NK-cell-elicited gasdermin-D-dependent hepatocyte pyroptosis induces neutrophil extracellular traps that facilitate HBV-related acute-on-chronic liver failure.

BACKGROUND AND AIMS: HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF. APPROACH AND RESULTS: We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF. CONCLUSIONS: Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

Lysosome-targeting and legumain-triggered 68Ga-labeled probe for enhanced tumor PET imaging.

Legumain is overexpressed in diverse tumors, serving as a significant tumor biomarker. Our study aimed to develop a new positron emission tomography (PET) probe [68Ga]Ga-NOTA-SF-AANM for imaging the expression level of legumain in vivo. The radio-labeling of [68Ga]Ga-NOTA-SF-AANM was accomplished within 15 min. The probe has good stability in vitro. NOTA-SF-AANM exhibited rapid response to recombinant human legumain enzyme, enabling intramolecular condensation cyclization. Cellular uptake and lysosomal co-localization experiments demonstrated that the probe was able to differentiate specifically between MDA-MB-468 and PC-3 cancer cells with varying degrees of legumain expression. PET imaging displayed a significant and persistent signal (3.59 ± 0.30 %ID/mL at 60 min) in MDA-MB-468 tumors, while PC-3 tumors exhibited lower radioactivity (1.08 ± 0.35 %ID/mL at 60 min), further validating the specific targeting of [68Ga]Ga-NOTA-SF-AANM towards legumain. [68Ga]Ga-NOTA-SF-AANM is a promising tool for precise diagnosis of legumain-related diseases due to its advantages in radio-labeling and accurate monitoring of legumain expression levels.

Design, Synthesis, and Biological Evaluation of Novel Nonsteroidal 18F-Labeled PET Probes Specifically Targeting Estrogen Receptor α.

The estrogen receptor α positive (ERα+) subtype represents nearly 70% of all breast cancers (BCs), which seriously threaten women's health. Positron emission computed tomography (PET) characterizes its superiority in detecting the recurrence and metastasis of BC. In this article, an array of novel PET probes ([18F]R-1, [18F]R-2, [18F]R-3, and [18F]R-4) targeting ERα based on the tetrahydropyridinyl indole scaffold were developed. Among them, [18F]R-3 and [18F]R-4 showed good target specificity toward ERα and could distinguish MCF-7 (ERα+) and MDA-MB-231 (ERα-) tumors efficiently. Especially, [18F]R-3 could differentiate the ERα positive/negative tumors successfully with a higher tumor-to-muscle uptake ratio (T/M) than that of [18F]R-4. The radioactivity of [18F]R-3 in the MCF-7 tumor was 5.24 ± 0.84%ID/mL and its T/M ratio was 2.49 ± 0.62 at 25 min postinjection, which might be the optimal imaging time point in PET scanning. On the contrary, [18F]R-3 did not accumulate in the MDA-MB-231 tumor at all. The autoradiography analysis of [18F]R-3 on the MCF-7 tumor-bearing mice model was consistent with the PET imaging results. [18F]R-3 exhibited the pharmacokinetic property of rapid distribution and slow clearance, making it suitable for use as a diagnostic PET probe. Overall, [18F]R-3 was capable of serving as a PET radiotracer to delineate the ERα+ tumor and was worthy of further exploitation.

M1 macrophage-derived exosomes promote intervertebral disc degeneration by enhancing nucleus pulposus cell senescence through LCN2/NF-κB signaling axis.

Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a history of trauma or long-term abnormal stress, which may lead to local inflammatory reaction causing by immune cells, and ultimately accelerates degeneration. Research has shown the significance of M1-type macrophages in IVDD; nevertheless, the precise mechanism and the route by which it influences the function of nucleus pulposus cell (NPC) remain unknown. Utilizing a rat acupuncture IVDD model and an NPC degeneration model induced by lipopolysaccharide (LPS), we investigated the function of M1 macrophage-derived exosomes (M1-Exos) in IVDD both in vivo and in vitro in this study. We found that M1-Exos enhanced LPS-induced NPC senescence, increased the number of SA-ß-gal-positive cells, blocked the cell cycle, and promoted the activation of P21 and P53. M1-Exos derived from supernatant pretreated with the exosome inhibitor GW4869 reversed this result in vivo and in vitro. RNA-seq showed that Lipocalin2 (LCN2) was enriched in M1-Exos and targeted the NF-κB pathway. The quantity of SA-ß-gal-positive cells was significantly reduced with the inhibition of LCN2, and the expression of P21 and P53 in NPCs was decreased. The same results were obtained in the acupuncture-induced IVDD model. In addition, inhibition of LCN2 promotes the expression of type II collagen (Col-2) and inhibits the expression of matrix metalloproteinase 13 (MMP13), thereby restoring the equilibrium of metabolism inside the extracellular matrix (ECM) in vitro and in vivo. In addition, the NF-κB pathway is crucial for regulating M1-Exo-mediated NPC senescence. After the addition of M1-Exos to LPS-treated NPCs, p-p65 activity was significantly activated, while si-LCN2 treatment significantly inhibited p-p65 activity. Therefore, this paper demonstrates that M1 macrophage-derived exosomes have the ability to deliver LCN2, which activates the NF-κB signaling pathway, and exacerbates IVDD by accelerating NPC senescence. This may shed new light on the mechanism of IVDD and bring a fresh approach to IVDD therapy.

Preparation and Bioevaluation of 18F-Labeled Small-Molecular Radiotracers via Sulfur(VI) Fluoride Exchange Chemistry for Imaging of Programmed Cell Death Protein Ligand 1 Expression in Tumors.

Nowadays, one of the most effective methods of tumor immunotherapy is blocking programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) immune checkpoints. However, there is still a significant challenge in selecting patients to benefit from immune checkpoint therapies. Positron emission tomography (PET), a noninvasive molecular imaging technique, offers a new approach to accurately detect PD-L1 expression and allows for a better prediction of response to PD-1/PD-L1 target immunotherapy. Here, we designed and synthesized a novel group of aryl fluorosulfate-containing small-molecule compounds (LGSu-1, LGSu-2, LGSu-3, and LGSu-4) based on the phenoxymethyl-biphenyl scaffold. After screening by the time-resolved fluorescence resonance energy transfer (TR-FRET) assay, the most potent compound LGSu-1 (half maximal inhibitory concentration (IC50): 15.53 nM) and the low-affinity compound LGSu-2 (IC50: 189.70 nM) as a control were selected for 18F-radiolabeling by sulfur(VI) fluoride exchange chemistry (SuFEx) to use for PET imaging. [18F]LGSu-1 and [18F]LGSu-2 were prepared by a one-step radiofluorination reaction in over 85% radioconversion and nearly 30% radiochemical yield. In B16-F10 melanoma cell assays, [18F]LGSu-1 (5.00 ± 0.06%AD) showed higher cellular uptake than [18F]LGSu-2 (2.55 ± 0.04%AD), in which cell uptake could be significantly blocked by the nonradioactivity LGSu-1. In vivo experiments, micro-PET imaging of B16-F10 tumor-bearing mice and radiographic autoradiography of tumor sections showed that [18F]LGSu-1 was more effectively accumulated in the tumor due to the higher binding affinity with PD-L1. The above experimental results confirmed the potential of the small-molecule probe LGSu-1 as a targeting PD-L1 imaging tracer in tumor tissues.

Ginseng-derived nanoparticles potentiate immune checkpoint antibody efficacy by reprogramming the cold tumor microenvironment.

Cold tumor microenvironment (TME) marked with low effector T cell infiltration leads to weak response to immune checkpoint inhibitor (ICI) treatment. Thus, switching cold to hot TME is critical to improve potent ICI therapy. Previously, we reported extracellular vesicle (EV)-like ginseng-derived nanoparticles (GDNPs) that were isolated from Panax ginseng C.A. Mey and can alter M2 polarization to delay the hot tumor B16F10 progression. However, the cold tumor is more common and challenging in the real world. Here, we explored a combinatorial strategy with both GDNPs and PD-1 (programmed cell death protein-1) monoclonal antibody (mAb), which exhibited the ability to alter cold TME and subsequently induce a durable systemic anti-tumor immunity in multiple murine tumor models. GDNPs enhanced PD-1 mAb anti-tumor efficacy in activating tumor-infiltrated T lymphocytes. Our results demonstrated that GDNPs could reprogram tumor-associated macrophages (TAMs) to increase CCL5 and CXCL9 secretion for recruiting CD8+ T cells into the tumor bed, which have the synergism to PD-1 mAb therapy with no detected systemic toxicity. In situ activation of TAMs by GDNPs may broadly serve as a facile platform to modulate the suppressive cold TME and optimize the PD-1 mAb immunotherapy in future clinical application.

