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We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong anticancer activity in multiple types of cancer cells, especially colorectal cancer. In this report, we provide evidence that OBD9 suppresses colorectal cancer growth by interfering with the Wnt signaling pathway, a main driver of cell growth in colorectal cancer. Specifically, we find that OBD9 induces autophagic degradation of TNIK (traf2 and Nck-interacting kinase), which promotes T-cell factor-4 (TCF4)/beta-catenin–mediated gene expression. Thus, OBD9 as a TNIK inhibitor blocks Wnt/beta-catenin signaling at the final step of transcriptional activation. We suggest that OBD9 provides a potential novel autophagy-mediated, Wnt-damping therapeutic strategy for the treatment of colorectal cancer.

Isobavachalcone (IBC) is one of the flavonoid components in Fructus Psoraleae, and has been found multiple pharmacological effects. However, the hepatotoxicity of IBC has been overlooked and not been carefully studied. We aim to find out the cytotoxicity of IBC on HepG2 cells, and explore the underlying mechanisms. HepG2 cells were treated with IBC for 24 h, then MTT assay and LDH assay were used to detect the cell viability. The apoptosis and reactive oxygen species (ROS) production were reflected by the flow cytometry. Using Seahorse Analyzer, we measured the mitochondrial respiratory capacity. The expression of oxidative stress and mitochondrial apoptosis-related proteins were determined by Western blot. The results showed that IBC induced the cell death and apoptosis of HepG2 cells. IBC initiated the accumulation of ROS in cells and impaired the mitochondrial function, triggered apoptosis and suppressed the phosphorylation of Akt. Additionally, scavenging ROS by the antioxidant N-acetyl-l-cysteine (NAC) reduced IBC-induced mitochondria damage and increased Akt phosphorylation. Taken together, IBC caused mitochondrial damage and induced hepatotoxicity by ROS accumulation and Akt suppression. Targeting oxidative stress and depressing mitochondrial damage may provide a theoretical basis for the treatment and prevention of IBC-induced hepatotoxicity in clinic.

Abstract: Hippo, an evolutionarily conserved kinase cascade reaction in organisms, can respond to a set of signals, such as mechanical signals and cell metabolism, to maintain cell growth, differentiation, tissue/organ development, and homeostasis. In the past ten years, Hippo has controlled the development of tissues and organs by regulating the process of cell proliferation, especially in the field of cardiac regeneration after myocardial infarction. This suggests that Hippo signaling is closely linked to cardiovascular disease. Atherosclerosis is the most common disease of the cardiovascular system. It is characterised by chronic inflammation of the vascular wall, mainly involving dysfunction of endothelial cells, smooth muscle cells, and macrophages. Oxidized Low density lipoprotein (LDL) damages the barrier function of endothelial cells, which enter the middle membrane of the vascular wall, accelerate the formation of foam cells, and promote the occurrence and development of atherosclerosis. Autophagy is associated with the development of atherosclerosis. However, the mechanism of Hippo regulation of atherosclerosis has not meant to be clarified. In view of the pivotal role of this signaling pathway in maintaining cell growth, proliferation, and differentiation, the imbalance of Hippo is related to atherosclerosis and related diseases. In this review, we emphasized Hippo as a hub for regulating atherosclerosis and discussed its potential targets in pathophysiology, human diseases, and related pharmacology.

Neocryptolepine derivatives have attracted great interest because of their unique cytotoxic activity. 8-Fluoroneocryptolepine (8FNC) was synthesized, and its cytotoxicity was evaluated by MTT assay in AGS gastric cancer cells and gastric mucosa GES-1 cells. 8-Fluoroneocryptolepine showed greater selectivity and cytotoxicity to AGS cells than the cisplatin (CIS) and fluorouracil (5-Fu) commonly used in clinical treatment of gastric cancer. Most importantly, we significantly improved the cytotoxic effect of 8FNC against AGS cells by structural modification and reduced the cytotoxicity against GES-1 cells compared with neocryptolepine. We further evaluated the activity of 8FNC against AGS cells

Thoracolumbar fractures have the characteristics of acute onset, rapid change, and severe trauma. The best way to treat thoracolumbar fractures is through fracture reduction surgery. The surgical methods include percutaneous pedicle screw, posterior percutaneous pedicle screw internal fixation, and open pedicle screw internal fixation.We searched the PubMed, Embase, and Medline English database from April 1991 to April 2021, and the keywords included "percutaneous tablet screen", "posterior percutaneous tablet screen fixation", "open tablet screen fixation", "fracture of thoracic vertebrae", "thoracic fractures", "thoracic", and "vascular fracture". RevMan5.3 provided by Cochrane was used for meta-analysis.A total of 9 articles were included in this study. Percutaneous pedicle screw fixation and posterior percutaneous pedicle screw fixation were adopted as the surgical methods, and patients were enrolled into experimental and control groups. Open pedicle screw internal fixation was set as the control group. The mean difference (MD) of operation time, blood loss, pain score, postoperative complications, screw debris rate, and hospital stay were -0.73, -192.16, -0.70, 1.49, 0.32, and -1.26, respectively; 95% confidence intervals (CIs) were (-0.94, -0.51), (-213.23, -171.09), (-0.82, -0.57), (0.47, 4.79), (0.10, 0.99), and (-1.82, -0.71), respectively; Z values were 6.71, 17.87, 10.95, 0.67, 1.97, and 4.46, respectively; and P values were0.00001,0.00001,0.00001, 0.50, 0.05, and0.00001, respectively.A total of 9 articles were included in this meta-analysis. Compared with open surgery, the use of percutaneous pedicle screw and posterior percutaneous pedicle screw fixation had less blood loss, shorter operation time, shorter hospital stay, less pain, as well as lower screw dislocation and postoperative infection rates, indicating that the use of percutaneous pedicle screw and posterior percutaneous pedicle screw fixation is more effective than open surgery.

OBJECTIVE The complex anatomical structures of cerebellopontine angle (CPA) pose a unique challenge to diffusion weighted imaging (DWI). This study aimed to compare the clinical utility of the prototypic 2D turbo gradient- and spin echo-BLADE-DWI (TGSE-BLADE-DWI) with that of readout-segmented echo-planar DWI (RESOLVE-DWI) and single-shot echo-planar DWI (SS-EPI-DWI) to visualize CPA anatomic structures and identify CPA tumors. METHODS A total of 8 volunteers and 36 patients with pathological CPA tumors were enrolled to perform the three DWI sequences at 3 T. Scan time of TGSE-BLADE-DWI, RESOLVE-DWI and SS-EPI-DWI was 5 min 51 s, 5 min 15 s and 1 min 22 s, respectively. Subjective analysis, including visualization of anatomical structures, geometric distortion, ghosting artifacts, lesion conspicuity, diagnostic confidence, and overall image quality of the three DWI sequences were scored and assessed. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and apparent diffusion coefficient (ADC) of CPA tumors were measured and compared. RESULTS A total of 39 lesions were identified, TGSE-BLADE-DWI detected all of them, RESOLVE-DWI 36 and SS-EPI-DWI 27. Significant differences were found in all the subjective parameters among the three DWI sequences (all p

