, HPV58 and HPV16 were in the top three and increased with age. Single infection was dominant (84.7%), followed by double infections (12.7%). The cervical cytology of 3899 HPV-positive people can be classified into negative for intraepithelial lesion and malignancy (NILM, 88.0%), atypical squamous cells of undetermined significance (ASC-US, 6.6%), atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion (ASC-H, 1.4%), low-grade squamous intraepithelial lesion (LSIL, 3.2%) and high-grade squamous intraepithelial lesion (HSIL, 0.8%). HPV16 infection rate increased with increasing severity of cervical cytology (χ2trend = 43.64, P < 0.01), whereas the infection rates of HPV52 (χ2trend = 13.89, P < 0.01) and HPV58 (χ2trend = 13.50, P < 0.01) showed opposite trends. CONCLUSION: The infection rate of female HPV high-risk screening in this region was 9.6% and mainly involved single infections. In addition, HPV16, HPV52 and HPV58 were closely related to the severity of cervical cytology. Effective screening, vaccination and education are needed. The 9-valent vaccine will be effective in reducing cervical pre-invasive disease. It would also be reasonable to state that the rising trend in HPV infection and high grade cytology with age emphasises the need to target older women with screening. Vaccination of younger women (aged ≤ 25) will lay the foundation for better cancer outcomes in the future.

Fluorescent silicon nanoparticle-based quantitative hemin assay.

Hemin with functions such as oxygen carrying, oxygen storing, promoting redox, and performing electron transfer is important for the health of organisms. In this paper, green synthetic silicon nanoparticles (Si-NPs) were synthesized and used for free hemin detection in serum (a low limit of detection (LOD), 29.5 nM). The quenching mechanism was investigated by UV-vis absorption spectra, time-resolved luminescence decay curve, and circular dichroism (CD) spectra. It was confirmed that multiple redox centers of hemin led to intensified effective collision and increased the electron transfer rate, therefore enhancing the dynamic quenching, and it was undeniable that the inner filter effect (IFE) also played a role in the quenching.