Case report: Pulmonary artery sarcoma diagnosed through rare brain metastases.

We present the case of a 33-year-old male referred across several hospitals because of suspected chronic thromboembolic pulmonary hypertension (CTEPH). Initially admitted in October 2022 for a recurrent, severe cough and diagnosed with CTEPH, he received anticoagulant therapy. However, his symptoms worsened, necessitating a transfer to another facility for thrombolysis treatment. Following an episode of syncope, an MRI scan revealed a metastatic brain tumor. Subsequently, he experienced a third transfer to our hospital, emergency surgery was performed to alleviate cerebral edema and excise a lesion in the left frontal lobe. Postoperative pathology was inconclusive, but a multidisciplinary team meeting, aided by experienced radiologists, eventually confirmed a diagnosis of pulmonary artery sarcoma (PAS) with systemic metastases. This case underscores the necessity of promptly ruling out PAS in patients presenting with significant emboli in the central pulmonary arteries and suggests early referral to specialized centers for suspected cases.

Machine Learning Modeling to Predict Atrial Fibrillation Detection in Embolic Stroke of Undetermined Source Patients.

BACKGROUND: In patients with embolic stroke of undetermined source (ESUS), occult atrial fibrillation (AF) has been implicated as a key source of cardioembolism. However, only a minority acquire implantable cardiac loop recorders (ILRs) to detect occult paroxysmal AF, partly due to financial cost and procedural inconvenience. Without the initiation of appropriate anticoagulation, these patients are at risk of increased ischemic stroke recurrence. Hence, cost-effective and accurate methods of predicting AF in ESUS patients are highly sought after. OBJECTIVE: We aimed to incorporate clinical and echocardiography data into machine learning (ML) algorithms for AF prediction on ILRs in ESUS. METHODS: This was a single-center cohort study that included 157 consecutive patients diagnosed with ESUS from October 2014 to October 2017 who had ILR evaluation. We developed four ML models, with hyperparameters tuned, to predict AF detection on an ILR. RESULTS: The median age of the cohort was 67 (IQR 59-74) years old and the median monitoring duration was 1051 (IQR 478-1287) days. Of the 157 patients, 32 (20.4%) had occult AF detected on the ILR. Support vector machine predicted for AF with a 95% confidence interval area under the receiver operating characteristic curve (AUC) of 0.736-0.737, multilayer perceptron with an AUC of 0.697-0.708, XGBoost with an AUC of 0.697-0.697, and random forest with an AUC of 0.663-0.674. ML feature importance found that age, HDL-C, and admitting heart rate were important non-echocardiography variables, while peak mitral A-wave velocity and left atrial volume were important echocardiography parameters aiding this prediction. CONCLUSION: Machine learning modeling incorporating clinical and echocardiographic variables predicted AF in ESUS patients with moderate accuracy.

How Rhizosphere Microbial Assemblage Is Influenced by Dragon Fruits with White and Red Flesh.

The synthesis of betalain using microorganisms is an innovative developmental technology, and the excavation of microorganisms closely related to betalain can provide certain theoretical and technical support to this technology. In this study, the characteristics of soil microbial community structures and their functions in the rhizospheres of white-fleshed dragon fruit (Hylocereus undatus) and red-fleshed dragon fruit (Hylocereus polyrhizus) were analyzed. The results show that the soil bacterial and fungal compositions in the rhizospheres were shaped differently between H. undatus and H. polyrhizus. Bacterial genera such as Kribbella and TM7a were the unique dominant soil bacterial genera in the rhizospheres of H. undatus, whereas Bradyrhizobium was the unique dominant soil bacterial genus in the rhizospheres of H. polyrhizus. Additionally, Myrothecium was the unique dominant soil fungal genus in the rhizospheres of H. polyrhizus, whereas Apiotrichum and Arachniotus were the unique dominant soil fungal genera in the rhizospheres of H. undatus. Moreover, TM7a, Novibacillus, Cupriavidus, Mesorhizobium, Trechispora, Madurella, Cercophora, and Polyschema were significantly enriched in the rhizospheres of H. undatus, whereas Penicillium, Blastobotrys, Phialemonium, Marasmius, and Pseudogymnoascus were significantly enriched in the rhizospheres of H. polyrhizus. Furthermore, the relative abundances of Ascomycota and Penicillium were significantly higher in the rhizospheres of H. polyrhizus than in those of H. undatus.