Diabetic cardiomyopathy (DCM) is a cardiovascular complication that tends to occur in patients with diabetes, obesity, or insulin resistance, with a higher late mortality rate. Sustained hyperglycemia, increased free fatty acids, or insulin resistance induces metabolic disorders in cardiac tissues and cells, leading to myocardial fibrosis, left ventricular hypertrophy, diastolic and/or systolic dysfunction, and finally develop into congestive heart failure. The close connection between all signaling pathways and the complex pathogenesis of DCM cause difficulties in finding effective targets for the treatment of DCM. It reported that hydrogen sulfide (H2S) could regulate cell energy substrate metabolism, reduce insulin resistance, protect cardiomyocytes, and improve myocardial function by acting on related key proteins such as differentiation cluster 36 (CD36) and glucose transporter 4 (GLUT4). In this article, the relative mechanisms of H2S in alleviating metabolic disorders of DCM were reviewed, and how H2S can better prevent and treat DCM in clinical practice will be discussed.

Parkinson's disease (PD) is a progressive neurological disorder, in which dopaminergic midbrain neurons degenerate, leading to dopamine depletion that is associated with neuronal death. In this Review, we initially describe the pathogenesis of PD and established therapies that unfortunately only delay progression of the disease. With a rapidly escalating incidence in PD, there is an urgent need to develop new therapies that not only halt progression but even reverse degeneration. Biomaterials are playing critical roles in these new therapies which include controlled and site-specific delivery of neurotrophins, increased engraftment of implanted neural stem cells, and redirection of endogenous stem cell populations away from their niche to encourage reparative mechanisms. This Review will therefore cover important design features of biomaterials used in regenerative medicine and tissue engineering strategies targeted at PD.

Background Lung cancer, the leading cause of cancer‐related deaths worldwide, has high morbidity rates. Video‐assisted thoracoscopic surgery (VATS) as day surgery makes surgical treatment ideally in time with the same quality of medical care. This study aimed to assess the safety of stage I NSCLC patients who underwent VATS at a day surgery center. Methods We retrospectively analyzed the clinical characteristics and tumor features of VATS patients at a single center, West China Hospital, from June 1, 2019, to December 31, 2020. Patients fulfilled all inclusion criteria, did not meet any exclusion criteria and underwent wedge resection, segmentectomy, or lobectomy with systematic lymph node dissection. Results The median patient age was 43 (range, 19–67) years. Of the 209 patients, most were women. A total of 108 (51.7%) patients underwent segmentectomy, 87 (41.6%) lobectomy, and 14 (6.7%) wedge resection with systematic lymph node dissection. According to the AJCC/UICC eighth edition of lung cancer stage grouping, stages IA, IA1, IA2, and IA3 were 195 (93.3%), 122 (58.4%), 50 (23.9%), and one (0.5%), respectively. A total of 36 (17.2%) patients were stage 0. Adenocarcinoma was predominantly the postoperative pathological diagnosis, as only 14 (6.7%) were benign. A total of 201 (96.17%) patients were discharged without a chest tube. The most common chief complaints were cough, incisional pain, and shortness of breath. No severe complications or life‐threatening emergencies were observed. Conclusions The day surgery mode of VATS for stage I NSCLC is safe and feasible, which makes surgical treatment ideally in time for stage I NSCLC patients with the same quality of medical care., The selection process of the study

Background A two-dimensional turbo gradient-echo and spin-echo diffusion-weighted pulse sequence with a non-Cartesian BLADE trajectory (TGSE BLADE) can eliminate image artifacts and distortion with clinically acceptable scan times. This process has the potential to overcome the shortcomings of current diffusion-weighted imaging (DWI) techniques, especially in the sinonasal region. Purpose To investigate the feasibility of TGSE BLADE in the assessment of sinonasal lesions and compare the quality of TGSE BLADE with RESOLVE images both qualitatively and quantitatively. Material and Methods A total of 36 patients with sinonasal lesions were included in this prospective study. DW images acquired using TGSE BLADE and RESOLVE were performed with the same acquisition time. Two independent observers evaluated the qualitative parameters (overall image quality, lesion visibility, and geometric distortion) and quantitative parameters (geometric distortion ratio [GDR], signal-to-noise ratio [SNR], contrast, contrast-to-noise ratio [CNR], and apparent diffusion coefficient [ADC] value) of the two sequences. Results Qualitative assessment revealed that TGSE BLADE exhibited higher overall image quality ( P Conclusion TGSE BLADE can reduce susceptibility artifacts and geometric distortion more than RESOLVE and appears to be a promising diffusion imaging sequence for the assessment of sinonasal lesions.

Introduction Pancreatic cancer is with the poorest prognosis of all common cancers worldwide. Despite the advances in treatment the results are poor throughout the different methods. Pancreatic resection still yields the best outcome. However only a quarter of the patients present at operable stage. HIFU is a noninvasive technique that can be used to treat pancreatic cancer. Aim The aim of this review is to perform a systematic review on the data about the resection rate after HIFU ablation in patients with borderline resectable pancreatic cancer (BRPC) and the impact of this technique over the oncological results. Materials and methods The PubMed and Wanfang databases were searched using keywords: pancreatic cancer, HIFU ablation and high-intensity focused ultrasound. All found articles were reviewed. The systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard guidelines. This study was financially supported by 2019 'Kuan-Ren Elite' Program of 2nd Affiliated Hospital of Chongqing Medical University, China (Grant no. KY2019G019). Results The English database search showed 109 papers, of which 3 met the inclusion criteria. The Wanfang database resulted in 110 papers; however, none met the inclusion criteria of the review. From the included studies 97 patients underwent neoadjuvant HIFU ablation ± chemotherapy. Thirty-four patients reached resection (35.1%). In two patients, residual tumor (R) classification was not reported. R0 resection rate in all reported patients is 30.5% (29/95). R1 resection rate is 3.2% (3/95). Conclusion HIFU is found to be safe and feasible in locally advanced and metastatic pancreatic cancer with proven downstaging and downsizing effects. Further research on role of HIFU ablation as a neoadjuvant treatment for borderline resectable pancreatic cancer is needed.

