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

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

CircRNA_0008668 Sponges miR-1301-3p to Promote the Inflammatory Response in Allergic Rhinitis by Upregulating GATA6 Expression.

AIMS: We aim to explore GATA6 modulation in allergic rhinitis (AR). BACKGROUND: Circular RNAs (circRNAs) and microRNAs (miRNAs) are involved in inflammatory responses; GATA6 is also known to regulate multiple inflammatory pathways. However, the mechanism of regulation of AR between them is unclear. OBJECTIVE: We expect that this study will provide new treatment options for AR from a GATA6 perspective. METHODS: In vitro, AR models were employed to examine the efficacy of our study, where we utilized monoclonal anti-2,4,6-dinitrophenyl immunoglobulin (Ig) E/human serum albumin (DNP-IgE/HSA) to induce rat basophilic leukemia cells (RBL-2H3 cells). Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed to measure the expression of circ_0008668, miR-1301-3p, GATA6, and cellular inflammatory markers. Enzyme-linked immunosorbent assay (ELISA) was used to measure concentrations of beta-hexosaminidase, histamine, and cellular inflammatory factors including TNF-α, IL-1ß, IL-4, and IL-5. In addition, western blot, RNA pull-down, and luciferase assays were performed to validate the molecular mechanism by which circ_ 0008668 and miR-1301-3p interactions promote GATA6 to ameliorate the inflammatory state of RBL-2H3 cells. RESULTS: In the in vitro model of AR, the expression levels of circ_0008668 and GATA6 were elevated, whereas that of miR-1301-3p was decreased. Pull-down assays confirmed that circ_0008668 efficiently binds miR-1301-3p and its overexpression leads to upregulation of the levels of GATA6, cellular inflammatory factors (IL-4, IL-5, TNF-α, and IL-1ß), and markers associated with inflammatory signaling pathways (NLRP3, ERK1/2, and P65 protein phosphorylation). In addition, miR-inhibitor with circRNA enhanced GATA6 and NLPR3 expression and activated inflammatory pathway activity. In particular, miR-mimic was effective in reversing the onset of this inflammatory state. CONCLUSION: Our results indicate that circ_0008668 promotes the inflammatory state of mast cells by sponging miR-1301-3p to target GATA6, which in turn affects the allergic response to AR. This process could improve the current diagnosis of AR patients and clinical treatment.

T cell-redirecting antibody for treatment of solid tumors via targeting mesothelin.

T cell engaging bispecific antibodies (TCBs) have recently become significant in cancer treatment. In this study we developed MSLN490, a novel TCB designed to target mesothelin (MSLN), a glycosylphosphatidylinositol (GPI)-linked glycoprotein highly expressed in various cancers, and evaluated its efficacy against solid tumors. CDR walking and phage display techniques were used to improve affinity of the parental antibody M912, resulting in a pool of antibodies with different affinities to MSLN. From this pool, various bispecific antibodies (BsAbs) were assembled. Notably, MSLN490 with its IgG-[L]-scFv structure displayed remarkable anti-tumor activity against MSLN-expressing tumors (EC50: 0.16 pM in HT-29-hMSLN cells). Furthermore, MSLN490 remained effective even in the presence of non-membrane-anchored MSLN (soluble MSLN). Moreover, the anti-tumor activity of MSLN490 was enhanced when combined with either Atezolizumab or TAA × CD28 BsAbs. Notably, a synergistic effect was observed between MSLN490 and paclitaxel, as paclitaxel disrupted the immunosuppressive microenvironment within solid tumors, enhancing immune cells infiltration and improved anti-tumor efficacy. Overall, MSLN490 exhibits robust anti-tumor activity, resilience to soluble MSLN interference, and enhanced anti-tumor effects when combined with other therapies, offering a promising future for the treatment of a variety of solid tumors. This study provides a strong foundation for further exploration of MSLN490's clinical potential.