Validation and performance of three scoring systems for predicting primary non-function and early allograft failure after liver transplantation.

BACKGROUND: Primary non-function (PNF) and early allograft failure (EAF) after liver transplantation (LT) seriously affect patient outcomes. In clinical practice, effective prognostic tools for early identifying recipients at high risk of PNF and EAF were urgently needed. Recently, the Model for Early Allograft Function (MEAF), PNF score by King's College (King-PNF) and Balance-and-Risk-Lactate (BAR-Lac) score were developed to assess the risks of PNF and EAF. This study aimed to externally validate and compare the prognostic performance of these three scores for predicting PNF and EAF. METHODS: A retrospective study included 720 patients with primary LT between January 2015 and December 2020. MEAF, King-PNF and BAR-Lac scores were compared using receiver operating characteristic (ROC) and the net reclassification improvement (NRI) and integrated discrimination improvement (IDI) analyses. RESULTS: Of all 720 patients, 28 (3.9%) developed PNF and 67 (9.3%) developed EAF in 3 months. The overall early allograft dysfunction (EAD) rate was 39.0%. The 3-month patient mortality was 8.6% while 1-year graft-failure-free survival was 89.2%. The median MEAF, King-PNF and BAR-Lac scores were 5.0 (3.5-6.3), -2.1 (-2.6 to -1.2), and 5.0 (2.0-11.0), respectively. For predicting PNF, MEAF and King-PNF scores had excellent area under curves (AUCs) of 0.871 and 0.891, superior to BAR-Lac (AUC = 0.830). The NRI and IDI analyses confirmed that King-PNF score had the best performance in predicting PNF while MEAF served as a better predictor of EAD. The EAF risk curve and 1-year graft-failure-free survival curve showed that King-PNF was superior to MEAF and BAR-Lac scores for stratifying the risk of EAF. CONCLUSIONS: MEAF, King-PNF and BAR-Lac were validated as practical and effective risk assessment tools of PNF. King-PNF score outperformed MEAF and BAR-Lac in predicting PNF and EAF within 6 months. BAR-Lac score had a huge advantage in the prediction for PNF without post-transplant variables. Proper use of these scores will help early identify PNF, standardize grading of EAF and reasonably select clinical endpoints in relative studies.

Effect of Neiyi Prescription of QIU on autophagy and angiogenic ability of endometriosis via the PPARγ/NF-κB signaling pathway.

OBJECTIVES: Neiyi Prescription of QIU (NYPQ) is a traditional Chinese medicine prescription for the treatment of endometriosis (EMS). Here, we aimed to examine the effects and mechanisms of NYPQ on angiogenic ability in EMS. STUDY DESIGN: EMS rats were established with estradiol valerate and autologous transplantation. EMS rats were intraperitoneally injected with chloroquine (CQ, 40 mg/kg), rapamycin (RAPA, 1 mg/kg), and monoclonal antibody VEGF (anti-VEGF, 3 mg/g/d) or administered 5, 10, 20 mg/g/d NYPQ decoction through oral gavage for 4 weeks, respectively. By the before and end of the treatment period, the volume of the endometriotic lesions was measured. The pathological morphology, angiogenesis, and the number of autophagosomes of the endometriotic lesion were observed by hematoxylin and eosin staining, immunohistochemistry, and transmission electron microscope, respectively. The cell viability, apoptosis, and angiogenesis of HUVECs were detected by MTT, flow cytometry, and lumen formation experiment, respectively. The expression levels of VEGF, autophagy-/apoptosis-/PPARγ/NF-κB- pathway-related proteins in endometrium tissues or HUVECs were detected by western blot assays. RESULTS: The autophagy agonist rapamycin reduced the lesion size, the microvessel density, and VEGF expression, and promoted the production of autophagosomes and the expression of autophagy-related proteins, while the autophagy inhibitor chloroquine had the opposite effects. In vivo, NYPQ could dose-dependently reduce lesion volume and microvessel density, ameliorate histopathological features and promote autophagosome production of ectopic endometrium. Moreover, serum-containing NYPQ could significantly inhibit the cell viability and tube formation of HUVECs and elevate HUVECs apoptosis. Besides, NYPQ significantly reduced VEGF and promoted autophagy-/apoptosis-related protein expressions. Also, NYPQ might promote autophagy and inhibit angiogenesis by activating the PPARγ/NF-κB pathway. CONCLUSIONS: Collectively, these findings indicate that NYPQ has therapeutic potential in experimentally induced peritoneal endometriosis, and its mechanism may be related to the activation of the PPARγ/NF-κB signaling pathway.