Maternal and collateral donors were associated with a higher incidence of graft

Depression is a mental disorder characterized by low mood, reduced interest, impaired cognitive function, and vegetative symptoms such as sleep disturbances or poor appetite. Iridoids are the active constituents in several Chinese classical antidepressant formulae such as Yueju Pill, Zhi-Zi-Hou-Po Decoction, Zhi-Zi-Chi Decoction, and Baihe Dihuang Decoction. Parallel to their wide usages, iridoids are considered potential lead compounds for the treatment of neurological diseases.The review summarizes the therapeutic potential and molecular mechanisms of iridoids in the prevention or treatment of depression and contributes to identifying research gaps in iridoids as potential antidepressant medication.The following key phrases were sought in PubMed, Google Scholar, Web of Science, and China National Knowledge Internet (CNKI) without time limitation to search all relevant articles withPlant iridoids (i.e., catalpol, geniposide, loganin), and secoiridoids (i.e., morroniside, gentiopicroside, oleuropein, swertiamarin), all showed significant improvement effects on depression.Iridoids exert antidepressant effects by elevating monoamine neurotransmitters, reducing pro-inflammatory factors, inhibiting hypothalamic-pituitary-adrenal (HPA) axis hyperactivity, increasing brain-derived neurotrophic factor (BDNF) and its receptors, and elevating intestinal microbial abundance. Further detailed studies on the pharmacokinetics, bioavailability, and key molecular targets of iridoids are also required in future research, ultimately to provide improvements to current antidepressant medications.

To evaluate the long-term survival benefits of high intensity focused ultrasound (HIFU) ablation in patients with hepatocellular carcinoma (HCC) combined with portal vein tumor thrombus (PVTT).The data of patients with HCC-PVTT treated with HIFU from January 2014 to December 2019 were retrospectively analyzed. All patients received HIFU ablation for both PVTT and liver tumor in one session. Perioperative adverse events (AEs) were recorded, and follow-up was performed postoperatively. The Kaplan-Meier method was used for survival analysis.Median follow-up was 13.75 ± 1.31 months. A total of 144 patients (male/female: 122/22, age: 54.15 ± 11.84 years old) were included in the study. A total of 267 liver tumors (tumor number: 1.87 ± 1.65, range 1-10) were treated with HIFU. The mean ± SD diameter of viable liver tumors was 100.98 ± 61.65 mm. The reported postoperative AEs of HIFU were skin edema (93.75%), local pain (69.44%) and fever (7.64%). There was no liver failure, gastrointestinal bleeding or perioperative death. The median overall survival (OS) time was 14 months, while the cumulative survival rates of 0.5, 1, 2 and 3 years were 79.0%, 58.6%, 33.3% and 5.9%, respectively. The median OS of PVTT types I, II and III was 22, 13 and 14 months, respectively, and the difference was not statistically significant (HIFU is a minimally invasive method for HCC-PVTT with fewer complications, which could prolong the OS. Patients with PVTT type III could benefit more from HIFU, compared to types I and II.

Multivalent antibody-recruiting glycopolymers (MARGs) composed of hyaluronic acid (HA) grafted with multiple copies of dinitrophenol (DNP) were developed for targeted cancer immunotherapy. Structure-activity studies demonstrated that the MARGs were able to specifically recognize CD44-positive cancer cells and displayed remarkable antibody-recruiting capacities and tumor cell killing activities dependent on the introduced multivalent effect and the length of PEG linker. One of the MARGs, HA-[PEG3 -DNP]8 , showed the best capacity for clustering anti-DNP antibodies onto CD44-positive cancer cells and displayed potent in vitro anti-cancer activity by triggering complement dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Moreover, we found that HA-[PEG3 -DNP]8 significantly inhibited the xenograft tumor growth of Babl/c nude mice bearing triple negative breast cancer cells, while it did not cause detectable histological cytotoxicity. Given the easy access of this type of natural glycopolymer and the practical synthesis approach, these MARGs provide promising immunotherapeutics for cancer immunotherapy.

Endothelial–mesenchymal transition (EndMT) is widely involved in the occurrence and development of cardiovascular diseases. Although there is no direct evidence, it is very promising as an effective target for the treatment of these diseases. Endothelial cells need to respond to the complex cardiovascular environment through EndMT, but sustained stimuli will cause the imbalance of EndMT. Blocking the signal transduction promoting EndMT is an effective method to control the imbalance of EndMT. In particular, we also discussed the potential role of endothelial cell apoptosis and autophagy in regulating the imbalance of EndMT. In addition, promoting mesenchymal-endothelial transformation (MEndT) is also a method to control the imbalance of EndMT. However, targeting EndMT to treat cardiovascular disease still faces many challenges. By reviewing the research progress of EndMT, we have put forward some insights and translated them into challenges and opportunities for new treatment strategies for cardiovascular diseases.

Background: There is a well-established relationship between cell cycle progression and the development of stomach adenocarcinoma. This study aimed to elucidate the molecular mechanism and biological function of APBB2 in gastric cancer. Methods: Gastric adenocarcinoma (GA) data were downloaded from the TCGA-GA and GEO databases and analyzed to explore differentially expressed miRNAs and mRNAs. Moreover, potential target mRNAs were also predicted. The relative level of gene and protein expression in GA cell lines and gastric mucosa cells was detected by q-PCR and Western blot, respectively. Moreover, the influence of APBB2 on proliferation, metastasis, and cell cycle changes in SGC-7901 and BGC-823 cells was evaluated. The binding relationship between the target miRNA and mRNA was confirmed with a dual-luciferase reporter assay. Results: High APBB2 expression was detected in GA patients, indicating that it may be represent a predictive biomarker for poor prognosis. Related experiments confirmed that APBB2 silencing inhibited GA cellular functions, including proliferation, cell cycle progression, migration, and invasion. In addition, to explore the molecular mechanism, our results indicated that the binding sites were located at hsa-mir-30a and the 3′-UTR of APBB2, suggesting that hsa-mir-30a can regulate the expression of APBB2. The biological functions of hsa-mir-30a were also evaluated. Hsa-mir-30a overexpression attenuated the proliferation and metastasis of cancer cells. In rescue experiments, hsa-mir-30a was confirmed to reverse the cell cycle promoting function associated with APBB2 overexpression. Conclusion: Our findings show that hsa-mir-30a can attenuate the development of GA by down-regulating APBB2 expression.

Background Epithelial-to-mesenchymal transition (EMT) is a critical event contributing to more aggressive phenotypes in cancer cells. EMT is frequently activated in radiation-targeted cells during the course of radiotherapy, which often endows cancers with acquired radioresistance. However, the upstream molecules driving the signaling pathways of radiation-induced EMT have not been fully delineated. Methods In this study, RNA-seq-based transcriptome analysis was performed to identify the early responsive genes of HeLa cells to γ-ray irradiation. EMT-associated genes were knocked down by siRNA technology or overexpressed in HeLa cells and A549 cells, and the resulting changes in phenotypes of EMT and radiosensitivity were assessed using qPCR and Western blotting analyses, migration assays, colony-forming ability and apoptosis of flow cytometer assays. Results Through RNA-seq-based transcriptome analysis, we found that LPAR5 is downregulated in the early response of HeLa cells to γ-ray irradiation. Radiation-induced alterations in LPAR5 expression were further revealed to be a bidirectional dynamic process in HeLa and A549 cells, i.e., the early downregulating phase at 2 ~ 4 h and the late upregulating phase at 24 h post-irradiation. Overexpression of LPAR5 prompts EMT programing and migration of cancer cells. Moreover, increased expression of LPAR5 is significantly associated with IR-induced EMT and confers radioresistance to cancer cells. Knockdown of LPAR5 suppressed IR-induced EMT by attenuating the activation of ERK signaling and downstream Snail, MMP1, and MMP9 expression. Conclusions LPAR5 is an important upstream regulator of IR-induced EMT that modulates the ERK/Snail pathway. This study provides further insights into understanding the mechanism of radiation-induced EMT and identifies promising targets for improving the effectiveness of cancer radiation therapy.