The efficacy and assessment value of the level of thyroglobulin wash-out after fine-needle aspiration cytodiagnosis in the evaluation of lymph node metastasis in papillary thyroid carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the efficacy and clinical value of US, FNAC,FNA-Tg and FNAC + FNA-Tg, as well as the cutoff values of FNA-Tg to evaluate LN metastasis. METHODS: We analyzed the diagnostic value of different US signs, the efficiency of US, FNAC, FNA-Tg and FNAC + FNA-Tg among the LN- and LN + groups, and the cutoff value of FNA-Tg to evaluate LN metastasis. We punctured LNs multiple times and measured the levels of FNA-Tg. Furthermore, the LNs were marked with immunohistochemical Tg and LCA to distinguish the presence of Tg in the para-cancerous tissue of the LNs. RESULTS: The s-Tg and FNA-Tg of the LN + group were higher than those of the LN- group (P = 0.018, ≤ 0.001). The LN + group had more abnormal US signs than the LN- group. The cutoff value of FNA-Tg was 3.2 ng/mL. US had a high sensitivity (92.42), but the specificity was not satisfactory (55.1). FNA-Tg had a higher sensitivity (92.42 vs. 89.39), specificity (100 vs. 93.88), and accuracy (92.42 vs. 83.27) than FNAC. However, the sensitivity of FNAC + FNA-Tg increased further, while the specificity and accuracy decreased slightly. The presence of Tg in the normal lymphocytes adjacent to the cancer was confirmed. CONCLUSION: Ultrasonography provides a noninvasive, dynamic, multidimensional assessment of LNs. With a cutoff value of 3.2 ng/mL, FNA-Tg has higher accuracy and a lower false-negative rate than various single diagnoses. However, FNAC combined with FNA-Tg does not cause additional pain to patients and offers a higher diagnostic efficacy and clinical value.

Cell-Impermeable Buffering Fluorogenic Probes for Live-Cell Super-Resolution Imaging of Plasma Membrane Morphology Dynamics.

Super-resolution fluorescence imaging has emerged as a potent tool for investigating the nanoscale structure and function of the plasma membrane (PM). Nevertheless, the challenge persists in achieving super-resolution imaging of PM dynamics due to limitations in probe photostability and issues with cell internalization staining. Herein, we report assembly-mediated buffering fluorogenic probes BMP-14 and BMP-16 exhibiting fast PM labeling and extended retention time (over 2 h) on PM. The incorporation of alkyl chains proves effective in promoting the aggregation of BMP-14 and BMP-16 into nonfluorescent nanoparticles to realize fluorogenicity and regulate the buffering capacity to rapidly replace photobleached probes ensuring stable long-term super-resolution imaging of PM. Utilizing these PM-buffering probes, we observed dynamic movements of PM filopodia and continuous shrinkage, leading to the formation of extracellular vesicles (EVs) using structured illumination microscopy (SIM). Furthermore, we discovered two distinct modes of EV fusion: one involving fusion through adjacent lipids and the other through filamentous lipid traction. The entire process of EV fusion outside the PM was dynamically tracked. Additionally, BMP-16 exhibited a unique capability of inducing single-molecule fluorescence blinking when used for cell membrane staining. This property makes BMP-16 suitable for the PAINT imaging of cell membranes.

Smart responsive in situ hydrogel systems applied in bone tissue engineering.

The repair of irregular bone tissue suffers severe clinical problems due to the scarcity of an appropriate therapeutic carrier that can match dynamic and complex bone damage. Fortunately, stimuli-responsive in situ hydrogel systems that are triggered by a special microenvironment could be an ideal method of regenerating bone tissue because of the injectability, in situ gelatin, and spatiotemporally tunable drug release. Herein, we introduce the two main stimulus-response approaches, exogenous and endogenous, to forming in situ hydrogels in bone tissue engineering. First, we summarize specific and distinct responses to an extensive range of external stimuli (e.g., ultraviolet, near-infrared, ultrasound, etc.) to form in situ hydrogels created from biocompatible materials modified by various functional groups or hybrid functional nanoparticles. Furthermore, "smart" hydrogels, which respond to endogenous physiological or environmental stimuli (e.g., temperature, pH, enzyme, etc.), can achieve in situ gelation by one injection in vivo without additional intervention. Moreover, the mild chemistry response-mediated in situ hydrogel systems also offer fascinating prospects in bone tissue engineering, such as a Diels-Alder, Michael addition, thiol-Michael addition, and Schiff reactions, etc. The recent developments and challenges of various smart in situ hydrogels and their application to drug administration and bone tissue engineering are discussed in this review. It is anticipated that advanced strategies and innovative ideas of in situ hydrogels will be exploited in the clinical field and increase the quality of life for patients with bone damage.