Effects of slight structural distortion on the luminescence performance in (Ca1-x Eux )WO4 luminescent materials.

(Ca1-x Eux )WO4 (x = 0-21 mol%) phosphors were prepared using the classical solid-state reaction method. The influence of Eu3+ ion doping on lattice structure was observed using powder X-ray diffraction and Fourier transform infrared spectroscopy. Furthermore, under this influence, the luminescence properties of all samples were analyzed. The results clearly illustrated that the element europium was successfully incorporated into the CaWO4 lattice with a scheelite structure in the form of a Eu3+ ion, which introduced a slight lattice distortion into the CaWO4 matrix. These lattice distortions had no effect on phase purity, but had regular effects on the intrinsic luminescence of the matrix and the f-f excitation transitions of Eu3+ activators. When the Eu3+ concentration was increased to 21 mol%, a local luminescence centre of [WO4 ]2- groups was detected in the matrix and manifested as the decay curves of [WO4 ]2- groups and luminescence changed from single exponential to double exponential fitting. Furthermore, the excitation transitions of Eu3+ between different energy levels (such as 7 F0 →5 L6 , 7 F0 →5 D2 ) also produced interesting changes. Based on analysis of photoluminescence spectra and the chromaticity coordinates in this study, it could be verified that the nonreversing energy transfer of [WO4 ]2- →Eu3+ was efficient and incomplete.

Molten salt synthesis and luminescence of Dy3+ -doped Y3 Al5 O12 phosphors.

Dy3+ -doped Y3 Al5 O12 phosphors were prepared at a relatively low temperature using molten salt synthesis. The phase of the prepared Dy3+ -doped Y3 Al5 O12 phosphors was confirmed using X-ray powder diffraction. Results indicated that Dy3+ doping did not change the Y3 Al5 O12 phase. Following excitation at 352 nm, emission spectra of the Dy3+ -doped Y3 Al5 O12 phosphors consisted of blue, yellow, and red emission bands. The influence of Dy3+ concentration and excitation wavelength on emission was investigated. The ratio of yellow light to blue light varied with change in Dy3+ doping concentration, due to changes in the structure around Dy3+ . Emission intensities also changed when the excitation wavelength was changed. This variation is luminescence generated a system for tunable white light for Dy3+ -doped Y3 Al5 O12 phosphors.

Hypercholesterolemia increases the production of leukotriene B4 in neutrophils by enhancing the nuclear localization of 5-lipoxygenase.

AIMS: Neutrophils can synthesize leukotriene B4 (LTB4) by activating the 5-lipoxygenase (5-LO)signaling pathway. LTB4 is a pro-inflammatory mediator associated with the etiology and progression of atherosclerosis. It can increase function and number of neutrophils in an autocrine manner. Since hypercholesterolemia is associated with an increase in the number and function of neutrophils, we hypothesized that this effect could be mediated through increased production of LTB4 in neutrophils. METHODS/RESULTS: Hypercholesterolemia was modeled in Wistar rats by feeding them with a high cholesterol diet. The induction of hypercholesterolemia caused an increase in the plasma levels of LTB4, following lipopolysaccharide stimulation. This effect was recapitulated in vitro, both in the presence and absence of stimulation with the activator of 5-LO, A23187. Neutrophils in hypercholesterolemia rats expressed similar total levels of 5-LO as control rats, but displayed increased nuclear localization of 5-LO, as well as elevated levels of phosphorylated 5-LO and ERK1/2. In vitro, MßCD/cholesterol complexes enriched cholesterol in neutrophils, resulted in similar changes in 5-LO/LTB4. In addition, these alterations could be inhibited with the ERK inhibitor PD98059. CONCLUSION: Hypercholesterolemia increases LTB4 production in neutrophils by increasing the nuclear localization of 5-LO, which is the result of its phosphorylation by activated ERK1/2.

Targeted delivery of activatable 131I-radiopharmaceutical for sustained radiotherapy with improved pharmacokinetics.