Bispecific antibodies (BsAbs) are next-generation therapeutics for complex cancer treatment. Herein, we developed a dual-targeting non-IgG format of bsAbs by using a bispecific nanobody (bsNb) that can simultaneously target EGFR and HER2 on tumor cells. Site-specific modification of the anti-EGFR-HER2 bsNb was conducted using the rhamnose (Rha) hapten via sortase A-mediated ligation to reconstitute the missing crystallizable fragment (Fc) effector biological functions. Functionally similar to bsAbs, bsNb-Rha conjugates retained dual-targeting activity and exerted potent anticancer effects via the Fc-domain-mediated engagement of endogenous anti-Rha antibodies. Further, an optimized bsNb-Rha conjugate exhibited markedly improved pharmacokinetics and efficient inhibitory effects against xenograft tumor growth in vivo. Our strategy provides a general and cost-effective platform to generate a new bsAb format for cancer immunotherapy.

Diffusion-weighted magnetic resonance imaging is prone to have susceptibility artifacts in an inhomogeneous magnetic field. We compared distortion and artifacts among three diffusion acquisition techniques (single-shot echo-planar imaging [SS-EPI DWI], readout-segmented EPI [RESOLVE DWI], and 2D turbo gradient- and spin-echo diffusion-weighted imaging with non-Cartesian BLADE trajectory [TGSE-BLADE DWI]) in healthy volunteers and in patients with a cerebral aneurysm clip. Seventeen healthy volunteers and 20 patients who had undergone surgical cerebral aneurysm clipping were prospectively enrolled. SS-EPI DWI, RESOLVE DWI, and TGSE-BLADE DWI of the brain were performed using 3 T scanners. Distortion was the least in TGSE-BLADE DWI, and lower in RESOLVE DWI than SS-EPI DWI near air–bone interfaces in healthy volunteers (P P P

The standard regimens for graft-versus-host disease (GvHD) prophylaxis in matched unrelated donor (MUD) transplantation were based on antithymocyte globulin (ATG) in combination with calcineurin inhibitors (CNIs). To improve the efficiency of GvHD prophylaxis in MUD peripheral blood stem cell transplantation (MUD-PBSCT), 51 patients with hematological malignancies received a novel regimen for GvHD prophylaxis, which is composed of low dose of ATG (5 mg/kg) plus low-dose posttransplant cyclophosphamide (PTCy, 50 mg/kg) (low-dose ATG/PTCy) combined with cyclosporine A (CsA) and mycophenolate mofetil (MMF). The cumulative incidences (CIs) of grades I–IV and II–IV acute GvHD (aGvHD) were 14.5% (95% CI, 9.4–19.6%) and 6.2% (95% CI, 2.8–9.6%) within 100 days after transplantation, respectively. The CI of mild-to-moderate chronic GvHD (cGvHD) within 1 year was 11.5% (95% CI, 6.6–16.4%). The 1-year probabilities of GvHD and relapse-free survival, relapse-free survival, and over survival were 70.6% (95% CI, 64.2–77.0%), 76.5% (95% CI, 70.6–82.4%), and 82.0% (95% CI, 76.5–87.5%), respectively. The CIs of CMV and EBV reactivation by day 180 were 10.4% (95% CI, 1.5–19.4%) and 8.3% (95% CI, 0.2–16.4%), respectively. The results suggested that low-dose ATG/PTCy combined with CsA/MMF as GvHD prophylaxis in MUD-PBSCT had promising activity.

Citrus fruit is a carotenoid and vitamin-rich food. Here, we investigated the effects of red, blue, and white light-transmittance bagging (LTB) on carotenoid (Car) metabolism during 'Moro' blood orange ripening. A total of 50 carotenoids were identified, and phytoene and violaxanthins were predominant in the pulp, accounting for over 82.12 % of total Cars. Red LTB increased the esterification of xanthophylls easily absorbed by the human body and promoted Car accumulation. The esterification of violaxanthin, lutein, β-cryptoxanthin, and zeaxanthin by caprate (C10), laurate (C12), myristate (C14), palmitic (C16), and oleate (C18) was the main contributor to the observed patterns. CsAt1g54570, a potential xanthophyll esterase, might mediate the esterification of β-cryptoxanthin. Our results shed light on the role of red LTB in enhancing Car esterification and accumulation in citrus pulp and provide a promising method for promoting Car accumulation during citrus production.

Background To compare the efficacy of three different fixation methods of fibula combined with external fixation of tibia for the treatment of extra-articular open fractures of distal tibia and fibula. Methods From January 2017 to July 2019, 91 cases of open fractures of distal tibia and fibula were treated with external fixator, and the fibula was fixed with non-fixation (group A, n = 35), plate-screw (group B, n = 30) and Kirschner wire (group C, n = 26). The operation time, intraoperative blood loss, surgical and implants costs, fracture healing time, postoperative complications, and American Orthopaedic Foot and Ankle surgery (AOFAS) scores were compared among the groups. Results Four patients were lost to follow-up, and 87 patients were followed up for 5–35 months (average, 14.2 months). The operation time of group C (114.92 ± 36.09 min) was shorter than that of group A (142.27 ± 47.05 min) and group B (184.00 ± 48.56 min) (P P > 0.05). The surgical and implants costs in group C (5.24 ± 1.21, thousand dollars) is lower than that in group A (6.48 ± 1.11, thousand dollars) and group B (9.37 ± 2.16, thousand dollars) (P P P P > 0.05). The excellent or good rate of ankle function was 69.70% in group A, 72.41% in group B and 84.00% in group C, with no statistical difference among the three groups (P > 0.05). Conclusion Compared with simple external fixator fixation and external fixator combined with plate-screw osteosynthesis, external fixator combined with K-wire intramedullary fixation shortens the operative time and fracture healing time, reduced costs and complications of fracture healing, while the blood loss, infection complications and ankle function recovery showed no difference with the other two groups. External fixator combined with plate-screw osteosynthesis had no advantage in treating extra-articular open fractures of distal tibia and fibula when compared with simple external fixation.

Fructus Psoraleae (FP), widely used in traditional medicine, is increasingly reported to cause serious hepatotoxicity in recent years. However, the main toxic constituents responsible for hepatotoxicity and the underlying mechanisms are poorly understood. In the present study, psoralen, a main and quality-control constituent of FP, was intragastrically administered to Sprague-Dawley rats at a dose of 60 mg/kg for 1, 3 and 7 days. Blood and selected tissue samples were collected and analyzed for biochemistry and histopathology to evaluate hepatotoxicity. The results showed that psoralen could induce hepatotoxicity by enhanced liver-to-body weight ratio and alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total cholesterol after administration for 3 days. In addition, histopathological examinations also indicated the hepatotoxicity induced by psoralen. Furthermore, the mRNA and protein levels of hepatic bile acid transporters were significantly changed, in which MRP4, ABCG5 and ABCG8 were repressed, while the protein level of NTCP tended to increase in the rat liver. Taken together, psoralen caused liver injury possibly through affecting bile acid transporters, leading to the disorder of bile acid transport and accumulation in hepatocytes.