Ruthenium-doped Ni(OH)2 to enhance the activity of methanol oxidation reaction and promote the efficiency of hydrogen production.

The coupling of the hydrogen evolution reaction (HER) and methanol oxidation reaction (MOR) to produce clean hydrogen energy with value-added chemicals has attracted substantial attention. However, achieving high selectivity for formate production in the MOR and high faradaic efficiency for H2 evolution remain significant challenges. In light of this, this study constructs an Ru/Ni(OH)2/NF catalyst on nickel foam (NF) and evaluates its electrochemical performance in the MOR and HER under alkaline conditions. The results indicate that the synergistic effect of Ni(OH)2 and Ru can promote the catalytic activity. At an overpotential of only 42 mV, the current density for the HER reaches 10 mA cm-2. Moreover, in a KOH solution containing 1 M methanol, a potential of only 1.36 V vs. RHE is required to achieve an MOR current density of 10 mA cm-2. Using Ru/Ni(OH)2/NF as a bifunctional catalyst, employed as both the anode and cathode, an MOR-coupled HER electrolysis cell can achieve a current density of 10 mA cm-2 with a voltage of only 1.45 V. Importantly, the faradaic efficiency (FE) for the hydrogen production at the cathode and formate (HCOO-) production at the anode approaches 100%. Therefore, this study holds significant practical implications for the development of methanol electro-oxidation for formate-coupled water electrolysis hydrogen production technology.

CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.

Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.

Plexin D1 negatively regulates macrophage-derived foam cell migration via the focal adhesion kinase/Paxillin pathway.

BACKGROUND: Macrophage-derived foam cell formation is a hallmark of atherosclerosis and is retained during plaque formation. Strategies to inhibit the accumulation of these cells hold promise as viable options for treating atherosclerosis. Plexin D1 (PLXND1), a member of the Plexin family, has elevated expression in atherosclerotic plaques and correlates with cell migration; however, its role in macrophages remains unclear. We hypothesize that the guidance receptor PLXND1 negatively regulating macrophage mobility to promote the progression of atherosclerosis. METHODS: We utilized a mouse model of atherosclerosis based on a high-fat diet and an ox-LDL- induced foam cell model to assess PLXND1 levels and their impact on cell migration. Through western blotting, Transwell assays, and immunofluorescence staining, we explored the potential mechanism by which PLXND1 mediates foam cell motility in atherosclerosis. RESULTS: Our study identifies a critical role for PLXND1 in atherosclerosis plaques and in a low-migration capacity foam cell model induced by ox-LDL. In the aortic sinus plaques of ApoE-/- mice, immunofluorescence staining revealed significant upregulation of PLXND1 and Sema3E, with colocalization in macrophages. In macrophages treated with ox-LDL, increased expression of PLXND1 led to reduced pseudopodia formation and decreased migratory capacity. PLXND1 is involved in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK. Additionally, FAK inhibitors counteract the ox-LDL-induced migration suppression by modulating the phosphorylation states of FAK, Paxillin and their downstream effectors CDC42 and PAK. CONCLUSION: Our findings indicate that PLXND1 plays a role in regulating macrophage migration by modulating the phosphorylation levels of FAK/Paxillin and downstream CDC42/PAK to promoting atherosclerosis.

Epimedii Folium decoction ameliorates osteoporosis in mice through NLRP3/caspase-1/IL-1ß signalling pathway and gut-bone axis.

