Dual Pigment Epithelium-derived Factor and Hepatocyte Growth Factor Overexpression: A New Therapy for Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease characterized by advanced pulmonary vasculature remodeling that is thought to be curable only through lung transplantation. The application of angiogenic hepatocyte growth factor (HGF) is reported to be protective in PH through its anti-vascular remodeling effect, but excessive HGF-mediated immature neovascularization is not conducive to the restoration of pulmonary perfusion because of apparent vascular leakage. As a canonical antiangiogenic molecule, pigment epithelium-derived factor (PEDF) inhibits angiogenesis and reduces vascular permeability in a variety of diseases. However, the effect of PEDF on HGF-based PH treatment remains to be determined. In this study, monocrotaline-induced PH rats and endothelial cells isolated from rat and human PH lung tissues were used. We assessed PH progression, right cardiac function, and pulmonary perfusion in HGF- and/or PEDF-treated rats with PH. Additionally, the receptor and mechanism responsible for the role of PEDF in HGF-based PH therapy were investigated. In this study, we found that HGF and PEDF jointly prevent PH development and improve right cardiac function in rats with PH. Moreover, PEDF delivery increases the pulmonary perfusion in PH lungs and inhibits immature angiogenesis and vascular endothelial (VE)-cadherin junction disintegration induced by HGF without affecting the therapeutic inhibition of pulmonary vascular remodeling by HGF. Mechanistically, PEDF targets VE growth factor receptor 2 and suppresses its phosphorylation at Y951 and Y1175 but not Y1214. Finally, VE growth factor receptor 2/VE protein tyrosine phosphatase/VE-cadherin complex formation and Akt and Erk1/2 inactivation were observed in rat and human PH lung endothelial cells. Collectively, our data indicate that PEDF additively enhances the efficacy of HGF against PH, which may provide new insights into treatment strategies for clinical PH.

Neuronal activity-related transcription is blunted in immature compared to mature dentate granule cells.

Immature dentate granule cells (DGCs) generated in the hippocampus during adulthood are believed to play a unique role in dentate gyrus (DG) function. Although immature DGCs have hyperexcitable membrane properties in vitro, the consequences of this hyperexcitability in vivo remain unclear. In particular, the relationship between experiences that activate the DG, such as exploration of a novel environment (NE), and downstream molecular processes that modify DG circuitry in response to cellular activation is unknown in this cell population. We first performed quantification of immediate early gene (IEG) proteins in immature (5-week-old) and mature (13-week-old) DGCs from mice exposed to a NE. Paradoxically, we observed lower IEG protein expression in hyperexcitable immature DGCs. We then isolated nuclei from active and inactive immature DGCs and performed single-nuclei RNA-Sequencing. Compared to mature nuclei collected from the same animal, immature DGC nuclei showed less activity-induced transcriptional change, even though they were classified as active based on expression of ARC protein. These results demonstrate that the coupling of spatial exploration, cellular activation, and transcriptional change differs between immature and mature DGCs, with blunted activity-induced changes in immature cells.

Identification of bona fide B2 SINE retrotransposon transcription through single-nucleus RNA-seq of the mouse hippocampus.

Currently, researchers rely on generalized methods to quantify transposable element (TE) RNA expression, such as RT-qPCR and RNA-seq, that do not distinguish between TEs expressed from their own promoter (bona fide) and TEs that are transcribed from a neighboring gene promoter such as within an intron or exon. This distinction is important owing to the differing functional roles of TEs depending on whether they are independently transcribed. Here we report a simple strategy to examine bona fide TE expression, termed BonaFide-TEseq. This approach can be used with any template-switch based library such as Smart-seq2 or the single-cell 5' gene expression kit from 10x, extending its utility to single-cell RNA-sequencing. This approach does not require TE-specific enrichment, enabling the simultaneous examination of TEs and protein-coding genes. We show that TEs identified through BonaFide-TEseq are expressed from their own promoter, rather than captured as internal products of genes. We reveal the utility of BonaFide-TEseq in the analysis of single-cell data and show that short-interspersed nuclear elements (SINEs) show cell type-specific expression profiles in the mouse hippocampus. We further show that, in response to a brief exposure of home-cage mice to a novel stimulus, SINEs are activated in dentate granule neurons in a time course that is similar to that of protein-coding immediate early genes. This work provides a simple alternative approach to assess bona fide TE transcription at single-cell resolution and provides a proof-of-concept using this method to identify SINE activation in a context that is relevant for normal learning and memory.

Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism.

Myocardial infarction (MI) causes disturbances in myocardial energy metabolism, ultimately leading to a poor prognosis. Cytosolic glycogen autophagy (glycophagy) and mitochondrial autophagy (mitophagy) are upregulated in MI to optimize energy metabolism but to a limited extent. Asiatic acid (AA), a pentacyclic triterpene derived from the traditional Chinese herb Centella asiatica, displays anti-inflammatory, antioxidant, and antiapoptotic activities. AA has been found to alleviate focal cerebral and liver ischemic injury by reversing mitochondrial dysfunction. In this study, we investigated whether AA exerted cardioprotective effects against MI by activating glycophagy and mitophagy to improve the energy balance. In vitro cardioprotective effects were examined in neonatal mouse cardiomyocytes subjected to oxygen-glucose deprivation for 12 h. Treatment with AA (2-50 µM) significantly increased cell viability and improved the energy metabolism evidenced by increased ATP level and phosphocreatine/ATP ratio. In vivo cardioprotective effects were studied in a mouse model of MI. Administration of AA (5-125 mg·kg-1·d-1, ig) significantly reduced infarct size and ischemic myocardial injury, and improved cardiac function. AA treatment also promoted mitophagy and relieved mitochondrial edema evidenced by increased number of mitophagosomes in ischemic myocardium in vivo and increased mitochondria-light chain 3 (LC3)-II colocalization in ODG-treated cardiomyocytes in vitro. Mitophagy activation was accompanied by activation of the AMPK signaling pathway. Knockdown of AMPK abolished AA-activated mitophagy. Furthermore, we showed that glycophagy was upregulated in OGD cardiomyocytes evidenced by increased starch binding domain protein 1 (STBD1)-GABA type A receptor-associated protein-like 1(GABARAPL1) interaction and extracellular acidification rate, whereas AA treatment further promoted glycophagy accompanied by PI3K/Akt activation. PI3K inhibitor LY294002 or Akt inhibitor GSK690693 blocked the effects of AA on glycophagy and glycolysis. Finally, simultaneous inhibition of glycophagy and mitophagy abolished the cardioprotective effects and energy regulation of AA. These results demonstrate that AA protects ischemic cardiomyocytes by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/Akt and AMPK pathways.

NGF nanoparticles enhance the potency of transplanted human umbilical cord mesenchymal stem cells for myocardial repair.

In this study, we investigated whether human umbilical cord mesenchymal stem cell (hUCMSC) fibrin patches loaded with nerve growth factor (NGF) poly(lactic-co-glycolic acid) (PLGA) nanoparticles could enhance the therapeutic potency of hUCMSCs for myocardial infarction (MI). In vitro, NGF significantly improved the proliferation of hUCMSCs and mitigated cytotoxicity and apoptosis under hypoxic injury. NGF also promoted the paracrine effects of hUCMSCs on angiogenesis and cardiomyocyte protection. The tyrosine kinase A (TrkA) and phosphoinositide 3-kinase (PI3K)-serine/threonine protein kinase (Akt) signaling pathways in hUCMSCs were involved in the NGF-induced protection. NGF PLGA nanoparticles continued to release NGF for at least 1 mo and also exerted a protective effect on hUCMSCs, the same with free NGF. In vivo, we treated MI mice with nothing (MI group), a cell-free fibrin patch with blank PLGA nanoparticles (MI + OP group), a cell-free fibrin patch with NGF nanoparticles (MI + NGF group), and hUCMSC fibrin patches with blank PLGA nanoparticles (MI + MSC group) or NGF PLGA nanoparticles (MSC + NGF group). Among these groups, the MSC + NGF group exhibited the best cardiac contractile function, the smallest infarct size, and the thickest ventricular wall. The application of NGF PLGA nanoparticles significantly improved the retention of transplanted hUCMSCs and enhanced their ability to reduce myocardial apoptosis and promote angiogenesis in the mouse heart after MI. These findings demonstrate the promising therapeutic potential of hUCMSC fibrin cardiac patches loaded with NGF PLGA nanoparticles.NEW & NOTEWORTHY NGF PLGA nanoparticles can exert a protective effect on hUCMSCs and promote the paracrine effects of hUCMSCs on angiogenesis and cardiomyocyte protection through TrkA-PI3K/Akt signaling pathway, the same with free NGF. The application of NGF PLGA nanoparticles in the hUCMSC fibrin cardiac patches can significantly improve the retention of transplanted hUCMSCs and enhance their ability to reduce myocardial apoptosis and promote angiogenesis in the mouse heart after MI.