Targeted radionuclide therapy (TRT) is an effective treatment for tumors. Self-condensation strategies can enhance the retention of radionuclides in tumors and enhance the anti-tumor effect. Considering legumain is overexpressed in multiple types of human cancers, a 131I-labeled radiopharmaceutical ([131I]MAAN) based on the self-condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine (Cys) was developed by us recently for treating legumain-overexpressed tumors. However, liver enrichment limits its application. In this study, a new radiopharmaceutical [131I]IM(HE)3AAN was designed and synthesized by introducing a hydrophilic peptide sequence His-Glu-His-Glu-His-Glu ((HE)3) into [131I]MAAN to optimize the pharmacokinetics. Upon activation by legumain under a reducing environment, hydrophilic [131I]IM(HE)3AAN could react with its precursor to form heterologous dimer [131I]H-Dimer that is highly hydrophobic. Cerenkov imaging revealed that [131I]IM(HE)3AAN displayed superior tumor selectivity and longer tumor retention time as compared with [131I]MAAN, with a significant reduction in the liver uptake. After an 18-day treatment with [131I]IM(HE)3AAN, the tumor proliferation was obviously inhibited, while no obvious injury was observed in the normal organs. These findings suggest that [131I]IM(HE)3AAN could serve as a promising drug candidate for treating legumain-overexpressed tumors.

Hysteroscopic cervical biopsy for women with persistent human papillomavirus infection after loop electrosurgical excision procedure: A case report.

BACKGROUND: Almost all cases of cervical cancer can be attributed to human papillomavirus (HPV) infection. The loop electrosurgical excision procedure (LEEP) is widely used to treat HPV-mediated disease; thus, cervical cancer is highly preventable. However, LEEP does not necessarily clear HPV rapidly and may affect the accuracy of the results of ThinPrep cytology test (TCT) and cervical biopsy due to the formation of cervical scars. CASE SUMMARY: A 40-year-old woman underwent LEEP for cervical intraepithelial neoplasia grade 1 approximately 10 years ago. Subsequent standard cervical cancer screening suggested persistent HPV-52 infection, but TCT results were negative. Cervical biopsy under colposcopy was performed thrice over a 10-year period, yielding negative pathology results. She developed abnormal vaginal bleeding after sexual activity, persisting for approximately 1 year, and underwent hysteroscopy in our hospital. Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix. CONCLUSION: Patients with long-term persistent, high-risk HPV infection and negative pathology results of cervical biopsy after LEEP are at risk of cervical cancer. Hysteroscopic resection of cervical canal tissue is recommended as a supplement to cervical biopsy because it helps define the lesion site and may yield a pathologic diagnosis.

TRPV3 promotes sebocyte inflammation via transcriptional modulating TLR2 in acne.

Acne is a common chronic inflammatory disease of the pilosebaceous unit. Transient receptor potential vanilloid 3 (TRPV3) is an ion channel that is involved in inflammatory dermatosis development. However, the involvement of TRPV3 in acne-related inflammation remains unclear. Here, we used acne-like mice and human sebocytes to examine the role of TRPV3 in the development of acne. We found that TRPV3 expression increased in the skin lesions of Propionibacterium acnes (P. acnes)-injected acne-like mice and the facial sebaceous glands (SGs) of acne patients. TRPV3 promoted inflammatory cytokines and chemokines secretion in human sebocytes and led to neutrophil infiltration surrounding the SGs in acne lesions, further exacerbating sebaceous inflammation and participating in acne development. Mechanistically, TRPV3 enhanced TLR2 level by promoting transcriptional factor phosphorylated-FOS-like antigen-1 (p-FOSL1) expression and its binding to the TLR2 promoter, leading to TLR2 upregulation and downstream NF-κB signaling activation. Genetic or pharmacological inhibition of TRPV3 both alleviated acne-like skin inflammation in mice via the TLR2-NF-κB axis. Thus, our study revealed the critical role of TRPV3 in sebaceous inflammation and indicated its potential as an acne therapeutic target.

TRPV3-Activated PARP1/AIFM1/MIF Axis through Oxidative Stress Contributes to Atopic Dermatitis.