In this study, 30 subjects were exposed to different combinations of air temperature (Ta : 24, 27, and 30°C) and CO2 level (8000, 10 000, and 12 000 ppm) in a high-humidity (RH: 85%) underground climate chamber. Subjective assessments, physiological responses, and cognitive performance were investigated. The results showed that as compared with exposure to Ta = 24°C, exposure to 30°C at all CO2 levels caused subjects to feel uncomfortably warm and experience stronger odor intensity, while increased mental effort and greater intensity of acute health symptoms were reported. However, no significant effects of Ta on task performance or physiological responses were found. This indicated that subjects had to exert more effort to maintain their performance in an uncomfortably warm environment. Increasing CO2 from 8000 to 12 000 ppm at all Ta caused subjects to report higher rates of headache, fatigue, agitation, and feeling depressed, although the results were statistically significant only at 24 and 27°C. The text typing performance and systolic blood pressure (SBP) decreased significantly at this exposure, whereas diastolic blood pressure (DBP) and thermal discomfort increased significantly. These effects suggest higher arousal/stress. No significant interaction effect of Ta and CO2 concentration on human responses was identified.

OBJECTIVE The aim of the study was to assess the peripheral rim instability and the clinical value of discoid meniscus. METHODS We retrospectively studied 79 magnetic resonance imaging (MRI) examinations of discoid meniscus from May 2017 to September 2019. The patient symptoms and physical findings were documented. The patients underwent "dedicated" 0.25 T supine and weight-bearing MRI examination. Finally, all patients underwent arthroscopy. RESULTS Sound/clicking during motion (P = 0.009) and limited extension (P = 0.044) of subjective symptoms, clunk during motion (P = 0.035), and flexion contracture (P = 0.012) of physical findings were significant predictors of peripheral rim instability. The comparison of the weight-bearing MRI with the supine position MRI demonstrated that the disformed discoid meniscus was shifted significantly and that no shift was displaced centrally (P = 0.001). A correlation between discoid meniscal displacement and the presence of peripheral rim instability in arthroscopy was noted (P < 0.001) using weight-bearing MRI. CONCLUSIONS The clinical symptoms of the patients combined with weight-bearing MRI can determine peripheral rim instability optimally.

High on-treatment platelet reactivity (HTPR) determined by platelet function assays is present in certain patients with ischemic stroke or transient ischemic attack (TIA). However, it is unclear whether HTPR is associated with poor clinical outcomes. Our study aimed to investigate the relationship of HTPR with recurrent vascular events in ischemic stroke or TIA.Pubmed (MEDLINE), EMBASE, and Cochrane Library were searched for eligible studies from inception to January 1, 2022. Stata 17.0 software was used to calculate the risk ratio (RR). Subgroup and sensitivity analyses were conducted to assess the source of heterogeneity. A random-effects model was used when heterogeneity was present. Primary endpoint of the meta-analysis was the risk ratio of recurrent vascular events in HTPR Patients. While stroke and TIA, all-cause death, early neurological deterioration, early new ischemic lesions, and stroke severity measured by National Institute of Health Stroke Scale (NIHSS) scores at admission were also pooled.Thirty articles (7995 patients) were eligible including 28 cohort studies and 2 prospective case-control studies. The prevalence of HTPR varied from 5.9% to 60%. HTPR was associated with an increased risk of recurrent vascular events (RR = 2.94, 95% CI 2.04-4.23), stroke recurrence (RR = 2.05; 95% CI 1.43-2.95), and all-cause mortality (RR = 2.43; 95% CI 1.83-3.22). Subgroup analysis showed that HTPR determined by optical aggregometry, Verify-Now system and 11dh TXB2 is related to a higher risk of recurrent vascular events (RR = 3.53, 95% CI 1.51-9.40; RR = 2.16, 95% CI 1.02-4.56; RR = 3.76, 95% CI 1.51-9.40, respectively). Moreover, patients with HTPR had an increased incidence of early neurological deterioration (RR = 2.75; 95% CI 1.76-4.30) and higher NIHSS scores at admission (Mean difference 0.19, 95% CI 0.01-0.36).This meta-analysis demonstrates HTPR is associated with higher risk of recurrent vascular events, early neurological deterioration and increased severity in patients with ischemic stroke and TIA. HTPR measured by platelet function assays may guide the use of antiplatelet agents in ischemic stroke and TIA.

Asymptomatic infection with SARS-CoV-2 is a major concern in the control of the COVID-19 pandemic. Many questions concerning asymptomatic infection remain to be answered, for example, what are the differences in infectivity and the immune response between asymptomatic and symptomatic infections? In this study, based on a cohort established by the Wuchang District Health Bureau of Wuhan in the early stage of the COVID-19 pandemic in Wuhan in 2019, we conducted a comprehensive analysis of the clinical, virological, immunological, and epidemiological data of asymptomatic infections. The major findings of this study included: 1) the asymptomatic cohort enrolled this study exhibited low-grade but recurrent activity of viral replication; 2) despite a lack of overt clinical symptoms, asymptomatic infections exhibited ongoing innate and adaptive immune responses; 3) however, the immune response from asymptomatic infections was not activated adequately, which may lead to delayed viral clearance. Given the fragile equilibrium between viral infection and host immunity, and the delayed viral clearance in asymptomatic individuals, close viral monitoring should be scheduled, and therapeutic intervention may be needed.

BACKGROUND The rare incidence of esophageal neuroendocrine carcinoma (NEC) and limited treatment experience result in insufficient clinical observations and unsuitable guidelines for its management. AIM To investigate the prognostic value of pretreatment contrast-enhanced computed tomography (CT) characteristics in patients with esophageal NEC. METHODS Seventy-seven esophageal NEC patients who received contrast-enhanced CT at two hospitals were enrolled in this study from June 2014 to December 2019. The clinical features and image characteristics were recorded accordingly. Univariate survival analysis was performed using the Kaplan-Meier method and log-rank test, and multivariate analysis was carried out with a Cox proportional hazards model. RESULTS The multivariate analysis performed using the Cox proportional hazards model showed that N stage, adjuvant chemotherapy, and degree of enhancement were independent prognostic factors for overall survival (OS). Meanwhile, adjuvant chemotherapy was an independent prognostic factor for progression-free survival (PFS). The hazard ratios (HRs) of N stage, adjuvant chemotherapy, and degree of enhancement (mild vs moderate/marked) for OS were 0.426 (P = 0.024), 3.862 (P = 0.006), and 2.169/0.809 (P = 0.037), respectively. The HR of adjuvant chemotherapy for PFS was 6.432 (P < 0.001). Adjuvant chemotherapy was significantly associated with degree of enhancement (P = 0.018). CONCLUSION Adjuvant chemotherapy is an independent prognostic factor for OS and PFS. Additionally, N stage and degree of enhancement are prognostic factors for OS in patients with esophageal NEC.

