Single-cell RNA sequencing reveals the MIF/ACKR3 receptor-ligand interaction between neutrophils and nucleus pulposus cells in intervertebral disc degeneration.

OBJECTIVES: To unravel the heterogeneity and function of microenvironmental neutrophils during intervertebral disc degeneration (IDD). METHODS: Single-cell RNA sequencing (scRNA-seq) was utilized to dissect the cellular landscape of neutrophils in intervertebral disc (IVD) tissues and their crosstalk with nucleus pulposus cells (NPCs). The expression levels of macrophage migration inhibitory factor (MIF) and ACKR3 in IVD tissues were detected. The MIF/ACKR3 axis was identified and its effects on IDD were investigated in vitro and in vivo. RESULTS: We sequenced here 71520 single cells from 5 control and 9 degenerated IVD samples using scRNA-seq. We identified a unique cluster of neutrophils abundant in degenerated IVD tissues that highly expressed MIF and was functionally enriched in extracellular matrix organization (ECMO). Cell-to-cell communication analyses showed that this ECMO-neutrophil subpopulation was closely interacted with an effector NPCs subtype, which displayed high expression of ACKR3. Further analyses revealed that MIF was positively correlated with ACKR3 and functioned via directly binding to ACKR3 on effector NPCs. MIF inhibition attenuated degenerative changes of NPCs and extracellular matrix, which could be partially reversed by ACKR3 overexpression. Clinically, a significant correlation of high MIF/ACKR3 expression with advanced IDD grade was observed. Furthermore, we also found a positive association between MIF+ ECMO-neutrophil counts and ACKR3+ effector NPCs density as well as higher expression of the MIF/ACKR3 signaling in areas where these two cell types were neighbors. CONCLUSIONS: These data suggest that ECMO-neutrophil promotes IDD progression by their communication with NPCs via the MIF/ACKR3 axis, which may shed light on therapeutic strategies.

Development and validation of a scale to measure hypertensive Chinese individual's behavior toward salt reduction consumption.

OBJECTIVE: This study aimed to develop and validate the Salt Reduction Behavior Scale (SRBS) to measure the behavior of hypertensive Chinese individuals in adhering to salt reduction practices. METHODS: The SRBS was constructed based on the Health Belief Model, consisting of five constructs: knowledge, perceived severity, perceived benefits, perceived barriers, and cues to action. Data were collected from 2,082 hypertensive patients in Beijing, China, who completed a questionnaire administered through an online platform. Kaiser-Meyer-Olkin (KMO) test was used to assess the adequacy of the sample and the Bartlett's test of sphericity to examine the factorability of the dataset. Confirmatory Factor Analysis (CFA) was used to assess the structural validity and reliability of the SRBS. RESULTS: The KMO analysis yielded a notably elevated value of 0.95, indicating that the data was highly suitable for Exploratory Factor Analysis (EFA). Bartlett's test of sphericity yielded a statistically significant test statistic (P < 0.001). The 32-item SRB questionnaire demonstrated strong internal consistency with a Cronbach's alpha coefficient of 0.923. A second-order Confirmatory Factor Analysis (CFA) revealed that, after removing the unrelated construct of barriers, SRB could be represented by four sub-constructs: knowledge, severity, benefits, and action. The final version of the SRBS consists of 21 items. These items displayed high factor loadings, indicating a strong relationship between the items and their respective sub-constructs. The discriminant validity analysis revealed that the SRBS sub-constructs were distinct from each other. The SRBS scores were positively correlated with self-reported salt reduction practices. This demonstrates that individuals with higher SRBS scores were more likely to engage in actual salt reduction behaviors, indicating concurrent validity. CONCLUSION: The results illustrate that the Salt Reduction Behavior Scale is a robust and comprehensive instrument for assessing salt reduction behavior among hypertensive Chinese individuals. The scale's specific sub-constructs provide a detailed understanding of their knowledge, attitudes, and practices related to salt consumption. Healthcare professionals and policymakers can utilize this tool to tailor interventions and educational programs to encourage healthier dietary habits, thereby reducing the risk of cardiovascular diseases in China.