AIM OF THE STUDY: This study aimed to determine the effect of Epimedium brevicornu Maxim. (EF) on osteoporosis (OP) and its underlying molecular mechanisms, and to explore the existence of the "Gut-Bone Axis". MATERIAL AND METHODS: The impact of EF decoction (EFD) on OP was evaluated using istopathological examination and biochemical assays. Targeted metabolomics was employed to identify key molecules and explore their molecular mechanisms. Alterations in the gut microbiota (GM) were evaluated by 16S rRNA gene sequencing. The role of the GM was clarified using an antibiotic cocktail and faecal microbiota transplantation. RESULTS: EFD significantly increased the weight (14.06%), femur length (4.34%), abdominal fat weight (61.14%), uterine weight (69.86%), and insulin-like growth factor 1 (IGF-1) levels (59.48%), while reducing serum type I collagen cross-linked carboxy-terminal peptide (CTX-I) levels (15.02%) in osteoporotic mice. The mechanism of action may involve the regulation of the NLRP3/cleaved caspase-1/IL-1ß signalling pathway in improving intestinal tight junction proteins and bone metabolism. Additionally, EFD modulated the abundance of related GM communities, such as Lactobacillus, Coriobacteriaceae, bacteria of family S24-7, Clostridiales, and Prevotella, and increased propionate and butyrate levels. Antibiotic-induced dysbiosis of gut bacteria disrupted OP regulation of bone metabolism, which was restored by the recovery of GM. CONCLUSIONS: Our study is the first to demonstrate that EFD works in an OP mouse model by utilising GM and butyric acid. Thus, EF shows promise as a potential remedy for OP in the future.

Endoscopic ultrasound-guided versus surgical pancreatic duct drainage after failed endoscopic retrograde pancreatography: a pilot comparative study.

BACKGROUND: Endoscopic ultrasound-guided pancreatic duct (PD) drainage (EUS-PDD) is being increasingly performed as an alternative method to surgical drainage to achieve PD decompression after failed endoscopic retrograde pancreatography (ERP). However, no directly study has compared EUS-PDD with surgical PD drainage after failed ERP in patients with chronic pancreatitis. METHODS: Consecutive patients who underwent EUS-PDD or longitudinal pancreaticojejunostomy after failed ERP were retrospectively identified from our endoscopy and medical information systems. The primary end point was the Izbicki pain score. The secondary end points were pain relief at the end of follow-up, procedure outcomes, adverse events, readmission, and reintervention. RESULTS: A total of 21 patients (11 EUS-PDD, 10 surgical drainages) were analyzed. There were no significant differences in mean Izbicki pain score (EUS-PDD, 13.6 ± 10.1 vs. surgical drainage 10.7 ± 7.9, p = 0.483) or complete/partial pain relief (60%/30% vs. 70%/30%, p = 0.752) at the end of follow-up of the two groups. The rates of overall adverse events (27.3% vs. 30.0%, p = 0.893) and readmission (63.6% vs. 40.0%, p = 0.290) were similar in the two treatment groups, while patients in EUS-PDD group required more reinterventions (45.5% vs. 0%, p = 0.039) compared with patients in the surgery group. CONCLUSION: EUS-PDD showed comparable pain relief and safety to surgical PD drainage after failed ERP, with a higher rate of reintervention. The selection of EUS-PDD or surgical drainage may be appropriate based on an individualized strategy.

Quinolone Antibiotics Inhibit the Rice Photosynthesis by Targeting Photosystem II Center Protein: Generational Differences and Mechanistic Insights.

Soil antibiotic pollution profoundly influences plant growth and photosynthetic performance, yet the main disturbed processes and the underlying mechanisms remain elusive. This study explored the photosynthetic toxicity of quinolone antibiotics across three generations on rice plants and clarified the mechanisms through experimental and computational studies. Marked variations across antibiotic generations were noted in their impact on rice photosynthesis with the level of inhibition intensifying from the second to the fourth generation. Omics analyses consistently targeted the light reaction phase of photosynthesis as the primary process impacted, emphasizing the particular vulnerability of photosystem II (PS II) to the antibiotic stress, as manifested by significant interruptions in the photon-mediated electron transport and O2 production. PS II center D2 protein (psbD) was identified as the primary target of the tested antibiotics, with the fourth-generation quinolones displaying the highest binding affinity to psbD. A predictive machine learning method was constructed to pinpoint antibiotic substructures that conferred enhanced affinity. As antibiotic generations evolve, the positive contribution of the carbonyl and carboxyl groups on the 4-quinolone core ring in the affinity interaction gradually intensified. This research illuminates the photosynthetic toxicities of antibiotics across generations, offering insights for the risk assessment of antibiotics and highlighting their potential threats to carbon fixation of agroecosystems.

Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.