Aim: Exosome-derived microRNAs (miRNAs) are potential diagnostic biomarkers. However, little is known about their effectiveness as diagnostic biomarkers of intracranial aneurysms (IAs). This study aimed to explore miRNA levels in plasma exosomes of patients with IA to identify potential biomarkers that predict the development and progress of IA. Methods: A total of 69 patients with IA and 30 healthy controls (HC) were recruited, among whom 30 had unruptured IA (UA), and 39 had ruptured IA (RA). The miRNA expression profiles of plasma exosomes in 12 IA patients (4 UA and 8 RA) and 4 HC were determined using next-generation sequencing. In addition, significantly differentially expressed miRNAs were further analyzed by Quantitative Real-Time PCR (qRT-PCR) in a validation cohort of 99 subjects. Results: From the sequencing analysis, 181 miRNAs were identified to be differently (p < 0.05) expressed. Of these, 9 miRNAs were up-regulated, and 20 were down-regulated in patients with UA compared with HC. Also, 21 were up-regulated, and 10 were down-regulated in patients with RA compared with HC. In addition, compared with UA, 92 miRNAs were up-regulated in RA, whereas 29 were down-regulated. Furthermore, qRT-PCR analysis confirmed that miR-145-5p and miR-29a-3p were up-regulated in IA samples. To distinguish IA patients from controls, the area under the receiver operating characteristic curve was 0.791 for miR-29a-3p, while that of miRNA-145-5p was 0.773 in terms of discriminating whether the aneurysm was ruptured. Conclusions: Circulating exosomal miRNAs can serve as biomarkers of the development and progression of IA.

Objective: In recent years, increasing studies found that pre-treatment red blood cell distribution width (RDW) could predict clinical outcomes in various cancers. However, the prognostic value of ...

Standard anti-thymocyte globulin (ATG) weight-based dosing often resulted in highly variable ATG exposure, which had profound effects on relapse and survival, especially in recipients with relatively low absolute lymphocyte count (ALC) before conditioning. Data regarding rabbit ATG pharmacokinetics and pharmacodynamics in the setting of HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) is lacking. We conducted a retrospective study on 90 consecutive patients who underwent haplo-PBSCT with low dose rabbit ATG (5 mg/kg) plus low dose post-transplant cyclophosphamide (50 mg/kg) based regimen for graft-versus-host disease (GvHD) prophylaxis. We compared serum concentration of ATG and post-transplant results between patients with ALC

Background Diffusion-weighted imaging (DWI) has become an important tool for the detection of cholesteatoma. The purpose of this study was to explore the value of 2D BLADE turbo gradient- and spin-echo imaging (TGSE BLADE) DWI in the quantitative diagnosis of recurrent temporal bone cholesteatoma (CS). Methods From March 2018 to October 2021, 67 patients with suspected recurrence of temporal bone CS after assessment by clinical otorhinolaryngologists who had undergone previous ear surgery for CS were prospectively evaluated by magnetic resonance imaging (MRI). Two radiologist assessed images independently. Quantitative parameters such as signal intensity ratio (SIR) calculated using, as a reference, the inferior temporal cortex (SIRT) and the background noise (SIRN), apparent diffusion coefficient (ADC) value, and ADC ratio (with pons as reference) measured on TGSE BLADE sequences were assessed. Using receiver operating characteristic (ROC) curve analysis, the optimal threshold and diagnostic performance for diagnosing recurrent CS were determined. Pair-wise comparison of the ROC curves was performed using the area under the ROC curve (AUC). Results Finally, 44 patients were included in this study, including 25 CS and 19 non-cholesteatoma (NCS). Mean SIRT and mean SIRN on TGSE BLADE DWI were significantly higher for CS than NCS lesions (p Conclusions Residual/recurrent temporal bone CS can be accurately detected using quantitative evaluation of TGSE BLADE DWI.

This study is to compare the accuracy of 2D BLADE turbo gradient- and spin-echo imaging (TGSE BLADE) diffusion-weighted imaging (DWI) with that of readout-segmented echo-planar (RESOLVE) DWI in the detection of primary and residual/recurrent temporal bone cholesteatoma.The prospective study population consisted of 58 patients who were underwent magnetic resonance (MR) imaging for the evaluation of suspected temporal bone cholesteatoma. Two radiologists independently evaluated the two sequences. Kappa (k) statistics, the intra-class correlation coefficient (ICC), and a paired t test were used for statistical analysis.Of the 58 patients included, all had histo-pathologically confirmed cholesteatomas. In ≤ 3 mm group (n = 13), TGSE BLADE sequence correctly identified all cases except one that was recorded as equivocal on both sequences because of high signal intensity on T1WI; while on RESOLVE sequences, 6 were positive, 4 were equivocal, and 3 were false negative. For 3 mm group (n = 45), detection performance was similar between the two sequences. The mean ADC of cholesteatoma on TGSE BLADE DWI was 0.923 × 10TGSE BLADE outperforms RESOLVE in the detection of small temporal bone cholesteatoma ≤ 3 mm.

To investigate whether an improved U2-Net model could be used to segment the median nerve and improve segmentation performance, we performed a retrospective study with 402 nerve images from patients who visited Huashan Hospital from October 2018 to July 2020; 249 images were from patients with carpal tunnel syndrome, and 153 were from healthy volunteers. From these, 320 cases were selected as training sets, and 82 cases were selected as test sets. The improved U2-Net model was used to segment each image. Dice coefficients (Dice), pixel accuracy (PA), mean intersection over union (MIoU) and average Hausdorff distance (AVD) were used to evaluate segmentation performance. Results revealed that the Dice, MIoU, PA and AVD values of our improved U2-Net were 72.85%, 79.66%, 95.92% and 51.37 mm, respectively, which were comparable to the actual ground truth; the ground truth came from the labeling of clinicians. However, the Dice, MIoU, PA and AVD values of U-Net were 43.19%, 65.57%, 86.22% and 74.82 mm, and those of Res-U-Net were 58.65%, 72.53%, 88.98% and 57.30 mm. Overall, our data suggest our improved U2-Net model might be used for segmentation of ultrasound median neural images.

