Cyclic stretch promotes vascular homing of endothelial progenitor cells via Acsl1 regulation of mitochondrial fatty acid oxidation.

Endothelial progenitor cells (EPCs) play an important role in vascular repair and re-endothelialization after vessel injury. EPCs in blood vessels are subjected to cyclic stretch (CS) due to the pulsatile pressure, but the role of CS in metabolic reprogramming of EPC, particularly its vascular homing and repair, is largely unknown. In the current study, physiological CS applied to EPCs at a magnitude of 10% and a frequency of 1 Hz significantly promoted their vascular adhesion and endothelial differentiation. CS enhanced mitochondrial elongation and oxidative phosphorylation (OXPHOS), as well as adenosine triphosphate production. Metabolomic study and Ultra-high performance liquid chromatography-mass spectrometry assay revealed that CS significantly decreased the content of long-chain fatty acids (LCFAs) and markedly induced long-chain fatty acyl-CoA synthetase 1 (Acsl1), which in turn facilitated the catabolism of LCFAs in mitochondria via fatty acid ß-oxidation and OXPHOS. In a rat carotid artery injury model, transplantation of EPCs overexpressing Acsl1 enhanced the adhesion and re-endothelialization of EPCs in vivo. MRI and vascular morphology staining showed that Acsl1 overexpression in EPCs improved vascular repair and inhibited vascular stenosis. This study reveals a mechanotransduction mechanism by which physiological CS enhances endothelial repair via EPC patency.

Marrow mesenchymal stem cell mediates diabetic nephropathy progression via modulation of Smad2/3/WTAP/m6A/ENO1 axis.

Diabetic nephropathy (DN) is one of the common microvascular complications in diabetic patients. Marrow mesenchymal stem cells (MSCs) have attracted attention in DN therapy but the underlying mechanism remains unclear. Here, we show that MSC administration alleviates high glucose (HG)-induced human kidney tubular epithelial cell (HK-2 cell) injury and ameliorates renal injury in DN mice. We identify that Smad2/3 is responsible for MSCs-regulated DN progression. The activity of Smad2/3 was predominantly upregulated in HG-induced HK-2 cell and DN mice and suppressed with MSC administration. Activation of Smad2/3 via transforming growth factor-ß1 (TGF-ß1) administration abrogates the protective effect of MSCs on HG-induced HK-2 cell injury and renal injury of DN mice. Smad2/3 has been reported to interact with methyltransferase of N6-methyladenosine (m6A) complex and we found a methyltransferase, Wilms' tumor 1-associating protein (WTAP), is involved in MSCs-Smad2/3-regulated DN development. Moreover, WTAP overexpression abrogates the improvement of MSCs on HG-induced HK-2 cell injury and renal injury of DN mice. Subsequently, α-enolase (ENO1) is the downstream target of WTAP-mediated m6A modification and contributes to the MSCs-mediated regulation. Collectively, these findings reveal a molecular mechanism in DN progression and indicate that Smad2/3/WTAP/ENO1 may present a target for MSCs-mediated DN therapy.

UPK3A+ umbrella cell damage mediated by TLR3-NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome.

Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A+ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A+ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A+ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A+ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A+ umbrella cells in HIC urothelium. Finally, we conducted in vitro and in vivo experiments to confirm the potential of the TLR3-NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.

Loss of aryl hydrocarbon receptor potentiates FoxM1 signaling to enhance self-renewal of colonic stem and progenitor cells.

The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that senses xenobiotics, diet, and gut microbial-derived metabolites, is increasingly recognized as a key regulator of intestinal biology. However, its effects on the function of colonic stem and progenitor cells remain largely unexplored. Here, we observed that inducible deletion of AhR in Lgr5+ stem cells increases the percentage of colonic stem cells and enhances organoid initiating capacity and growth of sorted stem and progenitor cells, while AhR activation has the opposite effect. Moreover, intestinal-specific AhR knockout increases basal stem cell and crypt injury-induced cell proliferation and promotes colon tumorigenesis in a preclinical colitis-associated tumor model by upregulating FoxM1 signaling. Mechanistically, AhR transcriptionally suppresses FoxM1 expression. Activation of AhR in human organoids recapitulates phenotypes observed in mice, such as reduction in the percentage of colonic stem cells, promotion of stem cell differentiation, and attenuation of FoxM1 signaling. These findings indicate that the AhR-FoxM1 axis, at least in part, mediates colonic stem/progenitor cell behavior.