Oxygen Vacancies Boosted Hydronium Intercalation: A Paradigm Shift in Aluminum-Based Batteries.

In aqueous aluminum-ion batteries (AAIBs), the insertion/extraction chemistry of Al3+ often leads to poor kinetics, whereas the rapid diffusion kinetics of hydronium ions (H3O+) may offer the solution. However, the presence of considerable Al3+ in the electrolyte hinders the insertion reaction of H3O+. Herein, we report how oxygen-deficient α-MoO3 nanosheets unlock selective H3O+ insertion in a mild aluminum-ion electrolyte. The abundant oxygen defects impede the insertion of Al3+ due to excessively strong adsorption, while allowing H3O+ to be inserted/diffused through the Grotthuss proton conduction mechanism. This research advances our understanding of the mechanism behind selective H3O+ insertion in mild electrolytes.

Hypoxic Bone Marrow Stromal Cells Secrete miR-140-5p and miR-28-3p That Target SPRED1 to Confer Drug Resistance in Multiple Myeloma.

Bone marrow stromal cell (BMSC)-derived small extracellular vesicles (sEV) promote drug resistance to bortezomib in multiple myeloma cells. Elucidating the components of BMSC sEV that induce drug resistance in multiple myeloma cells could help identify strategies to overcome resistance. Considering the hypoxic nature of the myeloma microenvironment, we explored the role of hypoxia in regulating BMSC sEV cargo and investigated whether hypoxia-driven sEV miRNAs contribute to the drug resistance in multiple myeloma cells. Hypoxia increased the release of sEVs from BMSCs, and these sEVs more strongly attenuated bortezomib sensitivity in multiple myeloma cells than sEVs from BMSCs under normoxic conditions. RNA sequencing revealed that significantly elevated levels of miR-140-5p and miR-28-3p were enclosed in hypoxic BMSC-derived sEVs. Both miR-140-5p and miR-28-3p conferred bortezomib resistance in multiple myeloma cells by synergistically targeting SPRED1, a member of the Sprouty protein family that regulates MAPK activation. SPRED1 inhibition reduced sensitivity to bortezomib in multiple myeloma cells through activating MAPK-related pathways and significantly promoted multiple myeloma bortezomib resistance and tumor growth in a mouse model. These findings shed light on the role of hypoxia-induced miRNAs shuttled in BMSC-derived sEVs to multiple myeloma cells in inducing drug resistance and identify the miR-140-5p/miR-28-3p/SPRED1/MAPK pathway as a potential targetable axis for treating multiple myeloma. SIGNIFICANCE: Hypoxia induces stromal cells to secrete extracellular vesicles with increased miR-140-5p and miR-28-3p that are transferred to multiple myeloma cells and drive drug resistance by increasing the MAPK signaling.

Transcriptome profile analysis revealed the potential mechanism of LIPUS treatment for Adriamycin-induced chronic kidney disease rat.