Targeted protein degradation technology holds great potential in biomedicine, particularly in treating tumors and other protein-related diseases. Research on intracellular protein degradation using molecular glues and PROTAC technology is leading, while research on the degradation of membrane proteins and extracellular proteins through the lysosomal pathway is still in the preclinical stage. The scarcity of useful targets is an immense limitation to technological advancement, making it essential to explore novel, potentially effective approaches for targeted lysosomal degradation. Here, we employed the glucose transporter Glut1 as an innovative lysosome-targeting receptor and devised the Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized potential Glut1 ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization and acquired antibody-glycooligomer conjugates through bioorthogonal reactions as lysosome-targeting protein degradation molecules, utilized in the management of PD-L1 high-expressing triple-negative breast cancer. The glucose transporter Glut1 as a lysosome-targeting receptor exhibits potential for the advancement of a broader array of medications in the future.

Origin of copper as a unique catalyst for C-C coupling in electrocatalytic CO2 reduction.

High yields of C2 products through electrocatalytic CO2 reduction (eCO2R) can only be obtained using Cu-based catalysts. Here, we adopt the generalized frontier molecular orbital (MO) theory based on first-principles calculations to identify the origin of this unique property of Cu. We use the grand canonical ensemble (or fixed potential) approach to ensure that the calculated Fermi level, which serves as the frontier orbital of the metal catalyst, accurately represents the applied electrode potentials. We determine that the key intermediate OCCO assumes a U-shape configuration with the two C atoms bonded to the Cu substrate. We identify the frontier MOs that are involved in the C-C coupling. The good alignment of the Fermi level of Cu with these frontier MOs is perceived to account for the excellent catalytic performance of Cu for C-C coupling. It is expected that these new insights could provide useful guidance in tuning Cu-based catalysts as well as designing non-Cu catalysts toward high-efficiency eCO2R.

Outcomes of endoscopic submucosal dissection versus esophagectomy for poorly differentiated superficial esophageal squamous cell carcinoma: A 10-year cohort study.

BACKGROUNDS: The efficacy of endoscopic submucosal dissection (ESD) to treat poorly differentiated superficial esophageal squamous cell carcinoma (SESCC) is unclear. AIMS: To exploring the efficacy and prognosis of ESD treatment poorly differentiated SESCC compared with esophagectomy. METHODS: A retrospective cohort study was conducted, the data of poorly differentiated SESCC patients who received ESD or esophagectomy from Jan 2011 to Jan 2021 were analyzed. Overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and procedure-related variables were compared between ESD and esophagectomy group. RESULTS: 95 patients underwent ESD, while 86 underwent esophagectomy. No significant differences were found between the two groups in OS (P = 0.587), DSS (P = 0.172), and RFS (P = 0.111). Oncologic outcomes were also similar between the two groups in propensity score-matched analysis. For T1a ESCC, the rates of R0 resection, LVI or nodal metastasis and additional therapy were similar between ESD and esophagectomy groups. But for T1b ESCC, the rates of positive resection margin and additional therapy were significantly higher in ESD group than those in esophagectomy group. CONCLUSIONS: ESD is a minimally invasive procedure that has comparable oncologic outcomes with esophagectomy for treatment poorly differentiated T1a ESCC. However, ESD is not suitable for poorly differentiated T1b ESCC, additional surgery or radiochemotherapy should be required.

AMPK induces PIAS3 mediated SUMOylation of E3 ubiquitin ligase Smurf1 impairing osteogenic differentiation and traumatic heterotopic ossification.

AMP-activated protein kinase (AMPK) is a typical sensor of intracellular energy metabolism. Our previous study revealed the role of activated AMPK in the suppression of osteogenic differentiation and traumatic heterotopic ossification, but the underlying mechanism remains poorly understood. The E3 ubiquitin ligase Smurf1 is a crucial regulator of osteogenic differentiation and bone formation. We report here that Smurf1 is primarily SUMOylated at a C-terminal lysine residue (K324), which enhances its activity, facilitating ALK2 proteolysis and subsequent bone morphogenetic protein (BMP) signaling pathway inhibition. Furthermore, SUMOylation of the SUMO E3 ligase PIAS3 and Smurf1 SUMOylation was suppressed during the osteogenic differentiation and traumatic heterotopic ossification. More importantly, we found that AMPK activation enhances the SUMOylation of Smurf1, which is mediated by PIAS3 and increases the association between PIAS3 and AMPK. Overall, our study revealed that Smurf1 can be SUMOylated by PIAS3, Furthermore, Smurf1 SUMOylation mediates osteogenic differentiation and traumatic heterotopic ossification through suppression of the BMP signaling pathway. This study revealed that promotion of Smurf1 SUMOylation by AMPK activation may be implicated in traumatic heterotopic ossification treatment.