Transcriptional responses to water stress and recovery in a drought-tolerant fescue wild grass (Festuca ovina; Poaceae).

Water stress associated with drought-like conditions is a major factor limiting plant growth and impacts productivity of natural plant communities and agricultural crops. Molecular responses of plants to water stress have been studied most extensively in model species and crops, few of which have evolved natural drought tolerance. In the current study, we examined physiological and transcriptomic responses at multiple timepoints during increasing water stress and following initial recovery from stress in a drought-tolerant C3 species, Festuca ovina. Results demonstrated non-linear transcriptomic changes during increasing stress, but largely linear declines in physiological measurements during this same period. Transcription factors represented approximately 12.7% of all differentially expressed genes. In total, 117 F. ovina homologs of previously identified and molecularly characterized drought-responsive plant genes were identified. This information will be valuable for further investigations of the molecular mechanisms involved in drought tolerance in C3 plants.

Lineage-based functional types: characterising functional diversity to enhance the representation of ecological behaviour in Land Surface Models.

Process-based vegetation models attempt to represent the wide range of trait variation in biomes by grouping ecologically similar species into plant functional types (PFTs). This approach has been successful in representing many aspects of plant physiology and biophysics but struggles to capture biogeographic history and ecological dynamics that determine biome boundaries and plant distributions. Grass-dominated ecosystems are broadly distributed across all vegetated continents and harbour large functional diversity, yet most Land Surface Models (LSMs) summarise grasses into two generic PFTs based primarily on differences between temperate C3 grasses and (sub)tropical C4 grasses. Incorporation of species-level trait variation is an active area of research to enhance the ecological realism of PFTs, which form the basis for vegetation processes and dynamics in LSMs. Using reported measurements, we developed grass functional trait values (physiological, structural, biochemical, anatomical, phenological, and disturbance-related) of dominant lineages to improve LSM representations. Our method is fundamentally different from previous efforts, as it uses phylogenetic relatedness to create lineage-based functional types (LFTs), situated between species-level trait data and PFT-level abstractions, thus providing a realistic representation of functional diversity and opening the door to the development of new vegetation models.

Inability to capture with increasing current strength: Is this near-field or far-field?

We present a case of wide-complex tachycardia in which the clinical electrophysiological diagnosis was considered to be bundle branch re-entry ventricular tachycardia. A series of ventricular entrainment attempts were performed from the left and right ventricular septum to confirm the diagnosis. Entrainment pacing with a general current output (10 mA) was performed from the right ventricular septum with manifest fusion and a post-pacing interval similar to tachycardia cycle length. Thereafter, another entrainment attempt with a greater current output (20 mA) was performed from the same site. Paradoxically, concealed fusion was demonstrated by selective RB capture only, though there was no clear "RB" potential seen. In this case, we attempt to explain and illustrate the mechanism of paradoxical near-field inability to capture with increasing current strength.

Phylogenetic trends and environmental correlates of nuclear genome size variation in Helianthus sunflowers.

Flowering plants serve as a powerful model for studying the evolution of nuclear genome size (GS) given the tremendous GS variation that exists both within and across angiosperm lineages. Helianthus sunflowers consist of c. 50 species native to North America that occupy diverse habitats and vary in ploidy level. In the current study, we generated a comprehensive GS database for 49 Helianthus species using flow cytometric approaches. We examined variability across the genus and present a comparative phylogenetic analysis of GS evolution in diploid Helianthus species. Results demonstrated that different clades of diploid Helianthus species showed evolutionary patterns of GS contraction, expansion and relative stasis, with annual diploid species evolving smaller GS with the highest rate of evolution. Phylogenetic comparative analyses of diploids revealed significant negative associations of GS with temperature seasonality and cell production rate, indicating that the evolution of larger GS in Helianthus diploids may be more permissible in habitats with longer growing seasons where selection for more rapid growth may be relaxed. The Helianthus GS database presented here and corresponding analyses of environmental and phenotypic correlates will facilitate ongoing and future research on the ultimate drivers of GS evolution in this well-studied North American plant genus.