Background: Developing effective therapeutic strategies to delay the progression of chronic kidney disease (CKD) remains a significant challenge. Low-intensity pulsed ultrasound (LIPUS) has demonstrated potential for treating CKD, but the underlying molecular mechanisms are still elusive. This study aimed to evaluate the therapeutic efficacy of LIPUS and to elucidate the involved genes and signaling pathways. Methods: The CKD model was established in rats using Adriamycin (ADR). The bilateral kidneys of CKD rats were continuously stimulated with LIPUS for a period of four weeks. The therapeutic efficacy was defined by renal function and histopathological evaluation. RNA sequencing was employed to profile the transcriptome of rat kidneys in each group. Cluster analysis was utilized to identify differentially expressed genes (DEGs), followed by enrichment analysis of their associated pathways using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Results: LIPUS treatment improved ADR-induced renal dysfunction in the CKD group. Renal fibrosis and pathological damages were also alleviated in the ADR + LIPUS group compared to the ADR group. Cluster analysis identified 844 DEGs. GO enrichment analysis revealed enrichment in inflammatory response terms, while KEGG enrichment analysis highlighted the nuclear factor kappa B (NF-κB) signaling and ferroptosis-related pathways. Conclusion: Continuous LIPUS treatment improved ADR-induced renal fibrosis and dysfunction. The therapeutic effect of LIPUS was primarily due to its ability to suppress the CKD-related inflammation, which was associated with the modulation of the NF-κB and ferroptosis signaling pathways. These findings provide a new insight into the potential molecular mechanisms of LIPUS in treating CKD. Further research is necessary to confirm these findings and to identify potential therapeutic targets within these pathways.

Case Report: Myocardial dissection caused by ruptured sinus of Valsalva aneurysm in association with a bicuspid aortic valve.

In this report, we present a case of left-right sinus fusion in a Ruptured sinus of Valsalva aneurysm (RSVA) that perforated into the myocardium, giving rise to myocardial dissection. The existence of an anomalous bicuspid aortic valve (BAV) is contemplated as a potential etiological element in this context. Employing multimodal imaging modalities, encompassing transthoracic echocardiography and computed tomography (CT), facilitated the visualization of a dissecting hematoma situated within the myocardium subsequent to the RSVA. Following this, our patient underwent an Cabrol surgical intervention, received patch repair, and underwent mitral valve annuloplasty, during which a three-year period transpired without the occurrence of any deleterious cardiac events. In summary, this report establishes the cornerstone for the surgical intervention of RSVA, shedding light on the efficacious handling of RSVA-associated myocardial dissection. It posits that the presence of a BAV may serve as a predisposing factor to RSVA rupture, potentially elevating the susceptibility to myocardial dissection. The utilization of diverse multimodal imaging methodologies played an indispensable role in the detection of a hematoma within the myocardial tissue subsequent to the RSVA rupture. The uneventful three-year postoperative follow-up of the patient underscores the efficacy of the undertaken interventions.

Deep belief improved bidirectional LSTM for multivariate time series forecasting.

Multivariate time series (MTS) play essential roles in daily life because most real-world time series datasets are multivariate and rich in time-dependent information. Traditional forecasting methods for MTS are time-consuming and filled with complicated limitations. One efficient method being explored within the dynamical systems is the extended short-term memory networks (LSTMs). However, existing MTS models only partially use the hidden spatial relationship as effectively as LSTMs. Shallow LSTMs are inadequate in extracting features from high-dimensional MTS; however, the multilayer bidirectional LSTM (BiLSTM) can learn more MTS features in both directions. This study tries to generate a novel and improved BiLSTM network (DBI-BiLSTM) based on a deep belief network (DBN), bidirectional propagation technique, and a chained structure. The deep structures are constructed by a DBN layer and multiple stacked BiLSTM layers, which increase the feature representation of DBI-BiLSTM and allow for the model to further learn the extended features in two directions. First, the input is processed by DBN to obtain comprehensive features. Then, the known features, divided into clusters based on a global sensitivity analysis method, are used as the inputs of every BiLSTM layer. Meanwhile, the previous outputs of the shallow layer are combined with the clustered features to reconstitute new input signals for the next deep layer. Four experimental real-world time series datasets illustrate our one-step-ahead prediction performance. The simulating results confirm that the DBI-BiLSTM not only outperforms the traditional shallow artificial neural networks (ANNs), deep LSTMs, and some recently improved LSTMs, but also learns more features of the MTS data. As compared with conventional LSTM, the percentage improvement of DBI-BiLSTM on the four MTS datasets is 85.41, 75.47, 61.66 and 30.72%, respectively.