Rice husk ash based growing media impact on cucumber and melon growth and quality.

Rice husk, an agricultural waste from the rice industry, can cause serious environmental pollution if not properly managed. However, rice husk ash (RHA) has been found to have many positive properties, making it a potential replacement for non-renewable peat in soilless planting. Thus, this study investigated the impact of a RHA composite substrate on the growth, photosynthetic parameters, and fruit quality of cucumber (Yuyi longxiang variety) and melon (Yutian yangjiaomi variety). The RHA, peat, vermiculite, and perlite were blended in varying proportions, with the conventional seedling substrate (peat:vermiculite:perlite = 1:1:1 volume ratio) serving as the control (CK). All plants were cultivated in barrels filled with 10L of the mixed substrates. The results from this study found that RHA 40 (RHA:peat:vermiculite:perlite = 4:4:1:1 volume ratio) significantly enhanced substrate ventilation and positively influenced the stem diameter, root activity, seedling index, chlorophyll content, net photosynthetic rate (Pn), stomatal conductance (Gs), and transpiration rate (Tr) of cucumber and melon plants. Additionally, plant planted using RHA 40, the individual fruit weight of cucumber and melon found to increase by 34.62% and 21.67%, respectively, as compared to the control. Aside from that, both cucumber and melon fruits had significantly higher sucrose, total soluble sugar, vitamin C, and soluble protein levels. This subsequently improved the activity of sucrose synthase and sucrose phosphate synthase in both cucumber and melon. In conclusion, the RHA 40 found to best promote cucumber and melon plant growth, increase plant leaf photosynthesis, and improve cucumber and melon fruit quality, making it a suitable substrate formula for cucumber and melon cultivation in place of peat.

Mask-Pyramid Network: A Novel Panoptic Segmentation Method.

In this paper, we introduce a novel panoptic segmentation method called the Mask-Pyramid Network. Existing Mask RCNN-based methods first generate a large number of box proposals and then filter them at each feature level, which requires a lot of computational resources, while most of the box proposals are suppressed and discarded in the Non-Maximum Suppression process. Additionally, for panoptic segmentation, it is a problem to properly fuse the semantic segmentation results with the Mask RCNN-produced instance segmentation results. To address these issues, we propose a new mask pyramid mechanism to distinguish objects and generate much fewer proposals by referring to existing segmented masks, so as to reduce computing resource consumption. The Mask-Pyramid Network generates object proposals and predicts masks from larger to smaller sizes. It records the pixel area occupied by the larger object masks, and then only generates proposals on the unoccupied areas. Each object mask is represented as a H × W × 1 logit, which fits well in format with the semantic segmentation logits. By applying SoftMax to the concatenated semantic and instance segmentation logits, it is easy and natural to fuse both segmentation results. We empirically demonstrate that the proposed Mask-Pyramid Network achieves comparable accuracy performance on the Cityscapes and COCO datasets. Furthermore, we demonstrate the computational efficiency of the proposed method and obtain competitive results.

Role and mechanism of esketamine in improving postoperative cognitive dysfunction in aged mice through the TLR4/MyD88/p38 MAPK pathway.

Postoperative cognitive dysfunction (POCD) is a significant concern for the elderly population worldwide. This study explored the effects of esketamine on aged mice with POCD and investigate its mechanism of action involving the TLR4/MyD88/MAPK pathway. We administrated esketamine, along with lipopolysaccharide or anisomycin, to the aged POCD mouse models. We assessed their cognitive function using the Morris water maze test. Additionally, we evaluated histopathological changes/neuronal apoptosis in the mouse hippocampal CA1 area through HE/TUNEL stainings. Furthermore, we measured IL-1ß/IL-6/TNF-α/TLR4/MyD88/MAPK (p-p38/p38) levels in mouse hippocampal tissues using ELISA/RT-qPCR/Western blotting. Lastly, we analyzed the interaction between TLR4 and MyD88 using a co-immunoprecipitation assay. Our findings showed that esketamine effectively mitigated POCD in aged mice. This was evident from the improved cognitive performance observed in the Morris water maze test, characterized by reduced escape latency/increased number of platform crossing/a higher percentage of time spent in the target quadrant. Furthermore, esketamine exhibited a protective effect against neuronal apoptosis and reduced the levels of inflammatory factors. These findings suggest that esketamine exerts an anti-inflammatory effect by downregulating TLR4/MyD88, thereby attenuating the inflammatory response associated with POCD. Additionally, esketamine suppressed the p38 MAPK pathway by inhibiting the TLR4/MyD88 signaling cascade. Esketamine demonstrated its efficacy in improving postoperative inflammation and cognitive impairment in aged mice by inhibiting the TLR4/MyD88 pathway. The activation of p38 MAPK signaling diminished the beneficial effects of esketamine in aged POCD mice. Collectively, the underlying mechanism of esketamine in mitigating POCD in aged mice involves the suppression of the TLR4/MyD88/p38 MAPK pathway.