TRPV3 is a temperature-sensitive calcium-permeable channel. In previous studies, we noticed prominent TUNEL-positive keratinocytes in patients with Olmsted syndrome and Trpv3+/G568V mice, both of which carry gain-of-function variants in the TRPV3 gene. However, it remains unclear how the keratinocytes die and whether this process contributes to more skin disorders. In this study, we showed that gain-of-function variant or pharmacological activation of TRPV3 resulted in poly(ADP-ribose) polymerase 1 (PARP1)/AIFM1/macrophage migration inhibitory factor axis-mediated parthanatos, which is an underestimated form of cell death in skin diseases. Chelating calcium, scavenging ROS, or inhibiting nitric oxide synthase effectively rescued the parthanatos, indicating that TRPV3 regulates parthanatos through calcium-mediated oxidative stress. Furthermore, inhibiting PARP1 downregulated TSLP and IL33 induced by TRPV3 activation in HaCaT cells, reduced immune cell infiltration, and ameliorated epidermal thickening in Trpv3+/G568V mice. Marked parthanatos was also detected in the skin of MC903-treated mice and patients with atopic dermatitis, whereas inhibiting PARP1 largely alleviated the MC903-induced dermatitis. In addition, stimulating parthanatos in mouse skin with methylnitronitrosoguanidine recapitulated many features of atopic dermatitis. These data demonstrate that the TRPV3-regulated parthanatos-associated PARP1/AIFM1/macrophage migration inhibitory factor axis is a critical contributor to the pathogenesis of Olmsted syndrome and atopic dermatitis, suggesting that modulating the PARP1/AIFM1/macrophage migration inhibitory factor axis is a promising therapy for these conditions.

Dual-Targeting PET Tracers Enable Enzyme-Mediated Self-Assembly for the PET Imaging of Legumain Activity.

Legumain, a lysosomal cysteine protease overexpressed in a variety of tumors, has been considered a promising biomarker for various cancers. Precise detection of legumain activity in the lysosome represents an important strategy for early diagnosis and prognosis of tumors. Small-molecule probes with the property of target-enabled self-assembly hold great potential for molecular imaging. In this study, we reported two dual-targeting radiotracers ([18F]SF-AAN-M and [18F]SF-AAN-HEM) with a property of legumain-mediated self-assembly for positron emission tomography (PET) imaging. Both the radiotracers were synthesized with high labeling yield (>50%) and the radiochemical purity was over 99% via one-step straightforward 18F-labeling. Both tracers were efficiently activated by the reducing agent and legumain to self-assemble into aggregates and showed enhanced retention in legumain-overexpressed MDA-MB-468 cells and tumors, indicating that the introduction of lysosome-targeting morpholine increased the tumor uptake and extended the retention of radiotracers in legumain-overexpressed tumors. In addition, [18F]SF-AAN-HEM with a hydrophilic (histidine-glutamate)3 tag displayed significantly reduced liver uptake with no conspicuous reduction in tumor uptake, affording high signal-to-noise ratios (tumor/liver and tumor/muscle). All of these results suggest that dual-targeting tracer [18F]SF-AAN-HEM could provide a promising tool for in vivo monitoring legumain activity in tumors.

Application of TPGS as an efflux inhibitor and a plasticizer in baicalein solid dispersion.

The oral bioavailability and efficacy of baicalein is dramatically limited by its low solubility and effect of efflux. In our study, we chose PVP-VA64 as a carrier and TPGS as a plasticizer and efflux inhibitor to prepare a solid dispersion of baicalein using hot-melt extrusion technology to improve its solubility and bioavailability. The hot-melt process and formulation were optimized, and a BAC-PVP VA64-TPGS solid dispersion (BPT-SD) was prepared. BAC exists in an amorphous or molecular state in BPT-SD. BPT-SD comprised irregular lumps and small particles without BAC or carrier characteristics. The dissolution efficiency of BPT-SD improved under sink conditions. FTIR showed a strong hydrogen bond between BAC and PVP-VA64 in BPT-SD. BPT-SD maintained good physical stability for 6 months. The apparent permeability coefficient of BAC in the Caco-2 cell model confirmed that BPT-SD had higher gastrointestinal membrane permeability. A rat pharmacokinetic study showed that BPT-SD had higher Cmax and AUC0-24h, shorter Tmax, and 2.88-fold higher bioavailability than BAC. A behavioral experiment in chronic unpredictable mild stress (CUMS) mice confirmed the antidepressant efficacy of BAC. BPT-SD reversed depression-like behavior in CUMS mice and improved BAC bioavailability. BAC preparation into a solid dispersion significantly enhanced dissolution performance and bioavailability.

Novel dry pericardiocentesis: Transvenous puncture of the right ventricle with the back end of a 0.014-inch PTCA guidewire and a 1.8 Fr microcatheter.