PKCα replaces AMPK to regulate mitophagy: Another PEDF role on ischaemic cardioprotection.

Both decreased autophagy positive regulator AMP activated protein kinase (AMPK) level and promoted mitophagy are observed in oxygen-glucose deprivation (OGD) cardiomyocytes treated with pigment epithelium-derived factor (PEDF). This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Our previous study reveals that PEDF increases the protein kinase Cα (PKCα) and phospho-PKCα (p-PKCα) contents to promote mitophagy. Thus, we investigated the association between PKCα and mitophagy. Here we identify an interaction between PKCα and Unc-51-like kinase 1 (ULK1), essential component of mitophagy. Further analyses show this is a direct interaction within a domain of ULK1 that termed the serine/threonine-rich domain (S/T domain). Notably, a deletion mutant ULK1 that lacks the binding domain is defective in mediating PEDF-induced mitophagy. Furthermore, we demonstrate that ULK1 is phosphorylated at Ser317/555/777 and Raptor is also phosphorylated by phospho-PKCα. Phospho-ULK1 (p-ULK1) at these sites are all essential for PEDF-induced mitophagy and reduce the release of mitochondrial ROS and DNA. This study therefore identifies a previously uncharacterized interaction between the ULK1 and PKCα that can replace the AMPK-dependent mitophagy processes.

Genomic abundance and transcriptional activity of diverse gypsy and copia long terminal repeat retrotransposons in three wild sunflower species.

BACKGROUND: Long terminal repeat (LTR) retrotransposons are highly abundant in plant genomes and require transcriptional activity for their proliferative mode of replication. These sequences exist in plant genomes as diverse sublineages within the main element superfamilies (i.e., gypsy and copia). While transcriptional activity of these elements is increasingly recognized as a regular attribute of plant transcriptomes, it is currently unknown the extent to which different sublineages of these elements are transcriptionally active both within and across species. In the current report, we utilize next generation sequencing methods to examine genomic copy number abundance of diverse LTR retrotransposon sublineages and their corresponding levels of transcriptional activity in three diploid wild sunflower species, Helianthus agrestis, H. carnosus and H. porteri. RESULTS: The diploid sunflower species under investigation differ in genome size 2.75-fold, with 2C values of 22.93 for H. agrestis, 12.31 for H. carnosus and 8.33 for H. porteri. The same diverse gypsy and copia sublineages of LTR retrotransposons were identified across species, but with gypsy sequences consistently more abundant than copia and with global gypsy sequence abundance positively correlated with nuclear genome size. Transcriptional activity was detected for multiple copia and gypsy sequences, with significantly higher activity levels detected for copia versus gypsy. Interestingly, of 11 elements identified as transcriptionally active, 5 exhibited detectable expression in all three species and 3 exhibited detectable expression in two species. CONCLUSIONS: Combined analyses of LTR retrotransposon genomic abundance and transcriptional activity across three sunflower species provides novel insights into genome size evolution and transposable element dynamics in this group. Despite considerable variation in nuclear genome size among species, relatively conserved patterns of LTR retrotransposon transcriptional activity were observed, with a highly overlapping set of copia and gypsy sequences observed to be transcriptionally active across species. A higher proportion of copia versus gypsy elements were found to be transcriptionally active and these sequences also were expressed at higher levels.

A novel modified physiologically relevant model for cardiac angiogenesis.

Angiogenesis assays are important tools for studying both the mechanisms of cardiac angiogenesis and the potential development of therapeutic strategies to ischemic heart diseases. Currently, various assays have been used to quantitate cardiac tubule formation, yet no consensus has been reached regarding a suitable assay for evaluating the efficacy of angiogenic stimulants or inhibitors. Most in vivo angiogenesis assays are complex and difficult to interpret, whereas traditional in vitro angiogenesis models measure only one aspect of this process. To bridge the gap between in vivo and in vitro angiogenesis assays, here, we have developed a novel modified cardiac explants matrigel assay. We observed the morphology of vascular sprouts formed in three forms of cardiac angiogenesis assays then used quantitative image analyses to further compare the morphological features of vascular sprouts formed in two cardiac explants angiogenesis assays. Vascular sprouts formed in the fibronectin group were less and short, whereas those formed in the matrigel group were significantly longer, consisting of more area and branch points. Moreover, we found the benefits of this matrigel model by observing the ability of cardiac explants to form vascular sprouts under normoxia or hypoxia condition in the presence of angiogenic stimulant and inhibitor, VEGF and PEDF. In summary, the above analyses revealed that the morphology of vascular sprouts formed in this model appears more representative of myocardial capillary formation in vivo, and this accessible, reliable angiogenic assay is a more physiologically relevant assay which allows further assessment of pharmacologic compounds on cardiac angiogenesis.