Platelet-derived microvesicles regulate vascular smooth muscle cell energy metabolism via PRKAA after intimal injury.

Vascular intimal injury initiates various cardiovascular disease processes. Exposure to subendothelial collagen can cause platelet activation, leading to collagen-activated platelet-derived microvesicles (aPMVs) secretion. In addition, vascular smooth muscle cells (VSMCs) exposed to large amounts of aPMVs undergo abnormal energy metabolism; they proliferate excessively and migrate after the loss of endothelium, eventually contributing to neointimal hyperplasia. However, the roles of aPMVs in VSMC energy metabolism are still unknown. Our carotid artery intimal injury model indicated that platelets adhered to injured blood vessels. In vitro, phosphorylated Pka (cAMP-dependent protein kinase) content was increased in aPMVs. We also found that aPMVs significantly reduced VSMC glycolysis and increased oxidative phosphorylation, and promoted VSMC migration and proliferation by upregulating phosphorylated PRKAA (α catalytic subunit of AMP-activated protein kinase) and phosphorylated FoxO1. Compound C, an inhibitor of PRKAA, effectively reversed the enhancement of cellular function and energy metabolism triggered by aPMVs in vitro and neointimal formation in vivo. We show that aPMVs can affect VSMC energy metabolism through the Pka-PRKAA-FoxO1 signaling pathway and this ultimately affects VSMC function, indicating that the shift in VSMC metabolic phenotype by aPMVs can be considered a potential target for the inhibition of hyperplasia. This provides a new perspective for regulating the abnormal activity of VSMCs after injury.

Safety, pharmacokinetics and pharmacodynamics of HRS-7535, a novel oral small molecule glucagon-like peptide-1 receptor agonist, in healthy participants: A phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose, and food effect trial.

AIM: To assess the safety, tolerability, pharmacokinetics (PKs) and pharmacodynamics of HRS-7535, a novel glucagon-like peptide-1 receptor agonist (GLP-1RA), in healthy participants. MATERIALS AND METHODS: This phase 1 trial consisted of single-ascending dose (SAD), food effect (FE) and multiple-ascending dose (MAD) parts. In the SAD part, participants were randomized (6:2) to receive HRS-7535 (at doses of 15, 60 and 120 mg; administered orally once daily) or placebo. In the FE part, participants were randomized (8:2) to receive a single dose of 90-mg HRS-7535 or placebo, in both fed and fasted states. In the MAD part, participants were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120-mg titration scheme]) or placebo for 28 days. The primary endpoints were safety and tolerability. RESULTS: Nausea and vomiting were the most frequently reported AEs across all three parts. In the SAD part, the median Tmax was 5.98-5.99 hours and the geometric mean t1/2 was 5.28-9.08 hours across the HRS-7535 dosing range. In the MAD part, the median Tmax was 5.98-10.98 hours and the geometric mean t1/2 was 6.48-8.42 hours on day 28 in participants on HRS-7535. PKs were approximately dose-proportional. On day 29 in the MAD part, the mean (percentage) reduction in body weight from baseline was 4.38 kg (6.63%) for participants who received HRS-7535, compared with 0.8 kg (1.18%) for those participants who received a placebo. CONCLUSIONS: HRS-7535 exhibited a safety and tolerability profile consistent with other GLP-1RAs and showed PKs suitable for once-daily dosing. These findings support further clinical development of HRS-7535 for type 2 diabetes.

A spontaneous hyperglycaemic cynomolgus monkey presents cognitive deficits, neurological dysfunction and cataract.