Circularly polarized chemiluminescence from planar chiral bis(adamantylidene-1,2-dioxetane)s.

Bis(adamantylidene-1,2-dioxetane), upon conjugation to a planar chiral scaffold of [2.2]paracyclophane, gave chemical-triggerable circularly polarized chemiluminescence with a dissymmetry factor of 1.1 × 10-3 scale, to which exciton chirality upon chemiexcitation was assigned as the origin.

Why different sugarcane cultivars show different resistant abilities to smut? : Comparisons of endophytic microbial compositions and metabolic functions in stems of sugarcane cultivars with different abilities to resist smut.

To elucidate the mechanisms underlying the resistance to smut of different sugarcane cultivars, endophytic bacterial and fungal compositions, functions and metabolites in the stems of the sugarcane cultivars were analyzed using high-throughput sequencing techniques and nontargeted metabolomics. The results showed that the levels of ethylene, salicylic acid and jasmonic acid in sugarcane varieties that were not sensitive to smut were all higher than those in sensitive sugarcane varieties. Moreover, endophytic fungi, such as Ramichloridium, Alternaria, Sarocladium, Epicoccum, and Exophiala species, could be considered antagonistic to sugarcane smut. Additionally, the highly active arginine and proline metabolism, pentose phosphate pathway, phenylpropanoid biosynthesis, and tyrosine metabolism in sugarcane varieties that were not sensitive to smut indicated that these pathways contribute to resistance to smut. All of the above results suggested that the relatively highly abundant antagonistic microbes and highly active metabolic functions of endophytes in non-smut-sensitive sugarcane cultivars were important for their relatively high resistance to smut.

Efficient and Selective Oxygenation of Cycloalkanes and Alkyl Aromatics with Oxygen through Synergistic Catalysis of Bimetallic Active Centers in Two-Dimensional Metal-Organic Frameworks Based on Metalloporphyrins.

Confined catalytic realms and synergistic catalysis sites were constructed using bimetallic active centers in two-dimensional metal-organic frameworks (MOFs) to achieve highly selective oxygenation of cycloalkanes and alkyl aromatics with oxygen towards partly oxygenated products. Every necessary characterization was carried out for all the two-dimensional MOFs. The selective oxygenation of cycloalkanes and alkyl aromatics with oxygen was accomplished with exceptional catalytic performance using two-dimensional MOF Co-TCPPNi as a catalyst. Employing Co-TCPPNi as a catalyst, both the conversion and selectivity were improved for all the hydrocarbons investigated. Less disordered autoxidation at mild conditions, inhibited free-radical diffusion by confined catalytic realms, and synergistic C-H bond oxygenation catalyzed by second metal center Ni employing oxygenation intermediate R-OOH as oxidant were the factors for the satisfying result of Co-TCPPNi as a catalyst. When homogeneous metalloporphyrin T(4-COOCH3)PPCo was replaced by Co-TCPPNi, the conversion in cyclohexane oxygenation was enhanced from 4.4% to 5.6%, and the selectivity of partly oxygenated products increased from 85.4% to 92.9%. The synergistic catalytic mechanisms were studied using EPR research, and a catalysis model was obtained for the oxygenation of C-H bonds with O2. This research offered a novel and essential reference for both the efficient and selective oxygenation of C-H bonds and other key chemical reactions involving free radicals.

Ultrafast Nucleation Reverses Dissolution of Transition Metal Ions for Robust Aqueous Batteries.