Background: Dry transthoracic pericardiocentesis is challenging and carries the risk of right ventricle (RV) or coronary artery injury. The RV can usually control bleeding automatically. For example, most perforations of the RV caused by pacemaker leads are treated without open surgery. Thus, we performed a transvenous puncture of the RV for dry pericardiocentesis with the back end of a 0.014-inch percutaneous transluminal coronary angioplasty (PTCA) guidewire and a 1.8 Fr microcatheter. Methods: The back end of a 0.014-inch PTCA guidewire within a 1.8 Fr microcatheter was used to transvenously punctured through the middle of the acute margin of the RV into the pericardial space in 12 Yorkshire swine and 5 beagles. PTCA balloons of different diameters were used to dilate the puncture holes for 15 min under anticoagulation in all the animals to assess the ability of the RV to control the bleeding. Then, for 3 days, the puncture hole was dilated by a 6 Fr catheter in 9 swine and 5 dogs. Results: The puncture was successful in all the animals. After withdrawal of the 2.5-mm balloon or the 6 Fr catheter, none of the animals exhibited pericardial effusion, as observed by echocardiography. There was no sustained ventricular arrhythmia or other complications. All the animals survived. Conclusion: Transvenous puncture of the right ventricle with the back end of a 0.014-inch PTCA guidewire and 1.8 Fr microcatheter may be feasible and have a good safety margin.

Biodegradable microplastics (BMPs): a new cause for concern?

With the increasingly serious pollution of plastics, biodegradable plastics (BDPs) have attracted attention as a new material that can replace conventional plastics in certain applications. The global production of BDPs also gradually increases in recent years. However, unfortunately, with the application of BDPs, some potential problems are gradually exposed. The biodegradability of BDPs needs suitable conditions, which is difficult for the natural environment to reach the necessary conditions. If the degradation conditions are not met, BDPs and conventional plastics are basically the same in terms of the longevity. The biodegradable microplastics (BMPs) can also be formed by BDPs entering the environment. Up to now, the research on the degradation and application of BDPs is relatively common. The environmental and ecological effects of the BMPs, the adsorption and release of toxic substances, and the role of BMPs as vectors of microorganisms, epiphytes, and plants still need to be studied. This paper focuses on the formation mechanism and the environmental behavior of BMPs. The role of BMPs as multiple stronger vectors of microorganisms and pollutants compared to conventional microplastics is also discussed. Systematic research on environmental pollution and ecotoxicology of BMPs should be carried out as soon as possible.

ZhiJingSan Inhibits Osteoclastogenesis via Regulating RANKL/NF-κB Signaling Pathway and Ameliorates Bone Erosion in Collagen-Induced Mouse Arthritis.

Bone erosion is the most evident pathological condition of rheumatoid arthritis (RA), which is the main cause of joint deformities and disability in RA patients. At present, the conventional RA drugs have not achieved satisfactory effect in improving bone erosion. ZhiJingSan (ZJS), which is a traditional Chinese prescription composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch, scolopendridae) and scorpion (dried body of Buthus martensii Karsch, Buthus), exhibits anti-rheumatism, analgesic and joint deformities improvement effects. This study aimed to assess the therapeutic effect of ZJS on RA bone erosion and to elucidate the underlying mechanism. The effect of ZJS on RA bone erosion was investigated in a murine model of bovine collagen-induced arthritis (CIA), and the underlying mechanism was investigated in vitro in an osteoclast differentiation cell model. Administration of ZJS delayed the onset of arthritis, alleviated joint inflammation, and attenuated bone erosion in the CIA mice. Meanwhile, ZJS decreased the serum levels of TNF-α, IL-6, and anti-bovine collagen II-specific antibodies. Furthermore, ZJS treatment reduced the number of osteoclasts and the expression of cathepsin K in the ankle joints of CIA mice. ZJS also inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and the expression of MMP9 and cathepsin K in vitro. Mechanistically, ZJS blocked RANKL-induced p65 phosphorylation, nucleation, and inhibited the expression of downstream NFATc1 and c-Fos in bone marrow-derived macrophages (BMMs). Taken together, ZJS exerts a therapeutic effect on bone erosion in CIA mice by inhibiting RANKL/NF-κB-mediated osteoclast differentiation, which suggested that ZJS is a promising prescription for treating RA bone erosion.