Advances in Research on Protein Arginine Methyltransferase 2: Functions and Diseases.

Protein arginine methylation stands as a prevalent post-translational modification process, exerting vital roles in cellular signal transduction, gene expression, and cell cycle regulation. Amidst the protein arginine methyltransferase (PRMT) family, PRMT2 stands as a less explored constituent. Nonetheless, its regulatory roles in transcriptional regulation, post-transcriptional modification, methylation activity regulation, immunoregulation, and developmental regulation have garnered attention. These capabilities enable PRMT2 to exert pivotal regulatory functions in certain malignancies, metabolic disorders, inflammatory diseases, and atherosclerosis. In this review, we highlight the structure and functions of PRMT2, emphasizing its association with diseases. We also discuss PRMT2 inhibitors and explore the potential for therapeutic targeting.

Omics for deciphering oral microecology / 国际口腔科学杂志·英文版

The human oral microbiome harbors one of the most diverse microbial communities in the human body, playing critical roles in oral and systemic health. Recent technological innovations are propelling the characterization and manipulation of oral microbiota. High-throughput sequencing enables comprehensive taxonomic and functional profiling of oral microbiomes. New long-read platforms improve genome assembly from complex samples. Single-cell genomics provides insights into uncultured taxa. Advanced imaging modalities including fluorescence, mass spectrometry, and Raman spectroscopy have enabled the visualization of the spatial organization and interactions of oral microbes with increasing resolution. Fluorescence techniques link phylogenetic identity with localization. Mass spectrometry imaging reveals metabolic niches and activities while Raman spectroscopy generates rapid biomolecular fingerprints for classification. Culturomics facilitates the isolation and cultivation of novel fastidious oral taxa using high-throughput approaches. Ongoing integration of these technologies holds the promise of transforming our understanding of oral microbiome assembly, gene expression, metabolites, microenvironments, virulence mechanisms, and microbe-host interfaces in the context of health and disease. However, significant knowledge gaps persist regarding community origins, developmental trajectories, homeostasis versus dysbiosis triggers, functional biomarkers, and strategies to deliberately reshape the oral microbiome for therapeutic benefit. The convergence of sequencing, imaging, cultureomics, synthetic systems, and biomimetic models will provide unprecedented insights into the oral microbiome and offer opportunities to predict, prevent, diagnose, and treat associated oral diseases.

Salicylaldehyde as an SET-HAT Bifunctional Photocatalyst for the Intermolecular Transalkylation of Phthalimide.

Salicylaldehyde works as an efficient photocatalyst for the intermolecular transalkylation of phthalimide. The well-designed dimethyl N-hydroxyphthalimide ester proves to be a good alkylation reagent. It inhibits the competing intramolecular alkylation of alkylating reagent, enabling the site-specific synthesis of N-substituted phthalimide.

Unveiling 2,000 years of differentiation among Tungusic-speaking populations: a revised phylogeny of the paternal founder lineage C2a-M48-SK1061.