Liver cirrhosis represents a type of end-stage liver disease with few effective therapies, which was characterized by damaged functional liver tissue due to long-term inflammation. Gasdermin D (GSDMD)-executed programmed necrosis is reported to be involved in inflammation. However, the role of GSDMD in liver cirrhosis remains unclear. In this study, we used a CCl

To explore highly selective targeting molecules of colorectal cancer (CRC) is a challenge. We previously identified a twelve-amino acid peptide (LPKTVSSDMSLN, namely P-LPK) by phage display technique which may specifically binds to CRC cells. Here we show that P-LPK selectively bind to a panel of human CRC cell lines and CRC tissues. In vivo, Gallium-68 (68Ga) labeled P-LPK exhibits selective accumulation at tumor sites. Then, we designed a peptide-conjugated drug comprising P-LPK and camptothecin (CPT) (namely P-LPK-CPT), and found P-LPK-CPT significantly inhibits tumor growth with fewer side effects in vitro and in vivo. Furthermore, through co-immunoprecipitation and molecular docking experiment, the glutamine transporter solute carrier 1 family member 5 (SLC1A5) was identified as the possible target of P-LPK. The binding ability of P-LPK and SLC1A5 is verified by surface plasmon resonance and immunofluorescence. Taken together, P-LPK-CPT is highly effective for CRC and deserves further development as a promising anti-tumor therapeutic for CRC, especially SLC1A5-high expression type.

Previous animal studies provided the evidence that prenatal titanium exposure can cause neurotoxicity in their offspring, while human data is vacant. Our aim was to identify the associations of prenatal titanium exposure with the child neurodevelopment. Participants in present study were recruited during early pregnancy between 2014 and 2017. Urinary concentrations of titanium at first trimester were determined. We assessed child neurodevelopment using the Chinese version of Gesell Developmental Schedules at first year follow-up. The multivariable linear regressions and the robust modified Poisson regressions were used to estimate the associations of specific gravity corrected urinary titanium concentrations with the child neurodevelopment. In adjusted models, children's developmental quotient scores in the language domain were 2.03 points (95% CI: -3.66, -0.40) lower in the highest tertile of prenatal urinary titanium than in the lowest tertile. Also, children with prenatal urinary titanium in the highest tertile had 1.42 times (95% CI: 1.17, 1.72) increased risk of language development delay compared to those in the lowest tertile. No statistically significant associations were observed between titanium exposure and child development delay in motor, adaptive and social areas. The findings indicated that prenatal higher titanium exposure was associated with impaired language development, suggesting that titanium might act as developmental neurotoxicants.

We describe our preliminary experience using a 2D turbo gradient- and spin-echo (TGSE) diffusion-weighted (DW) pulse sequence with non-Cartesian BLADE trajectory at 3 T in pediatric patients. We compared the TGSE BLADE to conventional DW spin-echo echo-planar imaging (SE-EPI) in pediatric brain imaging, assessing the presence of artifacts from signal pile-ups, geometric distortion, motion, susceptibility from air-tissue interface, shunts and orthodontia, and diagnostic image quality.Data were acquired in 53 patients (10.4 ± 7.9 years). All DW imaging data were acquired precontrast, with SE-EPI first. A four-point scale for rating was used-1 (best) and 4 (worst). A neuroradiologist scored the two sequences and further noted whether the TGSE BLADE approach or SE-EPI was preferred in each case. Apparent diffusion coefficients were compared quantitatively between the two sequences in a subset of 16 patients, in 41 separate regions of interests including caudate nucleus, putamen, globus pallidus, thalamus, and pathological areas.In 43.4% of the cases, TGSE BLADE was preferred; in 49.1% of the cases, both sequences were preferred equally. Average scores for SE-EPI were 2.2 ± 0.8 versus TGSE's 1.2 ± 0.4 in assessing diagnostic quality (p0.05). Motion artifacts were minimal on both sequences in 92.5% of the cases. In the TGSE BLADE scores, no case received a "4" for significant artifacts with marginally acceptable image quality. Apparent diffusion coefficients values between the two sequences were statistically similar, with a linear regression slope of 0.92 (rTGSE BLADE DW imaging exhibited less geometric distortion in the brain and reduced signal pile-ups in areas of high susceptibility than conventional SE-EPI.

Monoclonal antibodies (mAbs) with enhanced effector functions in cancer immunotherapy, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), could improve the clinical performance. Here, we develop an mAb-hapten conjugate strategy to augment the mAb effector functions with the engagement of endogenous antibodies. An "off-the-shelf" mAb, rituximab, is site-specifically conjugated with the rhamnose (Rha) hapten to generate rituximab-Rha conjugates. The octopus-like conjugates could recruit

Parvovirus B19 (PvB19) infection and PvB19 related pure red cell aplasia (PRCA) in recipients with allogeneic hematopoietic stem cell transplantation have been reported sporadically. However, clinical studies with large sample sizes are lacking, especially in patients undergoing HLA-haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). In addition, clinical features, immune reconstitution, and outcomes of these patients are not clear. We conducted a retrospective analysis of 164 patients who received haplo-PBSCT with low-dose anti-thymocyte globulin (ATG) plus low-dose posttransplant cyclophosphamide (PTCy)-based regimen as graft-versus-host disease (GVHD) prophylaxis. We analyzed the incidence of PvB19 related PRCA and compared the clinical characteristics, immune reconstitution, incidence of GVHD, relapse rate, and survival between patients with and without PvB19 related PRCA. A total of 14 (8.5%) recipients developed PvB19 related PRCA after a median of 5.3 months after haplo-PBSCT. These patients with PvB19 related PRCA had slower immune reconstitution, but similar incidences of GVHD, relapse rate, and overall survival compared with recipients without PvB19 related PRCA. PvB19 related PRCA indicated relative delayed and poor immune reconstitution of the recipients early after haplo-PBSCT. PvB19 related PRCA had no effects on GVHD, relapse, and survival.

Lung adenocarcinomas (LUAD) arise from precancerous lesions such as atypical adenomatous hyperplasia, which progress into adenocarcinoma in situ and minimally invasive adenocarcinoma, then finally into invasive adenocarcinoma. The cellular heterogeneity and molecular events underlying this stepwise progression remain unclear. In this study, we perform single-cell RNA sequencing of 268,471 cells collected from 25 patients in four histologic stages of LUAD and compare them to normal cell types. We detect a group of cells closely resembling alveolar type 2 cells (AT2) that emerged during atypical adenomatous hyperplasia and whose transcriptional profile began to diverge from that of AT2 cells as LUAD progressed, taking on feature characteristic of stem-like cells. We identify genes related to energy metabolism and ribosome synthesis that are upregulated in early stages of LUAD and may promote progression. MDK and TIMP1 could be potential biomarkers for understanding LUAD pathogenesis. Our work shed light on the underlying transcriptional signatures of distinct histologic stages of LUAD progression and our findings may facilitate early diagnosis., The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.

Background The fifth wave of H7N9 avian influenza virus caused a large number of human infections and a large number of poultry deaths in China. Since September 2017, mainland China has begun to vaccinate poultry with H5 + H7 avian influenza vaccine. We investigated the avian influenza virus infections in different types of live poultry markets and samples before and after genotype H5 + H7 vaccination in Nanchang, and analyzed the changes of the HA subtypes of AIVs. Methods From 2016 to 2019, we monitored different live poultry markets and collected specimens, using real-time reverse transcription polymerase chain reaction (RT-PCR) technology to detect the nucleic acid of type A avian influenza virus in the samples. The H5, H7 and H9 subtypes of influenza viruses were further classified for the positive results. The χ2 test was used to compare the differences in the separation rates of different avian influenza subtypes. Results We analyzed 5,196 samples collected before and after vaccination and found that the infection rate of AIV in wholesale market (21.73%) was lower than that in retail market (24.74%) (P Conclusions Since vaccination, the positive rates of H5 and H7 subtypes have decreased, but the positive rates of H9 subtypes have increased to varying degrees in different testing locations and all samples. This results show that the government should establish more complete measures to achieve long-term control of the avian influenza virus.