Chronic hyperglycaemia is a chief feature of diabetes mellitus and complicates with many systematic anomalies. Non-human primates (NHPs) are excellent for studying hyperglycaemia or diabetes and associated comorbidities, but lack behavioural observation. In the study, behavioural, brain imaging and histological analysis were performed in a case of spontaneously hyperglycaemic (HGM) Macaca fascicularis. The results were shown that the HGM monkey had persistent body weight loss, long-term hyperglycaemia, insulin resistance, dyslipidemia, but normal concentrations of insulin, C-peptide, insulin autoantibody, islet cell antibody and glutamic acid decarboxylase antibody. Importantly, an impaired working memory in a delayed response task and neurological dysfunctions were found in the HGM monkey. The tendency for atrophy in hippocampus was observed by magnetic resonance imaging. Lenticular opacification, lens fibres disruptions and vacuole formation also occurred to the HGM monkey. The data suggested that the spontaneous HGM monkey might present diabetes-like characteristics and associated neurobehavioral anomalies in this case. This study first reported cognitive deficits in a spontaneous hyperglycaemia NHPs, which might provide evidence to use macaque as a promising model for translational research in diabetes and neurological complications.

A sensory signature of unaffected biological parents predicts the risk of autism in their offspring.

AIM: Despite the emphasis on sensory dysfunction phenotypes in the revised diagnostic criteria for autism spectrum disorder (ASD), there has been limited research, particularly in the field of neurobiology, investigating the concordance in sensory features between individuals with ASD and their genetic relatives. Therefore, our objective was to examine whether neurobehavioral sensory patterns could serve as endophenotypic markers for ASD. METHODS: We combined questionnaire- and lab-based sensory evaluations with sensory fMRI measures to examine the patterns of sensory responsivity in 30 clinically diagnosed with ASD, 26 matched controls (CON), and 48 biological parents for both groups (27 parents of individuals with ASD [P-ASD] and 21 for individuals with CON [P-CON]). RESULTS: The ASD and P-ASD groups had higher sensory responsivity and rated sensory stimuli as more unpleasant than the CON and P-CON groups, respectively. They also exhibited greater hemodynamic responses within the sensory cortices. Overlapping activations were observed within these sensory cortices in the ASD and P-ASD groups. Using a machine learning approach with robust prediction models across cohorts, we demonstrated that the sensory profile of biological parents accurately predicted the likelihood of their offspring having ASD, achieving a prediction accuracy of 71.4%. CONCLUSIONS: These findings provide support for the hereditary basis of sensory alterations in ASD and suggest a potential avenue to improve ASD diagnosis by utilizing the sensory signature of biological parents, especially in families with a high risk of ASD. This approach holds promising prospects for early detection, even before the birth of the offspring.

LncRNA ASB16-AS1 accelerates cellular process and chemoresistance of ovarian cancer cells by regulating GOLM1 expression via targeting miR-3918.

BACKGROUND: Reportedly, ovarian cancer (OC) is a major threat to women's health. Long non-coding RNA (lncRNA) ASB16-AS1 has been uncovered to participate in cancer progression. Nevertheless, the role of ASB16-AS1 in OC remains to be revealed. PURPOSE: This study aimed to unveil the biological function of ASB16-AS1 and its underlying mechanisms in OC cells. METHODS: QRT-PCR was done to test ASB16-AS1 expression in OC cells. Functional assays were performed to evaluate the malignant behaviors and cisplatin resistance of OC cells. Mechanistic analyses were done to investigate the regulatory molecular mechanism in OC cells. RESULTS: ASB16-AS1 was found to be highly expressed in OC cells. ASB16-AS1 knockdown repressed proliferation, migration, and invasion of OC cells, while facilitating cell apoptosis. ASB16-AS1 was further validated to up-regulate GOLM1 through competitively binding with miR-3918. Moreover, miR-3918 overexpression was corroborated to suppress OC cell growth. Rescue assays further uncovered that ASB16-AS1 modulated the malignant processes of OC cells via targeting miR-3918/GOLM1 axis. CONCLUSION: ASB16-AS1 facilitates the malignant processes and chemoresistance of OC cells via serving as miR-3918 sponge and positively modulating GOLM1 expression.

Back translation for molecule generation.