Previous studies demonstrated Y chromosome haplogroup C2a-M48-SK1061 is the only founding paternal lineage of all Tungusic-speaking populations. To infer the differentiation history of these populations, we studied more sequences and constructed downstream structure of haplogroup C2a-M48-SK1061 with better resolution. In this study, we generated 100 new sequences and co-analyzed 140 sequences of C2a-M48-SK1061 to reconstruct a highly revised phylogenetic tree with age estimates. We also performed the analysis of the geographical distribution and spatial autocorrelation of sub-branches. Dozens of new sub-branches were discovered, many sub-branches were nearly unique for Ewenki, Evens, Oroqen, Xibe, Manchu, Daur, and Mongolian. The topology of these unique sub-branches is the key evidence for understanding the complex evolutionary relationship between different Tungusic-speaking populations. The revised phylogeny provided a clear pattern for the differentiation history of haplogroup C2a-M48-SK1061 in the past 2,000 years. This study showed that the divergence pattern of founder lineage is essential to understanding the differentiation history of populations.

Prevalence and risk factors for colonisation and infection with carbapenem-resistant Enterobacterales in intensive care units: A prospective multicentre study.

OBJECTIVES: This study aimed to investigate the prevalence and risk factors for carbapenem-resistant Enterobacterales colonisation/infection at admission and acquisition among patients admitted to the intensive care unit. RESEARCH METHODOLOGY/DESIGN: A prospective and multicentre study. SETTING: This study was conducted in 24 intensive care units in Anhui, China. MAIN OUTCOME MEASURES: Demographic and clinical data were collected, and rectal carbapenem-resistant Enterobacterales colonisation was detected by active screening. Multivariate logistic regression models were used to analyse factors associated with colonisation/infection with carbapenem-resistant Enterobacterales at admission and acquisition during the intensive care unit stay. RESULTS: There were 1133 intensive care unit patients included in this study. In total, 5.9% of patients with carbapenem-resistant Enterobacterales colonisation/infection at admission, and of which 56.7% were colonisations. Besides, 8.5% of patients acquired carbapenem-resistant Enterobacterales colonisation/infection during the intensive care stay, and of which 67.6% were colonisations. At admission, transfer from another hospital, admission to an intensive care unit within one year, colonisation/infection/epidemiological link with carbapenem-resistant Enterobacterales within one year, and exposure to any antibiotics within three months were risk factors for colonisation/infection with carbapenem-resistant Enterobacterales. During the intensive care stay, renal disease, an epidemiological link with carbapenem-resistant Enterobacterales, exposure to carbapenems and beta-lactams/beta-lactamase inhibitors, and intensive care stay of three weeks or longer were associated with acquisition. CONCLUSION: The prevalence of colonisation/infection with carbapenem-resistant Enterobacterales in intensive care units is of great concern and should be monitored systematically. Particularly for the 8.5% prevalence of carbapenem-resistant Enterobacterales acquisition during the intensive care stay needs enhanced infection prevention and control measures in these setting. Surveillance of colonisation/infection with carbapenem-resistant Enterobacterales at admission and during the patient's stay represents an early identification tool to prevent further transmission of carbapenem-resistant Enterobacterales. IMPLICATIONS FOR CLINICAL PRACTICE: Carbapenem-resistant Enterobacterales colonization screening at admission and during the patient's stay is an important tool to control carbapenem-resistant Enterobacterales spread in intensive care units.

The formation of proto-austronesians: insights from a revised phylogeography of the paternal founder lineage.

OBJECTIVES: Previous studies suggested that the Y-chromosome haplogroups O2-N6-B451-AM01756 and O1a-M119 are two founder lineages of proto-Austronesians at about five thousand years ago. The objective of this study was to investigate the formation of proto-Austronesians from the perspective of the paternal gene pool. MATERIALS AND METHODS: In this study, we developed a highly evised phylogenetic tree with age estimates for haplogroup O2-N6 and early branches of O1a-M119 (M110, F1036, and F819). In addition, we also explored the geographical distribution of eight sub-branches of O2-N6 and O1a-M119, and spatial autocorrelation analysis was conducted for each sub-branch. RESULTS: The paternal lineage combination of proto-Austronesians is a small subset of a diverse gene pool of populations from the mainland of East Asia. The distribution map and results of the spatial autocorrelation analysis suggested that the eastern coastal region of northern China is likely the source of lineage O2-N6 while the coastal region of southeastern China is likely the diffusion center of early branches of O1a-M119. We developed an evolutionary diagram for Austronesians and their ancestors in the past 18,000 years. DISCUSSION: We proposed that the millet farming community in North China is the common ancestor group of the Austronesians and the Han people, while the diverse ancient people in the southeast coastal areas of East Asia form the common ancestor group of the Austronesians and the East Asian mainland population. The demographic history of multiple ancestral groups of the most recent common ancestor group itself in the more ancient period is helpful to understand the deep roots of the genetic components and cultural traditions of Austronesians.

