Close relatives of MERS-CoV in bats use ACE2 as their functional receptors.

Middle East respiratory syndrome coronavirus (MERS-CoV) and several bat coronaviruses use dipeptidyl peptidase-4 (DPP4) as an entry receptor1-4. However, the receptor for NeoCoV-the closest known MERS-CoV relative found in bats-remains unclear5. Here, using a pseudotype virus entry assay, we found that NeoCoV and its close relative, PDF-2180, can efficiently bind to and use specific bat angiotensin-converting enzyme 2 (ACE2) orthologues and, less favourably, human ACE2 as entry receptors through their receptor-binding domains (RBDs) on the spike (S) proteins. Cryo-electron microscopy analysis revealed an RBD-ACE2 binding interface involving protein-glycan interactions, distinct from those of other known ACE2-using coronaviruses. We identified residues 337-342 of human ACE2 as a molecular determinant restricting NeoCoV entry, whereas a NeoCoV S pseudotyped virus containing a T510F RBD mutation efficiently entered cells expressing human ACE2. Although polyclonal SARS-CoV-2 antibodies or MERS-CoV RBD-specific nanobodies did not cross-neutralize NeoCoV or PDF-2180, an ACE2-specific antibody and two broadly neutralizing betacoronavirus antibodies efficiently inhibited these two pseudotyped viruses. We describe MERS-CoV-related viruses that use ACE2 as an entry receptor, underscoring a promiscuity of receptor use and a potential zoonotic threat.

Synthon-based ligand discovery in virtual libraries of over 11 billion compounds.

Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures1-4 and ultra-large libraries of virtual compounds5,6. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries7, new approaches to compound screening are needed8,9. Here we introduce a modular synthon-based approach-V-SYNTHES-to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold-synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant (Ki) = 0.9 nM) and CB2/CB1 selectivity (50-200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm.

The epidemiology of pregnancy loss: global burden, variable risk factors, and predictions.