Angiogenesis in heterotopic ossification: From mechanisms to clinical significance.

Heterotopic ossification (HO) refers to the formation of pathologic bone in nonskeletal tissues (including muscles, tendons or other soft tissues). HO typically occurs after a severe injury and can occur in any part of the body. HO lesions are highly vascularized. Angiogenesis, which is the formation of new blood vessels, plays an important role in the pathophysiology of HO. Surgical resection is considered an effective treatment for HO. However, it is difficult to completely remove new vessels, which can lead to the recurrence of HO and is often accompanied by significant problems such as intraoperative hemorrhage, demonstrating the important role of angiogenesis in HO. Here, we broadly summarize the current understanding of how angiogenesis contributes to HO; in particular, we focus on new insights into the cellular and signaling mechanisms underlying HO angiogenesis. We also review the development and current challenges associated with antiangiogenic therapy for HO.

LDL receptor in alphavirus entry: structural analysis and implications for antiviral therapy.

Various low-density lipoprotein receptors (LPRs) have been identified as entry factors for alphaviruses, and structures of the corresponding virion-receptor complexes have been determined. Here, we analyze the similarities and differences in the receptor binding modes of multiple alphaviruses to understand their ability to infect a wide range of hosts. We further discuss the challenges associated with the development of broad-spectrum treatment strategies against a diverse range of alphaviruses.

Structure-activity relationships of the intramolecular disulphide bonds in LEAP2, an antimicrobial peptide from Acrossocheilus fasciatus.

BACKGROUND: The liver-expressed antimicrobial peptide 2 (LEAP2) plays a pivotal role in the host's immune response against pathogenic microorganisms. Numerous such antimicrobial peptides have recently been shown to mitigate infection risk in fish, and studying those harboured by the economically important fish Acrossocheilus fasciatus is imperative for enhancing its immune responses against pathogenic microorganisms. In this study, we cloned and sequenced LEAP2 cDNA from A. fasciatus to examine its expression in immune tissues and investigate the structure-activity relationships of its intramolecular disulphide bonds. RESULTS: The predicted amino acid sequence of A. fasciatus LEAP2 was found to include a signal peptide, pro-domain, and mature peptide. Sequence analysis indicated that A. fasciatus LEAP2 is a member of the fish LEAP2A cluster and is closely related to Cyprinus carpio LEAP2A. A. fasciatus LEAP2 transcripts were expressed in various tissues, with the head kidney exhibiting the highest mRNA levels. Upon exposure to Aeromonas hydrophila infection, LEAP2 expression was significantly upregulated in the liver, head kidney, and spleen. A mature peptide of A. fasciatus LEAP2, consisting of two disulphide bonds (Af-LEAP2-cys), and a linear form of the LEAP2 mature peptide (Af-LEAP2) were chemically synthesised. The circular dichroism spectroscopy result shows differences between the secondary structures of Af-LEAP2 and Af-LEAP2-cys, with a lower proportion of alpha helix and a higher proportion of random coil in Af-LEAP2. Af-LEAP2 exhibited potent antimicrobial activity against most tested bacteria, including Acinetobacter guillouiae, Pseudomonas aeruginosa, Staphylococcus saprophyticus, and Staphylococcus warneri. In contrast, Af-LEAP2-cys demonstrated weak or no antibacterial activity against the tested bacteria. Af-LEAP2 had a disruptive effect on bacterial cell membrane integrity, whereas Af-LEAP2-cys did not exhibit this effect. Additionally, neither Af-LEAP2 nor Af-LEAP2-cys displayed any observable ability to hydrolyse the genomic DNA of P. aeruginosa. CONCLUSIONS: Our study provides clear evidence that linear LEAP2 exhibits better antibacterial activity than oxidised LEAP2, thereby confirming, for the first time, this phenomenon in fish.