Iron-Catalyzed Aerobic α,ß-Dehydrogenation.

An iron-catalyzed direct aerobic α,ß-dehydrogenation of carbonyls has been reported. The combination of tert-butyl nitrite and N-hydroxyphthalimide worked as the organo cocatalyst system; thus, no extra transition metal reagents are required. A large variety of lactams and flavanones as well as lactone and thiochromen-4-one could be produced via this method in high yields.

[Chemical constituents in Dolomiaea plants and their pharmacological activities: a review].

Dolomiaea plants are perennial herbs in the Asteraceae family with a long medicinal history. They are rich in chemical constituents, mainly including sesquiterpenes, phenylpropanoids, triterpenes, and steroids. The extracts and chemical constituents of Dolomiaea plants have various pharmacological effects, such as anti-inflammatory, antibacterial, antitumor, anti-gastric ulcer, hepatoprotective and choleretic effects. However, there are few reports on Dolomiaea plants. This study systematically reviewed the research progress on the chemical constituents and pharmacological effects of Dolomiaea plants to provide references for the further development and research of Dolomiaea plants.

Endo/Exo-Controllable Photocyclization by EnT-SET-Switch.

CBZ6, a redox-neutral non-donor-acceptor-type organo-photocatalyst, presents a strong reductive potential with an oxidative potential of -2.16 V (vs SCE). It can work as a photosensitizer for both single-electron transfer and triplet energy transfer processes. This feature enables site-selective control in the intramolecular hydroarylation of acrylamides. Both 5-exo-trig and 6-endo-trig cyclization products could be prepared regiospecfically under mild conditions. No transition metal, halogen-containing reagents, or additional reductant or oxidant is involved. This process provides a concise and environmentally sustainable access to a series of oxindoles and dihydroquinolinones.

The impacts of bronze age in the gene pool of Chinese: Insights from phylogeographics of Y-chromosomal haplogroup N1a2a-F1101.

Objectives: Previous studies of archaeology and history suggested that the rise and prosperity of Bronze Age culture in East Asia had made essential contribution to the formation of early state and civilization in this region. However, the impacts in perspective of genetics remain ambiguous. Previous genetic researches indicated the Y-chromosome Q1a1a-M120 and N1a2a-F1101 may be the two most important paternal lineages among the Bronze Age people in ancient northwest China. Here, we investigated the 9,000-years history of haplogroup N1a2a-F1101 with revised phylogenetic tree and spatial autocorrelation analysis. Materials and Methods: In this study, 229 sequences of N1a2a-F1101 were analyzed. We developed a highly-revised phylogenetic tree with age estimates for N1a2a-F1101. In addition, we also explored the geographical distribution of sub-lineages of N1a2a-F1101, and spatial autocorrelation analysis was conducted for each sub-branch. Results: The initial differentiation location of N1a2a-F1101 and its most closely related branch, N1a2b-P43, a major lineage of Uralic-speaking populations in northern Eurasia, is likely the west part of northeast China. After ~4 thousand years of bottleneck effect period, haplgroup N1a2a-F1101 experienced continuous expansion during the Chalcolithic age (~ 4.5 kya to 4 kya) and Bronze age (~ 4 kya to 2.5 kya) in northern China. Ancient DNA evidence supported that this haplogroup is the lineage of ruling family of Zhou Dynasty (~ 3 kya-2.2 kya) of ancient China. Discussion: In general, we proposed that the Bronze Age people in the border area between the eastern Eurasian steppe and northern China not only played a key role in promoting the early state and civilization of China, but also left significant traces in the gene pool of Chinese people.

Traditional Chinese medicine Euodiae Fructus: botany, traditional use, phytochemistry, pharmacology, toxicity and quality control.