Understanding miRNAs regulatory roles in epithelial-mesenchymal transition (EMT) would help establish new avenues for further uncovering the mechanisms underlying radiation-induced pulmonary fibrosis (RIPF) and identifying preventative and therapeutic targets. Here, we demonstrated that miR-541-5p repression by Myeloid Zinc Finger 1 (MZF1) promotes radiation-induced EMT and RIPF. Irradiation could decrease miR-541-5p expression in vitro and in vivo and inversely correlated to RIPF development. Ectopic miR-541-5p expression suppressed radiation-induced-EMT in vitro and in vivo. Knockdown of Slug, the functional target of miR-541-5p, inhibited EMT induction by irradiation. The upregulation of transcription factor MZF1 upon irradiation inhibited the expression of endogenous miR-541-5p and its primary precursor (pri-miR-541-5p), which regulated the effect of the Slug on the EMT process. Our finding showed that ectopic miR-541-5p expression mitigated RIPF in mice by targeting Slug. Thus, irradiation activates MZF1 to downregulate miR-541-5p in alveolar epithelial cells, promoting EMT and contributing to RIPF by targeting Slug. Our observation provides further understanding of the development of RIPF and determines potential preventative and therapeutic targets.

Gerberae Piloselloidis Herba (GPH), a commonly used traditional medicine in China, is derived from Gerbera piloselloides (Linn.) Cass. It is featured by its special bioactivities as antitussive, expectorant, anti-asthma, anti-bacterial, anti-tumor, uterine analgesia, and immunity-enhancing. With a long history of medication in ethnic minority areas in China, it is often used as an effective treatment for cough and sore throat as well as allergic asthma. Although our previous investigation also has discovered GPH performed effective treatment on allergic asthma, its underlying mechanism remains unclear.This research aims to reveal the pharmacological mechanism of GPH in the treatment for allergic asthma through combination of plasma pharmacology and network pharmacology.Firstly, the components of GPH in blood samples were identified using UHPLC- Q-Orbitrap HRMS. An interaction network of "compound-target-disease" was constructed based on the compounds confirmed in blood and on their corresponding targets of allergic asthma acquired from disease gene databases, predicting the possible biological targets and potential signal pathways of GPH with the network pharmacology analysis. Then, a molecular docking between the blood ingredients and the core targets was carried out using the Autodock Vina software. Subsequently, after establishing a mouse model with allergic asthma induced by ovalbumin (OVA), the effect of GPH on allergic asthma was evaluated by analyzing a series of indicators including behavior, lung pathological changes, inflammatory factors in serum and bronchoalveolar lavage fluid (BALF). Finally, the key pathway and targets predicted by network pharmacology and molecular docking were further verified using Western blot analysis.Eleven chemical constituents (such as arbutin, neochlorogenic acid, chlorogenic acid, etc.) were identified through the analysis of plasma samples, on which basis a total of 142 genes intersecting GPH and allergic asthma were collected by network pharmacology. After performing enrichment analysis of these genes in gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG), it was found that arbutin-related targets mainly focused on phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signal pathway, while luteolin and marmesin -related targets tended to locate at Interleukin-17 (IL-17) signal pathway. Meanwhile, the findings of molecular docking suggested that such components as arbutin, luteolin and marmesin entering into blood had good binding with the core targets related to PI3K/Akt and IL-17 pathways. In addition, GPH improved the OVA-induced asthma symptoms, the alveolar septa thickening and the infiltration of inflammatory cell around bronchi and bronchioles as well as reduced the levels of IgE, IL-8 and TNF-α in serum or BALF. Furthermore, GPH could inhibit the phosphorylation level of Akt and the expression of PI3K, an efficacy supported by the findings by way of Western blot which suggests that GPH in the treatment of allergic asthma was linked to PI3K/Akt signal pathway.In this study, a comprehensive strategy to combine the UPLC-Q-Orbitrap HRMS with network pharmacology was employed to clarify the mechanism of GPH against allergic asthma, a finding where GPH may inhibit PI3K/Akt signal pathway to protect mice from OVA-induced allergic asthma. This study provides a deeper understanding of the pharmacological mechanism of GPH in treatment of asthma, offering a scientific reference for further research and clinical application of GPH in terms of allergic asthma.

BackgroundInfluenza A viruses (IAVs) are zoonotic, segmented negative-stranded RNA viruses. The rapid mutation of IAVs results in host immune response escape and antiviral drug and vaccine resistance. RUNX1 is a transcription factor that not only plays essential roles in hematopoiesis, but also functions as a regulator in inflammation. However, its role in the innate immunity to IAV infection has not been well studied.MethodsTo investigate the effects of RUNX1 on IAV infection and explore the mechanisms that RUNX1 uses during IAV infection. We infected the human alveolar epithelial cell line (A549) with influenza virus A/Puerto Rico/8/34 (H1N1) (PR8) and examined RUNX1 expression by Western blot and qRT-PCR. We also knocked down or overexpressed RUNX1 in A549 cells, then evaluated viral replication by Western blot, qRT-PCR, and viral titration.ResultsWe found RUNX1 expression is induced by IAV H1N1 PR8 infection, but not by poly(I:C) treatment, in the human alveolar epithelial cell line A549. Knockdown of RUNX1 significantly inhibited IAV infection. Conversely, overexpression of RUNX1 efficiently promoted production of progeny viruses. Additionally, RUNX1 knockdown increased IFN-β and ISGs production while RUNX1 overexpression compromised IFN-β and ISGs production upon PR8 infection in A549 cells. We further showed that RUNX1 may attenuate the interferon signaling transduction by hampering the expression of IRF3 and STAT1 during IAV infection.ConclusionsTaken together, we found RUNX1 attenuates type I interferon signaling to facilitate IAV infection in A549 cells.

BACKGROUND Vitamin D deficiency has been reported to be associated with diabetic peripheral neuropathy (DPN). Our objective here was to evaluate the association between vitamin D levels and neuropathic symptoms in a Chinese population. MATERIAL AND METHODS A total of 4435 patients with type 2 diabetes (T2D) were recruited in this cross-sectional study. 25-dihydroxyvitamin D (25-(OH) D) serum concentration was measured by electrochemiluminescence assay (Cobas e601, Roche). DPN was clinically diagnosed by assessing neurological symptoms and performing current perception threshold (CPT) testing. Of all the patients, 2910 were CPT-positive and had assessed neurological symptoms. RESULTS In the vitamin D insufficiency group (