MOTIVATION: Molecule generation, which is to generate new molecules, is an important problem in bioinformatics. Typical tasks include generating molecules with given properties, molecular property improvement (i.e. improving specific properties of an input molecule), retrosynthesis (i.e. predicting the molecules that can be used to synthesize a target molecule), etc. Recently, deep-learning-based methods received more attention for molecule generation. The labeled data of bioinformatics is usually costly to obtain, but there are millions of unlabeled molecules. Inspired by the success of sequence generation in natural language processing with unlabeled data, we would like to explore an effective way of using unlabeled molecules for molecule generation. RESULTS: We propose a new method, back translation for molecule generation, which is a simple yet effective semisupervised method. Let X be the source domain, which is the collection of properties, the molecules to be optimized, etc. Let Y be the target domain which is the collection of molecules. In particular, given a main task which is about to learn a mapping from the source domain X to the target domain Y, we first train a reversed model g for the Y to X mapping. After that, we use g to back translate the unlabeled data in Y to X and obtain more synthetic data. Finally, we combine the synthetic data with the labeled data and train a model for the main task. We conduct experiments on molecular property improvement and retrosynthesis, and we achieve state-of-the-art results on four molecule generation tasks and one retrosynthesis benchmark, USPTO-50k. AVAILABILITY AND IMPLEMENTATION: Our code and data are available at https://github.com/fyabc/BT4MolGen. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Discovering drug-target interaction knowledge from biomedical literature.

MOTIVATION: The interaction between drugs and targets (DTI) in human body plays a crucial role in biomedical science and applications. As millions of papers come out every year in the biomedical domain, automatically discovering DTI knowledge from biomedical literature, which are usually triplets about drugs, targets and their interaction, becomes an urgent demand in the industry. Existing methods of discovering biological knowledge are mainly extractive approaches that often require detailed annotations (e.g. all mentions of biological entities, relations between every two entity mentions, etc.). However, it is difficult and costly to obtain sufficient annotations due to the requirement of expert knowledge from biomedical domains. RESULTS: To overcome these difficulties, we explore an end-to-end solution for this task by using generative approaches. We regard the DTI triplets as a sequence and use a Transformer-based model to directly generate them without using the detailed annotations of entities and relations. Further, we propose a semi-supervised method, which leverages the aforementioned end-to-end model to filter unlabeled literature and label them. Experimental results show that our method significantly outperforms extractive baselines on DTI discovery. We also create a dataset, KD-DTI, to advance this task and release it to the community. AVAILABILITY AND IMPLEMENTATION: Our code and data are available at https://github.com/bert-nmt/BERT-DTI. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Effect of SHR0302 on the pharmacokinetics of CYP3A4, CYP2C8, CYP2C9 and CYP2C19 probe substrates in healthy volunteers: A cocktail analysis.

AIMS: This study evaluated the effects of SHR0302 on the pharmacokinetics of cytochrome P450 (CYP) probe substrates. METHODS: We performed a single-centre, open-label, three-period drug-drug interaction (DDI) study in 24 healthy subjects (NCT05392127). Subjects received a single oral dose of 5 mg warfarin (CYP2C9), 20 mg omeprazole (CYP2C19) and 15 mg midazolam (CYP3A4) on Days 1, 8 and 22, and received 0.5 mg repaglinide (CYP2C8) on Days 7, 14 and 28. Multiple oral doses of 8 mg SHR0302 were administered once daily from Day 8 to Day 28. RESULTS: The exposure of S-warfarin and repaglinide were comparable before and after SHR0302 administration. AUC of midazolam was not affected by SHR0302, whereas the administration of SHR0302 slightly decreased the Cmax of midazolam by 7.6% (single dose) and 15.7% (once daily for 14 days). The AUC0-t , AUC0-inf , and Cmax of omeprazole were slightly decreased after a single dose of SHR0302 by 19.2%, 21.8% and 23.5%, respectively. In the presence of SHR0302 for 14 days, the AUC0-t , AUC0-inf , and Cmax of omeprazole were marginally reduced by 3.0%, 16.4% and 8.3%, respectively. According to the induction mechanism of the CYP enzyme, for the investigation of the induction effect, the results of multiple administrations of the perpetrator were more reliable than those of the single dose. CONCLUSIONS: The results demonstrated that co-administration of SHR0302 8 mg once daily is unlikely to have a clinically meaningful effect on the exposure of drugs metabolized by CYP3A4, CYP2C8, CYP2C9 and CYP2C19 in healthy subjects.