Euodiae Fructus, referred to as "Wuzhuyu" in Chinese, has been used as local and traditional herbal medicines in many regions, especially in China, Japan and Korea, for the treatment of gastrointestinal disorders, headache, emesis, aphtha, dermatophytosis, dysentery, etc. Substantial investigations into their chemical and pharmacological properties have been performed. Recently, interest in this plant has been focused on the different structural types of alkaloids like evodiamine, rutaecarpine, dehydroevodiamine and 1-methyl-2-undecyl-4(1H)-quinolone, which exhibit a wide range of pharmacological activities in preclinical models, such as anticancer, antibacterial, anti-inflammatory, anti-cardiovascular disease, etc. This review summarizes the up-to-date and comprehensive information concerning the botany, traditional uses, phytochemistry, pharmacology of Euodiae Fructus together with the toxicology and quality control, and discusses the possible direction and scope for future research on this plant.

Amide Proton Transfer-weighted MRI combined with serum prostate-specific antigen levels for differentiating malignant prostate lesions from benign prostate lesions: a retrospective cohort study.

BACKGROUND: Early diagnosis of prostate cancer improves its prognosis, while it is essential to upgrade screening tools. This study aimed to explore the value of a novel functional magnetic resonance imaging (MRI) technique, namely amide proton transfer (APT)-weighted MRI, combined with serum prostate-specific antigen (PSA) levels to differentiate malignant prostate lesions from benign prostate lesions. METHODS: Data of patients who underwent prostate examinations at Chongqing University Cancer Hospital between July 2019 and March 2022 were retrospectively analyzed. All patients underwent T2-weighted imaging (T2WI), APT, diffusion-weighted imaging (DWI), and dynamic contrast-enhanced (DCE) MRI. Two radiologists analyzed the images independently. The ability of the quantitative parameters alone or in different combinations in differentiating malignant prostate lesions from benign prostate lesions were compared by using receiver operating characteristic (ROC) curves. According to the DeLong test, the combined parameters were significantly different from the corresponding single parameter (P < 0.05). RESULTS: A total of 79 patients were finally enrolled, including 52 patients in the malignant group and 27 patients in the benign group. The separate assessment of indexes revealed that APTmax, APTmean, mean apparent diffusion coefficient (ADCmean), ADCmax, ADCmin, tPAD, free prostate-specific antigen (FPSA), FPSA/total prostate-specific antigen (tPSA), and PSA density (PSAD) were significantly different between the two groups (P < 0.05), while APTmin was not significantly different between the two groups (P > 0.05). APTmax and APTmean had the high values of area under the ROC curve (AUC), which were 0.780 and 0.710, respectively. APTmax had a high sensitivity, and APTmean had a high specificity. The combination of APTmax, APTmean, ADCmean, and PSAD had the highest AUC value (AUC: 0.880, sensitivity: 86.540, specificity: 78.260). CONCLUSION: APTmax, APTmean, ADCmean, ADCmin, tPAD, FPSA, and PSAD showed to have a high value in differentiating malignant prostate lesions from benign prostate lesions in the separate assessment of indexes. The combination of APTmax, APTmean, ADCmean, and PSAD had the highest diagnostic value.

Immunoproteasome inhibition prevents progression of castration-resistant prostate cancer.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment. This study aims to explore the effect and underlying mechanisms of immunoproteasome inhibition, a novel immunotherapy, on the progression of CRPC. METHODS: The immunoproteasome subunit LMP7 was silenced by using gene knockout or inhibited by the epoxyketone inhibitor ONX 0914 in a mouse CRPC tumour graft model and in interferon-γ-pretreated human CRPC cell lines in vitro. RESULTS: CRPC tissues reveal a significant "tumour-elicited" Th17-type inflammatory response which induces immunoproteasome subunit expression. LMP7 deficiency in host mice or in CRPC tumour grafts had no effect on the "tumour-elicited" Th17-type inflammatory response and tumour progression. However, the selective LMP7 inhibitor ONX 0914 strongly suppressed the "tumour-elicited" Th17-type inflammatory response and CRPC tumour progression. Treatment of wild-type mice receiving LMP7-deficient CRPC tumour grafts with ONX 0914 further suggested that immunoproteasome inhibition prevents CRPC progression through suppressing IL-17-induced angiogenesis and epithelial-mesenchymal transition via inactivation of COX-2/VEGF-A signalling and ß-catenin/Snail signalling. Treatment of LMP7-deficient mice receiving wild-type CRPC tumour grafts with ONX 0914 and inhibition of LMP7 in PC3 and 22Rv.1 cells with ONX 0914 showed that immunoproteasome inhibition also prevents CRPC progression through inducing CRPC cell apoptosis via activation of the unfolded protein response. CONCLUSIONS: We define a critical role of the immunoproteasome in CRPC and propose immunoproteasome inhibition as a promising therapeutic approach to suppress CRPC progression.