Monitoring Apoptosis of Breast Cancer Xenograft After Paclitaxel Treatment With 99mTc-Labeled Duramycin SPECT/CT.

Our goal was to validate the feasibility of(99m)Tc-duramycin as a potential apoptosis probe for monitoring tumor response to paclitaxel in breast cancer xenografts. The binding of(99m)Tc-duramycin to phosphatidylethanolamine was validated in vitro using paclitaxel-treated human breast carcinoma MDA-MB-231 cells. Female BALB/c mice (n = 5) bearing breast cancer xenografts were randomized into 2 groups and intraperitoneally injected with 40 mg/kg paclitaxel or phosphate-buffered saline.(99m)Tc-duramycin (37-55.5 MBq) was injected at 72 hours posttreatment, and single-photon emission computed tomography/computed tomography was performed at 2 hours postinjection. Apoptotic cells and activated caspase 3 in explanted tumor tissue were measured by flow cytometry. Cellular ultrastructural changes were assessed by light and transmission electron microscopy.(99m)Tc-duramycin with radiochemical purity of >90% exhibited rapid blood clearance and predominantly renal clearance. The tumor-to-muscle ratio in the paclitaxel-treated group (5.29 ± 0.62) was significantly higher than that in the control. Tumor volume was decreased dramatically, whereas tumor uptake of(99m)Tc-duramycin (ex vivo) significantly increased following paclitaxel treatment, which was consistent with apoptotic index, histological findings, and ultrastructural changes. Our data demonstrated the feasibility of(99m)Tc-duramycin for early detection of apoptosis after paclitaxel chemotherapy in breast carcinoma xenografts.

Phylogeography of the inshore fish, Bostrychus sinensis, along the Pacific coastline of China.

This study assesses the phylogeography of the Chinese four-eyed sleeper (Bostrychus sinensis) with one mitochondrial and one nuclear genes and two morphological characters. Phylogenetic and population genetic analyses of the sequences reveals two phylogeographic lineages from the East and South China Seas, which are corroborated by the morphological data. The vicariance of the two lineages is attributed to the Pleistocene Ice Age exposure of the Taiwan Strait and consequent connection of Taiwan to the mainland, which thereby introduced an ecological barrier to gene flow between populations in the East and South China Seas. The distributions of the two lineages now overlap in the East China Sea and this secondary contact is attributed to biased northward migration along the two main currents of the Taiwan Strait following its interglacial re-flooding. In conclusion, this study reinforces the importance of "vicariance, then secondary contact" due to Late Pliocene and Pleistocene sea-level changes to the phylogeography of marine species. Specifically, it corroborates the importance of Pleistocene sea-level changes in the Taiwan Strait to the phylogeography of Chinese inshore species.

PEDF Inhibits the Activation of NLRP3 Inflammasome in Hypoxia Cardiomyocytes through PEDF Receptor/Phospholipase A2.

The nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome has been linked to sterile inflammation, which is involved in ischemic injury in myocardial cells. Pigment epithelium-derived factor (PEDF) is a multifunctional secreted glycoprotein with many biological activities, such as anti-inflammatory, antioxidant and anti-angiogenic properties. However, it is not known whether and how PEDF acts to regulate the activation of the NLRP3 inflammasome in cardiomyocytes. In the present study, we used the neonatal cardiomyocytes models of ischemia-like conditions to evaluate the mitochondrial fission and the activation of the NLRP3 inflammasome. We also determined the mechanism by which PEDF inhibits hypoxia-induced activation of the NLRP3 inflammasome. We found that PEDF decreased the activation of the NLRP3 inflammasome in neonatal cardiomyocytes through pigment epithelial-derived factor receptor/calcium-independent phospholipase A2 (PEDFR/iPLA2). Meanwhile, PEDF reduced Drp1-induced mitochondrial fission and mitochondrial fission-induced mitochondrial DNA (mtDNA), as well as mitochondrial reactive oxygen species (mtROS) release into cytosol through PEDFR/iPLA2. We also found that PEDF inhibited mitochondrial fission-induced NLRP3 inflammasome activation. Furthermore, previous research has found that endogenous cytosolic mtDNA and mtROS can serve as activators of NLRP3 inflammasome activity. Therefore, we hypothesized that PEDF can protect against hypoxia-induced activation of the NLRP3 inflammasome by inhibiting mitochondrial fission though PEDFR/iPLA2.

Urokinase-type plasminogen activator receptor regulates apoptotic sensitivity of colon cancer HCT116 cell line to TRAIL via JNK-p53 pathway.

The urokinase-type plasminogen activator receptor (uPAR) serves not only as an anchor for urokinase-type plasminogen activator but also participates in intracellular signal transduction events. In this study, we investigated whether uPAR could modulate TRAIL-induced apoptosis in human colon cancer cells HCT116. Using an antisense strategy, we established a stable HCT116 cell line with down-regulated uPAR. The sensitivity to TRAIL-induced apoptosis was evaluated by FACS analysis. Our results show that the inhibition of uPAR could sensitize HCT116 to TRAIL-induced apoptosis. uPAR inhibition changed the expression of mitochondrial apoptotic pathway proteins, including Bcl-2, Bax, Bid and p53, in a pro-apoptotic manner. We also found that the inhibition of uPAR down-regulated the phosphorylation of FAK, ERK and JNK. The inhibition of p53 by RNA interference rescued cells from enhanced apoptosis, thus indicating that p53 is critical for enhancing TRAIL-induced apoptosis. Furthermore, JNK, but not ERK, inhibition involved in the up-regulation of p53. JNK negatively regulated p53 protein level. Overall, our results show that uPAR inhibition can sensitize colon cancer cells HCT116 to TRAIL-induced apoptosis via active p53 and mitochondrial apoptotic pathways that JNK inhibition is involved.

Scombroid fishes provide novel insights into the trait/rate associations of molecular evolution.

The study of which life history traits primarily affect molecular evolutionary rates is often confounded by the covariance of these traits. Scombroid fishes (billfishes, tunas, barracudas, and their relatives) are unusual in that their mass-specific metabolic rate is positively associated with body size. This study exploits this atypical pattern of trait variation, which allows for direct tests of whether mass-specific metabolic rate or body size is the more important factor of molecular evolutionary rates. We inferred a phylogeny for scombroids from a supermatrix of molecular and morphological characters and used new phylogenetic comparative approaches to assess the associations of body size and mass-specific metabolic rate with substitution rate. As predicted by the body size hypothesis, there is a negative correlation between body size and substitution rate. However, unexpectedly, we also find a negative association between mass-specific metabolic and substitution rates. These relationships are supported by analyses of the total molecular data, separate mitochondrial and nuclear genes, and individual loci, and they are robust to phylogenetic uncertainty. The molecular evolutionary rates of scombroids are primarily tied to body size. This study demonstrates that groups with novel patterns of trait variation can be particularly informative for identifying which life history traits are the primary factors of molecular evolutionary rates.

Comparison of analgesic effects of percutaneous and transthoracic intercostal nerve block in video-assisted thoracic surgery: a propensity score-matched study.

BACKGROUND: This study aimed to compare the analgesic efficacy of transthoracic intercostal nerve block (TINB) and percutaneous intercostal nerve block (PINB) for video-assisted thoracic surgery (VATS) using a retrospective analysis. METHODS: A total of 336 patients who underwent VATS between January 2021 and June 2022 were reviewed retrospectively. Of the participants, 194 received TINB and were assigned to the T group, while 142 patients received PINB and were assigned to the P group. Both groups received 25 ml of ropivacaine via TINB or PINB at the end of the surgery. The study measured opioid consumption, pain scores, analgesic satisfaction, and safety. Propensity score matching (PSM) analysis was performed to minimize selection bias due to nonrandom assignment. RESULTS: After propensity score matching, 86 patients from each group were selected for analysis. The P group had significantly lower cumulative opioid consumption than the T group (p < 0.01). The Visual Analogue Scale (VAS) scores were lower for the P group than the T group at 6 and 12 h post-surgery (p < 0.01); however, there was no significant difference in the scores between the two groups at 3, 24, and 48 h (p > 0.05). The analgesic satisfaction in the P group was higher than in the T group (p < 0.05). The incidence of back pain, nausea or vomiting, pruritus, dizziness, and skin numbness between the two groups was statistically insignificant (p > 0.05). CONCLUSION: The study suggests that PINB provides superior analgesia for patients undergoing thoracic surgery compared to TINB without any extra adverse effects.