STUDY QUESTION: Is the incidence of pregnancy loss correlated with various geographic, socio-demographic, and age stratifications at the societal and national levels, and what are the risk factors associated with pregnancy loss at the individual level? SUMMARY ANSWER: The epidemiological trends and disease burden of pregnancy loss were correlated with various geographic, socio-demographic, and age stratifications, and we identified that poor health condition, smoking, sedentary behaviour, lower educational level, and lower maternal birth weight may significantly increase the risk of pregnancy loss. WHAT IS KNOWN ALREADY: Several studies have used national, regional, or single-centre data to describe trends in the burden of pregnancy loss, and previous observational studies have identified some variable factors possibly associated with pregnancy loss. However, a comprehensive analysis of global trends and predictions of pregnancy loss are lacking, and the conclusions have been inconsistent. STUDY DESIGN, SIZE, DURATION: We have utilized the data from Global Burden of Disease (GBD) 2019 to provide an overview of the trends in pregnancy loss in 204 countries and regions worldwide from 1990 to 2019, and have made a forecast for the next 10 years. Moreover, we applied a variety of statistical genetics methods to analyse 34 239 pregnancy loss and 89 340 non-pregnancy loss cases from the FinnGen consortium to comprehensively assess the bidirectional causality of variable factors with pregnancy loss from an individual perspective. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analysed trends in the incidence, disability-adjusted life years (DALYs), and maternal mortality of pregnancy loss at global, regional, national, socio-demographic index (SDI), and age levels. The autoregressive integrated moving average (ARIMA) model was used to predict trends by 2030. Finally, we used two-sample Mendelian randomization (MR) and multivariate MR (MVMR) analyses to explore the relationship between the pregnancy loss and variables closely related to physical condition, physical activity, lifestyle, sleep conditions, basic conditions. MAIN RESULTS AND THE ROLE OF CHANCE: In 2019, there were approximately 42.39 million cases of pregnancy loss worldwide. Globally, the incidence, DALYs, and mortality of pregnancy loss showed a decreasing trend between 1990 and 2019, although the number was increasing in some countries. The age-standardized incidence, DALYs, and mortality rate were negatively correlated with SDI level and show a further decline by 2030. Based on MR analyses, we confirmed that genetically predicted overall health rating (inverse-variance weighted (IVW) odds ratio (OR), 1.68; 95% CI, 1.34-2.13; P = 5.10 × 10-6), smoking initiation (IVW OR, 1.26; 95% CI, 1.16-1.38; P = 1.90 × 10-9), sedentary behaviour (IVW OR, 1.56; 95% CI, 1.20-2.01; P = 2.76 × 10-5), educational level (IVW OR, 0.64; 95% CI, 0.55-0.73; P = 6.56 × 10-10), and maternal birth weight (IVW OR, 0.70; 95% CI, 0.58-0.85; P = 2.98 × 10-4) were significantly related to the risk of pregnancy loss, whereas body mass index (IVW OR, 1.10; 95% CI, 1.03-1.17; P = 5.31 × 10-3), alcohol consumption (IVW OR, 1.74; 95% CI, 1.03-2.95; P = 0.04), insomnia (IVW OR, 1.66; 95% CI, 1.14-2.42; P = 7.00 × 10-3), and moderate-to-vigorous physical activity (IVW OR, 0.59; 95% CI, 0.37-0.95; P = 2.85 × 10-2) were suggestively associated with the risk of pregnancy loss. These results were supported by sensitivity and directional analyses. LIMITATIONS, REASONS FOR CAUTION: Despite efforts to standardize GBD data from all over the world, uncertainties in data quality control regarding ascertainment of pregnancy loss, medical care accessibility, cultural differences, and socioeconomic status still exist. Furthermore, the population in the MRstudy was limited to Europeans, which means that the results may not be extrapolated to people of other origins. WIDER IMPLICATIONS OF THE FINDINGS: Our study provides for the first time an overview of the epidemiological trends and disease burden of pregnancy loss related with SDI, region, country, and age, and predicts changes in future trends up to 2030. In addition, findings support that genetic susceptibility, smoking, health condition, and sedentary behaviour may be powerful indicators of an increased risk of pregnancy loss. These results would be beneficial for policy makers of different countries and regions to improve prevention implementation. STUDY FUNDING/COMPETING INTERESTS: This work was supported by grants 2021JH2/10300093, from the Science and Technology Projects of Liaoning Province, China. All authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Salvianolic Acid B Alleviates High Glucose-Induced Vascular Smooth Muscle Cell Inflammation by Upregulating the miR-486a-5p Expression.

The macrovascular complications of diabetes cause high mortality and disability in patients with type 2 diabetes mellitus (T2DM). The inflammatory response of vascular smooth muscle cell (VSMC) runs through its pathophysiological process. Salvianolic acid B (Sal B) exhibits beneficial effects on the cardiovascular system. However, its role and mechanism in diabetic vascular inflammatory response remain unclear. In this study, we found that Sal B reduced vascular inflammation in diabetic mice and high glucose- (HG-) induced VSMC inflammation. Subsequently, we found that Sal B reduced HG-induced VSMC inflammation by downregulating FOXO1. Furthermore, miR-486a-5p expression was obviously reduced in HG-treated VSMC. Sal B attenuated HG-induced VSMC inflammation by upregulating miR-486a-5p. Loss- and gain-of-function experiments had proven that the transfection of the miR-486a-5p mimic inhibited HG-induced VSMC inflammation whereas that of the miR-486a-5p inhibitor promoted HG-induced VSMC inflammation, thereby leading to the amelioration of vascular inflammation in the diabetic mice. Furthermore, studies had shown that miR-486a-5p inhibited FOXO1 expression by directly targeting its 3'-UTR. In conclusion, Sal B alleviates the inflammatory response of VSMC by upregulating miR-486a-5p and aggravating its inhibition of FOXO1 expression. Sal B exerts a significant anti-inflammatory effect in HG-induced VSMC inflammation by modulating the miR-486a-5p/FOXO1 axis.

Effects and mechanisms of N6-methyladenosine RNA methylation in environmental pollutant-induced carcinogenesis.

Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.

Dihydroartemisinin-driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer.

Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.

Mechanical properties and peculiarities of molecular crystals.