Co-inhibition of immunoproteasome subunits LMP2 and LMP7 enables prevention of transplant arteriosclerosis.

AIMS: The loss of vascular wall cells in allotransplanted arteries is the initial event leading to transplant arteriosclerosis (TA) and ensuing loss of allograft function. Pharmacological agents able to prevent TA are currently lacking. We previously showed that selective inhibition of the immunoproteasome prevented the chronic rejection of renal allografts. However, the role and mechanisms of selective inhibition of a single immunoproteasome subunit to prevent immune-mediated vascular allograft rejection and TA is not clear. METHODS AND RESULTS: The effect and potential mechanism of combined or individual inhibition of peptidolytically active immunoproteasome LMP7 (ß5i) and LMP2 (ß1i) subunits on immune rejection-mediated TA was investigated using the epoxyketone inhibitor ONX 0914, and the recently developed LMP7-selective inhibitor KZR-329 and LMP2-selective inhibitor KZR-504 in a rat aorta transplantation model. We find that co-inhibition of LMP7 and LMP2 in allogeneic recipients significantly suppressed T-cell activation and function by expressing inhibitory surface markers and then activating inhibitory signals. Moreover, co-inhibition of LMP7 and LMP2 substantially reduced the number of immunoglobulin G-secreting cells and plasma cells and production of alloantibodies through activating the unfolded protein response and incapacitating the survival niche of plasma cells in the bone marrow. Consequentially, the accumulation of inflammatory cytokines, complement, and antibodies is reduced and the apoptosis of vascular wall cells decreased in aortic allografts via LMP7 and LMP2 co-inhibition with ONX 0914 treatment or combined KZR-329 and KZR-504 treatment. However, neither individual inhibition of LMP7 by KZR-329 nor individual inhibition of LMP2 by KZR-504 showed suppression of immune rejection and TA. CONCLUSIONS: We define a critical role of LMP7 and LMP2 in TA and strongly propose co-inhibition of both immunoproteasome subunits as promising therapeutic approach to suppress TA and allograft rejection.

An esterase-responsive ibuprofen nano-micelle pre-modified embryo derived nucleus pulposus progenitor cells promote the regeneration of intervertebral disc degeneration.

Stem cell-based transplantation is a promising therapeutic approach for intervertebral disc degeneration (IDD). Current limitations of stem cells include with their insufficient cell source, poor proliferation capacity, low nucleus pulposus (NP)-specific differentiation potential, and inability to avoid pyroptosis caused by the acidic IDD microenvironment after transplantation. To address these challenges, embryo-derived long-term expandable nucleus pulposus progenitor cells (NPPCs) and esterase-responsive ibuprofen nano-micelles (PEG-PIB) were prepared for synergistic transplantation. In this study, we propose a biomaterial pre-modification cell strategy; the PEG-PIB were endocytosed to pre-modify the NPPCs with adaptability in harsh IDD microenvironment through inhibiting pyroptosis. The results indicated that the PEG-PIB pre-modified NPPCs exhibited inhibition of pyroptosis in vitro; their further synergistic transplantation yielded effective functional recovery, histological regeneration, and inhibition of pyroptosis during IDD regeneration. Herein, we offer a novel biomaterial pre-modification cell strategy for synergistic transplantation with promising therapeutic effects in IDD regeneration.