The dissolution of transition metal ions causes the notorious peeling of active substances and attenuates electrochemical capacity. Frustrated by the ceaseless task of pushing a boulder up a mountain, Sisyphus of the Greek myth yearned for a treasure to be unearthed that could bolster his efforts. Inspirationally, by using ferricyanide ions (Fe(CN)63-) in an electrolyte as a driving force and taking advantage of the fast nucleation rate of copper hexacyanoferrate (CuHCF), we successfully reversed the dissolution of Fe and Cu ions that typically occurs during cycling. The capacity retention increased from 5.7% to 99.4% at 0.5 A g-1 after 10,000 cycles, and extreme stability of 99.8% at 1 A g-1 after 40,000 cycles was achieved. Fe(CN)63- enables atom-by-atom substitution during the electrochemical process, enhancing conductivity and reducing volume change. Moreover, we demonstrate that this approach is applicable to various aqueous batteries (i.e., NH4+, Li+, Na+, K+, Mg2+, Ca2+, and Al3+).

Responses of sediment nitrogen forms and bacterial communities to different aquatic nitrogen conditions in three submerged macrophyte-type ecological treatment systems.

Ecological treatment system (ETS) has been recognized as a promising technology for mitigating agricultural non-point pollution, whereas it remains to be seen how nitrogen (N) forms and bacterial communities in ETS sediments respond to different aquatic N conditions. Therefore, a four-month microcosm experiment was conducted to investigate the effects of three aquatic N conditions (2 mg/L NH4+-N, 2 mg/L NO3--N and 1 mg/L NH4+-N + 1 mg/L NO3--N) on sediment N forms and bacterial communities in three ETSs vegetated by Potamogeton malaianus, Vallisneria natans and artificial aquatic plant, respectively. Through analysis of four transferable N fractions, the valence states of N in ion-exchange and weak acid extractable fractions were found to be mainly determined by aquatic N conditions, while significant N accumulation was observed only in strong oxidant extractable and strong alkali extractable fractions. Sediment N profiles were primarily influenced by time and plant types, with N condition having secondary effect, while sediment bacterial community structures experienced a significant shift over time and were slightly influenced by plant types. Sediment functional genes related to N fixation, nitrification, assimilable nitrate reduction, dissimilatory nitrite reduction (DNRA) and denitrification were substantially enriched in month 4, and the bacterial co-occurrence network exhibited less complexity but more stability under NO3- condition compared to others. Furthermore, certain sediment N fractions were found to have strong relationships with specific sediment bacteria, such as nitrifiers, denitrifiers and DNRA bacteria. Our findings highlight the significant influence of aquatic N condition in submerged macrophyte-type ETSs on sediment N forms and bacterial communities.

Low-intensity pulsed ultrasound and parathyroid hormone improve muscle atrophy in estrogen deficiency mice.

Due to aging and long-term estrogen deficiency, postmenopausal women suffer muscle atrophy (MA), which is characterized by decreased muscle mass and muscle quality. Low-intensity pulsed ultrasound (LIPUS) is an acoustic wave inducing biological effects mainly by the mechanical stimulation and used as a non-invasive physical therapy for muscle repair. Parathyroid hormone (PTH) is an 84-amino-acid polypeptide, and its bioactive fragment [PTH (1-34)] has potential application in the treatment of MA. We speculate that the combination of physical therapy (i.e., the LIPUS) and regulatory hormone (i.e., the PTH) would be more effective in the treatment of MA. The objective of this study was to evaluate the individual and combined effects of LIPUS and PTH therapy on MA in estrogen deficiency mice. Seventy 8-week-old female C57BL/6J mice were used in this study and the MA model was induced by an intraperitoneal injection of 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days. The VCD-induced MA mice were randomly divided into MA, LIPUS, PTH and LIPUS + PTH (Combined) groups (n = 10/group). In the LIPUS group, the mice were treated by LIPUS in bilateral quadriceps muscles for 20 min, five times a week for 6 weeks. In the PTH group, the mice received subcutaneous injection of PTH (1-34) (80 ug/kg/d) five times a week, for 6 weeks. In the Combined group, the PTH was administrated 30 min before each LIPUS session. Hematoxylin-eosin (H&E) staining, serum biochemical analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were applied to evaluate the therapeutic effects of related treatments. The results showed that the MA mice had a disordered estrus cycle, significantly decreased muscle mass and myofibers cross-sectional area (CSA). After treatments, LIPUS, PTH and Combined groups had a significantly increased CSA, compared with the MA mice without treatment. In addition, Combined group had a significantly increased mRNA expression of Pax7, MyoD and MyoG, compared with LIPUS and PTH monotherapy groups. Our findings indicated that the combination of LIPUS and PTH treatment improves muscle regeneration ability, which might have potential for treating MA in postmenopausal women.