In the last century, molecular crystals functioned predominantly as a means for determining the molecular structures via X-ray diffraction, albeit as the century came to a close the response of molecular crystals to electric, magnetic, and light fields revealed that the physical properties of molecular crystals were as rich as the diversity of molecules themselves. In this century, the mechanical properties of molecular crystals have continued to enhance our understanding of the colligative responses of weakly bound molecules to internal frustration and applied forces. Here, the authors review the main themes of research that have developed in recent decades, prefaced by an overview of the particular considerations that distinguish molecular crystals from traditional materials such as metals and ceramics. Many molecular crystals will deform themselves as they grow under some conditions. Whether they respond to intrinsic stress or external forces or interactions among the fields of growing crystals remains an open question. Photoreactivity in single crystals has been a leading theme in organic solid-state chemistry; however, the focus of research has been traditionally on reaction stereo- and regio-specificity. However, as light-induced chemistry builds stress in crystals anisotropically, all types of motions can be actuated. The correlation between photochemistry and the responses of single crystals-jumping, twisting, fracturing, delaminating, rocking, and rolling-has become a well-defined field of research in its own right: photomechanics. The advancement of our understanding requires theoretical and high-performance computations. Computational crystallography not only supports interpretations of mechanical responses, but predicts the responses itself. This requires the engagement of classical force-field based molecular dynamics simulations, density functional theory-based approaches, and the use of machine learning to divine patterns to which algorithms can be better suited than people. The integration of mechanics with the transport of electrons and photons is considered for practical applications in flexible organic electronics and photonics. Dynamic crystals that respond rapidly and reversibly to heat and light can function as switches and actuators. Progress in identifying efficient shape-shifting crystals is also discussed. Finally, the importance of mechanical properties to milling and tableting of pharmaceuticals in an industry still dominated by active ingredients composed of small molecule crystals is reviewed. A dearth of data on the strength, hardness, Young's modulus, and fracture toughness of molecular crystals underscores the need for refinement of measurement techniques and conceptual tools. The need for benchmark data is emphasized throughout.

Identification of immune-related lncRNA in sepsis by construction of ceRNA network and integrating bioinformatic analysis.

BACKGROUND: Sepsis is a high mortality disease which seriously threatens human life and health, for which the pathogenetic mechanism still unclear. There is increasing evidence showed that immune and inflammation responses are key players in the development of sepsis pathology. LncRNAs, which act as ceRNAs, have critical roles in various diseases. However, the regulatory roles of ceRNA in the immunopathogenesis of sepsis have not yet been elucidated. RESULTS: In this study, we aimed to identify immune biomarkers associated with sepsis. We first generated a global immune-associated ceRNA (IMCE) network based on data describing interactions pairs of gene-miRNA and miRNA-lncRNA. Afterward, we excavated a dysregulated sepsis immune-associated ceRNA (SPIMC) network from the global IMCE network by means of a multi-step computational approach. Functional enrichment indicated that lncRNAs in SPIMC network have pivotal roles in the immune mechanism underlying sepsis. Subsequently, we identified module and hub genes (CD4 and STAT4) via construction of a sepsis immune-related PPI network. Then, we identified hub genes based on the modular structure of PPI network and generated a ceRNA subnetwork to analyze key lncRNAs associated with sepsis. Finally, 6 lncRNAs (LINC00265, LINC00893, NDUFA6-AS1, NOP14-AS1, PRKCQ-AS1 and ZNF674-AS1) that identified as immune biomarkers of sepsis. Moreover, the CIBERSORT algorithm and the infiltration of circulating immune cells types were performed to identify the inflammatory state of sepsis. Correlation analyses between immune cells and sepsis immune biomarkers showed that the LINC00265 was strongly positive correlated with the macrophages M2 (r = 0.77). CONCLUSION: Collectively, these results may suggest that these lncRNAs (LINC00265, LINC00893, NDUFA6-AS1, NOP14-AS1, PRKCQ-AS1 and ZNF674-AS1) played important roles in the immune pathogenesis of sepsis and provide potential therapeutic targets for further researches on immune therapy treatment in patients with sepsis.

Model and experimental verification of SOP transient in OPGW based on direct strike lightning.