Meta-Analysis of Electroencephalographic Correlates and Cognitive Performance for Acute Exercise-Induced Modulation.

INTRODUCTION: Although abundant research delving into the acute exercise-induced modulation of cognitive performance and the P300-ERP component has been conducted, there is a lack of consensus regarding whether or not this type of intervention has a beneficial effect on cognition and how it relates to the P300-ERP. METHODS: To examine the possible sources of this discrepancy, we conducted a meta-analysis of ERP results together with cognitive performance that were systemically stratified by relevant demographic and methodological moderators. RESULTS: Our results indicate that while acute exercise exerted an overall stable effect on cognitive improvement, associated with enlarged P300 amplitudes, the effect size varied across factors of age, biological sex, exercise intensity, exercise type, control type, and experimental design. Future research taking into consideration modulating factors as to avoid misestimating the beneficial effects of acute exercise are encouraged. CONCLUSION: All in all, and to our knowledge, this is the first meta-analysis quantitatively summarizing the relevant literature on the associations between P300-ERP correlates, acute exercise, and its positive influence on attention and cognitive performance in healthy individuals.

Mature B-cell lymphoma with acute myelitis as the first presentation: a case report and literature review.

BACKGROUND: Lymphomas are malignant tumors of the immune system that arise in lymphoid organs and can impact the central nervous system. However, lymphomas with acute myelitis as the first manifestation are exceedingly rare, and most of them are symptoms of spinal cord damage due to the lack of specificity in their clinical manifestations. The rate of early misdiagnosis is exceedingly high, and the prognosis is dire. Here, we report a case of mature B-cell lymphoma with acute myelitis as the first presentation and review the related literature. CASE PRESENTATION: In this study, We report a case of a 70-year-old male patient with bilateral lower extremity weakness, bowel and bladder dysfunction, and recurrent fever. A paraureteral mass was seen beneath the right kidney on imaging, and the final pathological biopsy revealed: CD20 ( +), mature B-cell tumor, The patient refused to undergo additional tests to ascertain the type of lymphoma and subsequent therapy and asked to be discharged. In mid-November 2020, the patient died. CONCLUSIONS: This case report shows that patients with lymphoma can present with acute myelitis as the first symptom, especially if they have recurrent fever, that conventional treatment for myelitis is ineffective, and that tumors are considered after other causes of myelitis have been ruled out. Furthermore, a focused search for tumor-related evidence, as well as early identification and therapy, may help patients live longer lives.

Rapamycin attenuates pyroptosis by suppressing mTOR phosphorylation and promoting autophagy in LPS-induced bronchopulmonary dysplasia.

PURPOSE/AIM: Bronchopulmonary dysplasia (BPD) is associated with poor survival in preterm infants. Intrauterine infection can aggravate the degree of obstruction of alveolar development in premature infants; however, the pathogenic mechanism remains unclear. In this study, we sought to determine whether pyroptosis could be inhibited by downregulating mammalian target of rapamycin (mTOR) activation and inducing autophagy in BPD-affected lung tissue. MATERIALS AND METHODS: We established a neonatal rat model of BPD induced by intrauterine infection via intraperitoneally injecting pregnant rats with lipopolysaccharide (LPS). Subsequently, mTOR levels and pyroptosis were evaluated using immunohistochemistry, immunofluorescence, TUNEL staining, and western blotting. The Shapiro-Wilk test was employed to assess the normality of the experimental data. Unpaired t-tests were used to compare the means between two groups, and comparisons between multiple groups were performed using analysis of variance. RESULTS: Pyroptosis of lung epithelial cells increased in BPD lung tissues. After administering an mTOR phosphorylation inhibitor (rapamycin) to neonatal rats with BPD, the level of autophagy increased, while the expression of autophagy cargo adaptors, LC3 and p62, did not differ. Following rapamycin treatment, NLRP3, Pro-caspase-1, caspase-1, pro-IL-1ß, IL-1ß, IL-18/Pro-IL-18, N-GSDMD/GSDMD, Pro-caspase-11, and caspase-11 were negatively regulated in BPD lung tissues. The opposite results were observed after treatment with the autophagy inhibitor MHY1485, showing an increase in pyroptosis and a significant decrease in the number of alveoli in BPD. CONCLUSIONS: Rapamycin reduces pyroptosis in neonatal rats with LPS-induced BPD by inhibiting mTOR phosphorylation and inducing autophagy; hence, it may represent a potential therapeutic for treating BPD.