Overexpressed pigment epithelium-derived factor alleviates pulmonary hypertension in two rat models induced by monocrotaline and SU5416/hypoxia.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by vascular remodeling and is associated with endothelial-to-mesenchymal transition (EndoMT). The pigment epithelium-derived factor (PEDF), a secretory protein widely distributed in multiple organs, has been shown to demonstrate anti-EndoMT activity in cardiovascular diseases. In the present study, the role of PEDF in PH was investigated. METHODS: For PEDF overexpression, Sprague Dawley rats were infected with an adeno-associated virus through injection via the internal jugular vein. To establish PH models, the animals were subjected to monocrotaline or Sugen/hypoxia. Four weeks later, pulmonary artery angiography was performed, and hemodynamic parameters, right ventricular function, and vascular remodeling were evaluated. EndoMT and cell proliferation in the pulmonary arteries were assessed via immunofluorescence staining. Moreover, pulmonary artery endothelial cells (PAECs) isolated from experimental PH rats were cultured to investigate the underlying molecular mechanisms involved. RESULTS: PEDF expression was significantly downregulated in PAECs from PH patients and PH model rats. Overexpressed PEDF alleviated the development of PH by improving pulmonary artery morphology and perfusion, reducing pulmonary artery pressure, improving right ventricular function, and alleviating vascular remodeling. PEDF inhibits EndoMT and reduces excessive PAEC proliferation. Moreover, PEDF overexpression reduced EndoMT in cultured PAECs by competitively inhibiting the binding of wnt to LRP6 and downregulating phosphorylation at the 1490 site of LRP6. CONCLUSIONS: Our findings suggest that PEDF may be a potential therapeutic target for PH. We also found that PEDF can inhibit EndoMT in PAECs and may exert these effects by inhibiting the Wnt/LRP6/ß-catenin pathway.

Combination of Losartan and Platinum Nanoparticles with Photothermal Therapy Induces Immunogenic Cell Death Effective Against Neuroblastoma.

Introduction: Photothermal therapy (PTT) is a promising therapeutic procedure with minimal side effects, which can not only kill tumor directly but also cause immunogenic cell death (ICD). However, most solid tumors, including neuroblastoma, are abundant in fibroblasts, which limit the penetration and delivery of nanoparticles. Losartan is an antihypertensive drug approved by the FDA, and it has been proved to have the effect of breaking down excessive ECM network. Methods: In this study, we investigated the application and potential mechanism of the combination of mesoporous platinum nanoparticles (MPNs) and losartan in the PTT of neuroblastoma by establishing neuroblastoma models in vitro and in vivo. Results: Compared to the MPNs group without 808 nm laser irradiation, Neuro-2a cells pretreated with PTT and losartan showed lower survival rates, increased surface calreticulin, and higher release of HMGB1 and ATP. The group also exhibited the highest anti-tumor efficacy in vivo, with a tumor suppression ratio of approximately 80%. Meanwhile, we found that CD3+ T cells, CD4+ T cells and CD8+ T cells from the peripheral blood of experimental group mice were significantly higher than control groups, and CD8+PD-1+ cells were significantly lower than those in MPNs + Los group and Los + laser group. And the expression of PD-1 and α-SMA in Neuro-2a tumors tissue was reduced. Furthermore, losartan could reduce damage of liver function caused by MPNs and laser treatment. Conclusion: This study demonstrated that losartan-induced fibroblasts ablation increased the penetration of MPNs into tumors. Enhanced penetration allowed PTT to kill more tumor cells and synergistically activate immune cells, leading to ICD, indicating the great promise of the strategy for treating neuroblastoma in vivo.