Pulsed frequency modulated ultrasound promotes therapeutic effects of osteoporosis induced by ovarian failure in mice.

Low-intensity pulsed ultrasound (LIPUS) has been proved to be an effective technique for the treatment of osteoporosis. To better activate the bone formation-related markers, promote the different stages of osteogenesis, and further enhance the therapeutic effects of ultrasound, this study employed pulsed frequency modulated ultrasound (pFMUS) to treat mice with osteoporosis, which was caused by ovarian failure due to 4-vinylcyclohexene dioxide (VCD) injection. Healthy 8-week-old female C57BL/6J mice were randomly divided into four groups: Sham (S), VCD-control (V), VCD + LIPUS (VU), and VCD + pFMUS (VFU). VU and VFU groups were treated by LIPUS and pFMUS, respectively. Serum analysis, micro-computed tomography (micro-CT), mechanical testing and hematoxylin and eosin (HE) staining were performed to evaluate the therapeutic effects of ultrasound. Quantitative reverse-transcription PCR (qRT-PCR) and western blot analysis were used to explore the mechanism of ultrasound on osteoporosis. Results showed that pFMUS might have better therapeutic effects than traditional LIPUS in terms of bone microstructure and bone strength. In addition, pFMUS could promote bone formation by activating phosphoinositide-3 kinase/protein kinase B (PI3K/Akt) pathway, and slow down bone resorption by increasing osteoprotegerin/receptor activator of nuclear factor κB ligand (OPG/RANKL) ratio. This study is of positive prognostic significance when understanding the mechanism of ultrasound regulation on osteoporosis and establishing novel treatment plan of osteoporosis by multi-frequency ultrasound.

Cultivation-dependent and cultivation-independent investigation of O-methylated pollutant-producing bacteria in three drinking water treatment plants.

O-methylated pollutants (OMPs) are emerging contaminants in drinking water and mainly produced through bacterial O-methylation. However, the information of OMP-producing bacteria (OMPPB) in drinking water treatment plant (DWTP) is largely unknown so far. In this study, the OMPPB in water samples from three DWTPs (XL, JX and NX) were investigated by using cultivation-dependent and cultivation-independent technologies. Four OMPs were detected and their odor and toxicity risks were assessed. Formation potentials (FPs) of 2,4,6-trichloanisole, 2,3,6-trichloanisole, 2,4,6-tribromoanisole, pentachloroanisole and diclofenac methyl ester were determined in water samples and their values shifted significantly among DWTPs. A most probable number (MPN) method was established to quantify OMPPB numbers and the relationships between total haloanisole FPs (HAFPs) (y) and OMPPB numbers (x) in three DWTPs could be described by the following functions: y = 0.496×0.373 (XL), y = 0.041×0.465 (JX) and y = 0.218×0.237 (NX). Several genera like Bacillus, Ralstonia, Brevundimonas, etc. were newly found OMPPB among the cultivable bacteria, and their OMP products were evaluated in terms of quantity and environment risks (odor, toxicity and bioaccumulation). High-throughput sequencing revealed treatment process was the main driving factor to shape the OMPPB community structures and Mantel test showed HAFP profile was significantly influenced by Mycobacterium and Pelomonas. PICURSt2 analysis discovered four phenolic O-methyltransferases (OMTs) and four carboxylic OMTs which might be responsible for OMP formation. Several strategies were recommended to assess risk and control contamination brought by OMPPB in DWTPs.