Non-suicidal self-injury and professional psychological help-seeking among Chinese left-behind children: prevalence and influencing factors.

BACKGROUND: Non-suicidal self-injury (NSSI) is a risk factor for suicide. This study aimed to investigate the prevalence of NSSI and professional psychological help-seeking status and influencing factors among left-behind children (LBC) in China. METHODS: We implemented a population-based cross-sectional study in participants aged 10-18 years. Sociodemographic characteristics, NSSI, help-seeking status and coping style were measured by self-reported questionnaires. A total of 16,866 valid questionnaires were collected, including 6096 LBC. Binary logistic regression models were used to analyze the factors influencing NSSI and professional psychological help-seeking. RESULTS: The incidence of NSSI among LBC was 4.6%, significantly higher than that of non-left-behind children (NLBC). This incidence was higher among girls. Moreover, 53.9% of LBC with NSSI did not receive any treatment and only 22.0% sought professional psychological help. LBC often adopt emotion-oriented coping styles, specifically, those with NSSI. LBC with NSSI who seek professional help tend to adopt problem-oriented coping styles. Logistic regression analysis revealed that girls, learning stage, single-parent, remarried families, patience, and emotional venting were risk factors for NSSI in LBC, while problem-solving and social support seeking were protective factors. Moreover, problem-solving was also a predictor for seeking professional psychological help, patience will prevent it. LIMITATIONS: This was an online survey. CONCLUSIONS: The prevalence of NSSI in LBC is high. Gender, grade, family structure, and coping style affect the occurrence of NSSI among LBC. Only a few LBC with NSSI seek professional psychological help, while the coping style will affect the help-seeking behavior.

Magnetofection of miR-21 promoted by electromagnetic field and iron oxide nanoparticles via the p38 MAPK pathway contributes to osteogenesis and angiogenesis for intervertebral fusion.

BACKGROUND: Magnetofection-mediated gene delivery shows great therapeutic potential through the regulation of the direction and degree of differentiation. Lumbar degenerative disc disease (DDD) is a serious global orthopaedic problem. However, even though intervertebral fusion is the gold standard for the treatment of DDD, its therapeutic effect is unsatisfactory. Here, we described a novel magnetofection system for delivering therapeutic miRNAs to promote osteogenesis and angiogenesis in patients with lumbar DDD. RESULTS: Co-stimulation with electromagnetic field (EMF) and iron oxide nanoparticles (IONPs) enhanced magnetofection efficiency significantly. Moreover, in vitro, magnetofection of miR-21 into bone marrow mesenchymal stem cells (BMSCs) and human umbilical endothelial cells (HUVECs) influenced their cellular behaviour and promoted osteogenesis and angiogenesis. Then, gene-edited seed cells were planted onto polycaprolactone (PCL) and hydroxyapatite (HA) scaffolds (PCL/HA scaffolds) and evolved into the ideal tissue-engineered bone to promote intervertebral fusion. Finally, our results showed that EMF and polyethyleneimine (PEI)@IONPs were enhancing transfection efficiency by activating the p38 MAPK pathway. CONCLUSION: Our findings illustrate that a magnetofection system for delivering miR-21 into BMSCs and HUVECs promoted osteogenesis and angiogenesis in vitro and in vivo and that magnetofection transfection efficiency improved significantly under the co-stimulation of EMF and IONPs. Moreover, it relied on the activation of p38 MAPK pathway. This magnetofection system could be a promising therapeutic approach for various orthopaedic diseases.

Mesenchymal stem cells, as glioma exosomal immunosuppressive signal multipliers, enhance MDSCs immunosuppressive activity through the miR-21/SP1/DNMT1 positive feedback loop.