We introduce inductive lightning and direct lightning that affect the state of polarization (SOP) of signal light in optical ground wire (OPGW) of power transmission line, deduce the helical component of direct lightning on OPGW, and establish the transient model of signal SOP in OPGW based on direct lightning. We also monitored actual optical transport network (OTN) systems deployed on OPGW in thunderstorm-prone areas for three months, recorded error codes and SOP transients of more than 1.5 Mrad/s using a bit error rate tester and a polarimeter accordingly. The highest SOP transient rate was up to 43 Mrad/s. Finally, we verify the accuracy of the model through simulation and experiment comparison.

Two-stage equalization for ultra-fast RSOP and inter symbol interference compensation based on a simplified Kalman filter.

We propose a two-stage equalization based on a simplified Kalman filter, which is used to solve the rapid rotation of the state of polarization (RSOP) that is caused by lightning strikes on optical cables and the extra inter symbol interference (ISI) introduced in the system. By analyzing the special expression of matrix coefficient in the Kalman filter under polarization demultiplexing, the simplified idea of a Kalman filter is provided, and its updating process is transformed into a kind of multiple-input-multiple-output (MIMO) structure algorithm. At the same time, the second stage finite impulse response filter is used to solve the ISI that is difficult to be solved by a Kalman filter. The performance of the proposed algorithm was tested in a coherent system of 28Gbaud PDM-QPSK/16QAM. The results confirm that on the basis of lower complexity than a Kalman filter, the proposed algorithm reduces its complexity by more than 30% compared to traditional MIMO equalization algorithm under the premise of linear operation, and which also can handle RSOP of 20 Mrad/s. When the system suffers from the extra ISI due to the limited device bandwidth, the optical signal to noise ratio of the proposed algorithm is about 4 dB lower than the Kalman filter at the same bit error rate.

MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII.

Epidermal growth factor receptor variant III (EGFRvIII) is a mutant isoform of EGFR with a deletion of exons 2-7 making it insensitive to EGF stimulation and downstream signal constitutive activation. However, the mechanism underlying the stability of EGFRvIII remains unclear. Based on CRISPR-Cas9 library screening, we found that mucin1 (MUC1) is essential for EGFRvIII glioma cell survival and temozolomide (TMZ) resistance. We revealed that MUC1-C was upregulated in EGFRvIII-positive cells, where it enhanced the stability of EGFRvIII. Knockdown of MUC1-C increased the colocalization of EGFRvIII and lysosomes. Upregulation of MUC1 occurred in an NF-κB dependent manner, and inhibition of the NF-κB pathway could interrupt the EGFRvIII-MUC1 feedback loop by inhibiting MUC1-C. In a previous report, we identified AC1Q3QWB (AQB), a small molecule that could inhibit the phosphorylation of NF-κB. By screening the structural analogs of AQB, we obtained EPIC-1027, which could inhibit the NF-κB pathway more effectively. EPIC-1027 disrupted the EGFRvIII-MUC1-C positive feedback loop in vitro and in vivo, inhibited glioma progression, and promoted sensitization to TMZ. In conclusion, we revealed the pivotal role of MUC1-C in stabilizing EGFRvIII in glioblastoma (GBM) and identified a small molecule, EPIC-1027, with great potential in GBM treatment.

Establishing stereochemical comparability in phosphorothioate oligonucleotides with nuclease P1 digestion coupled with LCMS analysis.

Stereochemical comparability is critical for ensuring manufacturing consistency in therapeutic phosphorothioate oligonucleotides. Currently, analytical methods for this assessment are limited. We hereby report on a novel protocol capable of detecting a stereochemistry change in a single phosphorothioate linkage by employing nuclease P1 digestion of the oligonucleotide with subsequent LCMS analysis of the resulting fragments. The method proves valuable for establishing stereochemical comparability and for ensuring manufacturing consistency of oligonucleotide therapeutics.

Comparison of endotracheal aspirate and bronchoalveolar lavage fluid metagenomic next-generation sequencing in severe pneumonia: a nested, matched case-control study.