Poly(glycidyl azide) as Photo-Crosslinker for Polymers.

Crosslinking polymers to form networks is a universal and routinely applied strategy to improve their stability and endow them with solvent resistance, adhesion properties, etc. However, the chemical crosslinking of common commercial polymers, especially for those without functional groups, cannot be achieved readily. In this study, we utilized low-molecular weight poly(glycidyl azide) (GAP) as polymeric crosslinkers to crosslink various commercial polymers via simple ultraviolet light irradiation. The azide groups were shown to decompose upon photo-irradiation and be converted to highly reactive nitrene species, which are able to insert into carbon-hydrogen bonds and thus crosslink the polymeric matrices. This strategy was demonstrated successfully in several commercial polymers. In particular, it was found that the crosslinking is highly localized, which could endow the polymeric matrices with a decent degree of crosslinking without significantly influencing other properties, suggesting a novel and robust method to crosslink polymeric materials.

Essential role of MESP1-RING1A complex in cardiac differentiation.

Heart development is controlled by a complex transcriptional network composed of transcription factors and epigenetic regulators. Mutations in key developmental transcription factor MESP1 and chromatin factors, such as PRC1 and cohesin components, have been found in human congenital heart diseases (CHDs), although their functional mechanism during heart development remains elusive. Here, we find that MESP1 interacts with RING1A/RING1, the core component of PRC1. RING1A depletion impairs human cardiomyocyte differentiation, and cardiac abnormalities similar to those in patients with MESP1 mutations were observed in Ring1A knockout mice. Mechanistically, MESP1 associates with RING1A to activate cardiogenic genes through promoter-enhancer interactions regulated by cohesin and CTCF and histone acetylation mediated by p300. Importantly, CHD mutations of MESP1 significantly affect such mechanisms and impair target gene activation. Together, our results demonstrate the importance of MESP1-RING1A complex in heart development and provide insights into the pathogenic mechanisms of CHDs caused by mutations in MESP1, PRC1, and cohesin components.

In vivo self-assembled siRNA as a modality for combination therapy of ulcerative colitis.

Given the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.

Quercitrin protects human bronchial epithelial cells from oxidative damage.

Chronic obstructive pulmonary disease (COPD) is mainly caused by cigarette smoking (CS), with oxidative stress being one key component during its pathogenesis. This study aimed to investigate the effects of quercitrin (QE) on cigarette smoke extract (CSE)-induced cell apoptosis and oxidative stress in human bronchial epithelial cells (HBECs) and its underlying mechanism. HBECs were treated with 2% CSE for 24 h to establish in vitro COPD cellular models. CCK-8 assay and flow cytometry analysis were performed to evaluate cell viability and apoptosis, respectively. Western blotting was applied to examine protein levels and ELISA kits were used to examine contents of the indicated oxidant/antioxidant markers. The results demonstrated that CSE promoted apoptosis and suppressed viability of HBECs and QE reversed these effects. CSE caused increase in T-AOC, superoxide dismutase, and glutathione (GSH) peroxidase contents and decrease in MDA, reactive oxygen species , and GSH contents in HBECs, which were rescued by QE treatment. The CSE-induced Nrf2 nuclear translocation and elevation of NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) expression were also reversed by QE in HBECs. The mitogen-activated protein kinase (MAPK) signaling was activated by CSE and further suppressed by QE in HBECs. Collectively, QE exerts a protective role in HBECs against cell apoptosis and oxidative damage via inactivation of the Nrf2/HO-1/NQO1 pathway and the MAPK/ERK pathway.