BACKGROUND: The immunosuppressive microenvironment in glioma induces immunotherapy resistance and is associated with poor prognosis. Glioma-associated mesenchymal stem cells (GA-MSCs) play an important role in the formation of the immunosuppressive microenvironment, but the mechanism is still not clear. RESULTS: We found that GA-MSCs promoted the expression of CD73, an ectonucleotidase that drives immunosuppressive microenvironment maintenance by generating adenosine, on myeloid-derived suppressor cells (MDSCs) through immunosuppressive exosomal miR-21 signaling. This process was similar to the immunosuppressive signaling mediated by glioma exosomal miR-21 but more intense. Further study showed that the miR-21/SP1/DNMT1 positive feedback loop in MSCs triggered by glioma exosomal CD44 upregulated MSC exosomal miR-21 expression, amplifying the glioma exosomal immunosuppressive signal. Modified dendritic cell-derived exosomes (Dex) carrying miR-21 inhibitors could target GA-MSCs and reduce CD73 expression on MDSCs, synergizing with anti-PD-1 monoclonal antibody (mAb). CONCLUSIONS: Overall, this work reveals the critical role of MSCs in the glioma microenvironment as signal multipliers to enhance immunosuppressive signaling of glioma exosomes, and disrupting the positive feedback loop in MSCs with modified Dex could improve PD-1 blockade therapy.

Proteomic Profiling of Gastric Signet Ring Cell Carcinoma Tissues Reveals Characteristic Changes of the Complement Cascade Pathway.

Signet ring cell carcinoma (SRCC) is a histological subtype of gastric cancer with distinct features in multiple aspects compared with adenocarcinomas (ACs). The lack of a systematic molecular overview of this disease has led to slow progress in its clinical practice. In the present proteomics study, gastric tissues were collected from tumors and adjacent tissues, including 14 SRCCs and 34 ACs, and laser capture microdissection (LCM) was employed to eradicate the cellular heterogeneity of the tissues. The proteomes of tissues were profiled by data-independent acquisition (DIA) mass spectrometry (MS). Based on the over 6000 proteins quantified, univariate analysis and pathway enrichment revealed that some proteins and pathways demonstrated differences between SRCC and ACs. Importantly, the upregulation of a majority of complement-related proteins was notable for SRCC but not for ACs. A hypothesis, based on the proteomics evidence, was proposed that the complement cascade was evoked in the SRCC microenvironment upon infiltration, and the SRCC cells survived the complement cytotoxicity by secreting endogenous negative regulators. Moreover, an attempt was made to establish appropriate cell models for gastric SRCC through proteomic comparison of the 15 gastric cell lines and gastric tumors. The predictions of a supervised classifier suggested that none of these gastric cell lines qualified to mimic SRCC. This study discovered that the complement cascade is activated at a higher level in gastric SRCC than in ACs.

Developing a population-state decision system for intelligently reprogramming extracellular electron transfer in Shewanella oneidensis.

The unique extracellular electron transfer (EET) ability has positioned electroactive bacteria (EAB) as a major class of cellular chassis for genetic engineering aimed at favorable environmental, energy, and geoscience applications. However, previous efforts to genetically enhance EET ability have often impaired the basal metabolism and cellular growth due to the competition for the limited cellular resource. Here, we design a quorum sensing-based population-state decision (PSD) system for intelligently reprogramming the EET regulation system, which allows the rebalanced allocation of the cellular resource upon the bacterial growth state. We demonstrate that the electron output from Shewanella oneidensis MR-1 could be greatly enhanced by the PSD system via shifting the dominant metabolic flux from initial bacterial growth to subsequent EET enhancement (i.e., after reaching a certain population-state threshold). The strain engineered with this system achieved up to 4.8-fold EET enhancement and exhibited a substantially improved pollutant reduction ability, increasing the reduction efficiencies of methyl orange and hexavalent chromium by 18.8- and 5.5-fold, respectively. Moreover, the PSD system outcompeted the constant expression system in managing EET enhancement, resulting in considerably enhanced electron output and pollutant bioreduction capability. The PSD system provides a powerful tool for intelligently managing extracellular electron transfer and may inspire the development of new-generation smart bioelectrical devices for various applications.