OBJECTIVES: To compare clinical outcomes in patients with severe pneumonia according to the diagnostic strategy used. METHODS: In this retrospective, nested, case-control study, patients with severe pneumonia who had undergone endotracheal aspirate (ETA) metagenomic next-generation sequencing of (mNGS) testing (n = 53) were matched at a ratio of 1 to 2 (n = 106) by sex, age, underlying diseases, immune status, disease severity scores, and type of pneumonia with patients who had undergone bronchoalveolar lavage fluid (BALF) mNGS. The microbiological characteristics and patient's prognosis of the two groups were compared. RESULTS: An overall comparison between the two groups showed no significant differences in bacterial, fungal, viral, or mixed infections. However, subgroup analysis of 18 patients who received paired ETA and BALF mNGS showed a complete agreement rate for the two specimens of 33.3%. There were more cases for whom targeted treatment was initiated (36.79% vs. 22.64%; P = 0.043) and fewer cases who received no clinical benefit after mNGS (5.66% vs. 15.09%; P = 0.048) in the BALF group. The pneumonia improvement rate in the BALF group was significantly higher than in the ETA group (73.58% vs. 87.74%, P = 0.024). However, there were no significant differences in ICU mortality or 28-day mortality. CONCLUSIONS: We do not recommend using ETA mNGS as the first-choice method for analyzing airway pathogenic specimens from severe pneumonia patients.

The significance of ophthalmological features in diagnosis of thyroid-associated ophthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder. It has discriminable appearance. This study was conducted to dig the clinical significance of demographic characteristics and ophthalmologic diagram features in TAO diagnosis and stage/severity evaluation. RESULTS: We included 320 males and 633 females, with an average age of 41.75 ± 13.75. A majority of TAO patients had hyperthyroidism, and most of them were in the inactive stage and at the moderate level. The thyroid function type, stage and severity were closely associated with hypopsia, eyelid congestion, conjunctival congestion, corneal ulcer, ocular motility disorder, best corrected visual acuity, and extraocular muscle thickening. Using these features, we established different logistic regression models to predict thyroid function subtypes, abnormal thyroid function, stage, and severity, in which the AUC of the ROC curve and accuracies were satisfactory. CONCLUSION: Together, TAO subtype, stage and severity can be diagnosed by auxiliary references including demographic factors, symptoms from complains, and image features. These non-invasive indices can be applied in a timely manner in clinical estimating TAO status.

Heavy metal-mediated adsorption of antibiotic tetracycline and ciprofloxacin on two microplastics: Insights into the role of complexation.

Microplastics (MPs) have recently become an emerging environmental concern. Nevertheless, limited information is known about the adsorption of MPs for organic contaminants under combined heavy metals pollution, with an emphasis on the role of complexation. Thus, this study aims to comprehensively compare and investigate the adsorption performance of antibiotic tetracycline (TC) and ciprofloxacin (CIP) on two polar MPs (polyamide (PA) and polyvinyl chloride (PVC)) affected by Cu(II) and Cd(II) with contrasting complexation abilities. Batch adsorption experiments were used in combination with speciation calculation, zeta potential determination, FTIR spectroscopy characterization and investigation of the affinity of MPs for heavy metals. Results showed that the sorption kinetics and isotherms of TC and CIP on PA and PVC could be well fitted to pseudo-second-order and Langmuir models, respectively, both in the absence and presence of Cu and Cd, suggesting that multiple interactions and monolayer adsorption played an important role in the adsorption process. The presence of Cu substantially improved TC and CIP adsorption and obviously changed the pH dependence of their adsorption onto both MPs, which may result from the Cu-induced strong complexation with TC and CIP. The presence of Cd slightly enhanced TC adsorption on both MPs while reduced CIP adsorption especially on PVC, which may be ascribed to the Cd-induced cationic bridging effects in TC adsorption and the competitive adsorption of Cd in CIP adsorption. Therefore, the heavy metal-mediated complexation effects may play a dominant role in antibiotic adsorption by MPs only in the presence of heavy metals with strong complexation ability while the adsorption performance in the presence of heavy metals with negligible complexation capacity may be influenced by effects other than complexation. This study helps further understand the heavy metal-mediated adsorption behavior of organic contaminants on polar MPs and the role of complexation reactions therein.

Laser-triggered intelligent drug delivery and anti-cancer photodynamic therapy using platelets as the vehicle.

In our previous study, target drug delivery and treatment of malignant tumors have been achieved by using platelets as carriers loading nano-chemotherapeutic agents (ND-DOX). However, drug release from ND-DOX-loaded platelets is dependent on negative platelet activation by tumor cells, whose activation is not significant enough for the resulting drug release to take an effective anti-tumor effect. Exploring strategies to proactively manipulate the controlled release of drug-laden platelets is imperative. The present study innovatively revealed that photodynamic action can activate platelets in a spatiotemporally controlled manner. Consequently, based on the previous study, platelets were used to load iron oxide-polyglycerol-doxorubicin-chlorin e6 composites (IO-PG-DOX-Ce6), wherein the laser-triggered drug release ability and anti-tumor capability were demonstrated. The findings suggested that IO-PG-DOX-Ce6 could be stably loaded by platelets in high volume without any decrease in viability. Importantly and interestingly, drug-loaded platelets were significantly activated by laser irradiation, characterized by intracellular ROS accumulation and up-regulation of CD62p. Additionally, scanning electron microscopy (SEM) and hydrated particle size results also showed a significant aggregation response of laser irradiated-drug-loaded platelets. Further transmission electron microscopy (TEM) measurements indicated that the activated platelets released extracellularly their cargo drug after laser exposure, which could be taken up by co-cultured tumor cells. Finally, the co-culture model of drug-loaded platelets and tumor cells proved that laser-triggered delivery system of platelets could effectively damage the DNA and promote apoptosis of tumor cells. Overall, the present study discovers a drug-loaded platelets delivery using photodynamic effect, enabling laser-controlled intelligent drug delivery and anti-tumor therapy, which provides a novel and feasible approach for clinical application of cytopharmaceuticals.

What is the context?1. Platelets were applied to load IO-PG-DOX-Ce6, wherein the laser-triggered drug release and anti-tumor effect were investigated in vitro.2. The findings indicated that IO-PG-DOX-Ce6 could be stably loaded by platelets in high volume without any decrease in viability, which may attribute to the activation of autophagy in platelets.3. IO-PG-DOX-Ce6-loaded platelets could be significantly activated by laser irradiation (690 nm).4. Activated platelets released extracellularly their cargo drug after laser exposure, which could be taken up by co-cultured tumor cells5. The co-culture model of drug-loaded platelets and tumor cells proved that the laser-triggered delivery system of platelets could effectively damage the DNA and promote apoptosis of tumor cells.What is new?1. Platelets could be utilized as the vehicle to load photosensitizer-loaded-nano-drug.2. Photodynamic action can activate platelets in a spatiotemporally controlled manner, which could be a tool to regulate the activation of platelets.3. The laser-triggered activation of drug-loaded platelets allows for target release of cargo.4. The limitation of the current research is that only in vitro experiments were carried out to demonstrate our conclusions.What is impact?The present work provides a novel and feasible approach for the clinical application of cytopharmaceuticals.

Metal-organic framework-encapsulated dihydroartemisinin nanoparticles induces apoptotic cell death in ovarian cancer by blocking ROMO1-mediated ROS production.

Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.

Recombinant human thrombopoietin therapy for primary immune thrombocytopenia in pregnancy: a retrospective comparative cohort study.

BACKGROUND: Treatment options for pregnant women with immune thrombocytopenia (ITP) who do not respond to first-line treatment are limited. Few studies have reported the use of recombinant human thrombopoietin (rhTPO) for this subset of patients. AIMS: To investigate the efficacy and safety of rhTPO in ITP during pregnancy and determine obstetric outcomes and predictors of treatment response. METHODS: From July 2013 to October 2022, the data of 81 pregnant women with ITP and a platelet count < 30 × 109/L who did not respond to steroids and/or intravenous immunoglobulin were retrospectively analysed. Of these patients, 33 received rhTPO treatment (rhTPO group) while 48 did not (control group). Baseline characteristics, haematological disease outcomes before delivery, obstetric outcomes, and adverse events were compared between groups. In the rhTPO group, a generalised estimating equation (GEE) was used to investigate the factors influencing the response to rhTPO treatment. RESULTS: The baseline characteristics were comparable between both groups (P > 0.05, both). Compared with controls, rhTPO patients had higher platelet counts (median [interquartile range]: 42 [21.5-67.5] vs. 25 [19-29] × 109/L, P = 0.002), lower bleeding rate (6.1% vs. 25%, P = 0.027), and lower platelet transfusion rate before delivery (57.6% vs. 97.9%, P < 0.001). Gestational weeks of delivery (37.6 [37-38.4] vs 37.1 [37-37.2] weeks, P = 0.001) were longer in the rhTPO group than in the control group. The rates of caesarean section, postpartum haemorrhage, foetal or neonatal complications, and complication types in both groups were similar (all P > 0.05). No liver or renal function impairment or thrombosis cases were observed in the rhTPO group. GEE analysis revealed that the baseline mean platelet volume (MPV) (odds ratio [OR]: 0.522, P = 0.002) and platelet-to-lymphocyte ratio (PLR) (OR: 1.214, P = 0.025) were predictors of response to rhTPO treatment. CONCLUSION: rhTPO may be an effective and safe treatment option for pregnancies with ITP that do not respond to first-line treatment; it may have slightly prolonged the gestational age of delivery. Patients with a low baseline MPV and high baseline PLR may be more responsive to rhTPO treatment. The present study serves as a foundation for future research.

Bach1 modulates AKT3 transcription to participate in hyperglycaemia-mediated EndMT in vascular endothelial cells.

Hyperglycaemia-mediated endothelial-to-mesenchymal transition (EndMT) is involved in the occurrence and progression of cardiovascular complications in diabetic patients. Previous studies reported that AKT serine/threonine kinase 3 (AKT3) and Bric-a-brac/Tramtrack/Broad (BTB) and cap'n'collar (CNC) homology 1 (bach1) participates in endothelial injury and epithelial-to-mesenchymal transition. In the present study, we proposed that bach1 regulates AKT3 transcription, thus involved in hyperglycaemia-mediated EndMT in vascular endothelium. Our results indicated that hyperglycaemia/high glucose increased AKT3 expression and induced EndMT in aorta of diabetic rats and hyperglycaemic human umbilical vein endothelial cells (HUVECs). Moreover, inhibition of AKT3 expression reversed high glucose-mediated EndMT in HUVECs. Further, hyperglycaemia/high glucose augmented bach1 expression in aorta of diabetic rats and hyperglycaemic HUVECs. Furthermore, si-bach1 countered high glucose-induced AKT3 expression and EndMT in HUVECs. In addition, the effect of bach1 overexpression is similar to that of high glucose treatment, which was reversed by si-AKT3. ChIP assays found bach1 enriched in the promoter region of AKT3. Bach1 overexpression augmented AKT3 promoter activity, which lost after specific binding site mutation. Bach1 was involved in hyperglycaemia-induced EndMT via modulation of AKT3 transcription.

Research on Mindfulness-Based Stress Reduction in Breast Cancer Patients Undergoing Chemotherapy: An Observational Pilot Study.

Objective: Mindfulness-Based Stress Reduction (MBSR) therapy has been very effective intervention across worldwide. Herein we aimed to investigate the effect of MBSR intervention on anxiety, depression among breast cancer patients undergoing postoperative chemotherapy. Methods: 225 breast cancer patients in our hospital were divided into two groups, 106 patients in the MBSR group received Mindfulness-Based Stress Reduction intervention, while 111 patients in the control group were given routine nursing. The Self-rating Anxiety Scale (SAS), self-rating depression scale (SDS), and functional assessment of cancer therapy-breast cancer (FACT-B) were used to assess the effect of MBSR intervention on breast cancer patients undergoing postoperative chemotherapy. Results: There were significant differences in the scores of physiological statuses, social and family status, emotional status, functional status, additional attention and total score after intervention between two groups (P < .05). The difference between SDS and SAS were statistically significant between the two groups (P < .05). The score of SDS and SAS were significantly improved in the MBSR group compared with the control group (P < .05). Conclusion: MBSR therapy could effectively improve the quality of life of patients with breast cancer patients with chemotherapy, mainly focusing on psychological aspects, while the effect of the physiological intervention was not significant.