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Psoriasis, an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course, continues to be primarily managed through topical therapy. While oral administration of tyrosine kinase 2 inhibitors (TYK2i) stands as an effective approach for psoriasis treatment, the potential efficacy of topical application of TYK2i remains unexplored. Herein, the carbomer/alginic acid hydrogel is embedded with borneol (BO) as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy. The hydrogel system, i.e., TYK2i-BO-gel, exhibits significantly improved preventative and therapeutic effects in mice models of psoriasiform dermatitis, as evidenced by phenotypical images, psoriasis severity score index (PSI), histology, immunohistochemical staining, and PCR analysis. Remarkably, TYK2i-BO-gel outperforms conventional topical corticosteroid therapy by significantly preventing psoriatic lesion recurrence as measured by a nearly 50 % reduction in ear thickness changes (p

As concerns about personal health continue to escalate, there is an urgent need to innovate the development and production of photopolymeric 3D printing thermoset materials with inherent antibacterial properties and high elongation, paving the way for significant advances in 3D printing technology. In this work, two acrylate compounds (CMA and CAMA)with inherent antibacterial properties were synthesized using renewable monomers derived from citronellol and cinnamyl alcohol. The chemical structures of the two acrylate compounds were verified via Fourier transform infrared spectroscopy(FT-IR) and 1H NMR. The addition of these compounds to the photopolymeric 3D printing resin system can facilitate the production of 3D printed thermoset materials with inherent antibacterial properties. The mechanical and antibacterial properties of photopolymeric 3D printing thermosets were assessed utilizing tensile tests and oscillation methods. The results show that the addition of CMA and CAMA can significantly improve the fracture elongation and antibacterial performance of photopolymeric 3D printing thermosets. The improved systems exhibited the highest antibacterial rate (94.2 % and 98.9 %, respectively), and fracture productivities (47 % and 50 %, respectively). These results highlight the significant impact of integrating CMA and CAMA to enhance the toughness and antibacterial effects of photopolymeric 3D printing systems.

Abstract Introduction Fifteen to 25% of patients with colorectal cancer have combined liver metastases at the time of diagnosis, whereas an additional 15 to 25% will develop liver metastases after curative resection of primary colorectal cancer, with the vast majority (80–90%) of liver metastases unresponsive to curative resection at first. Colorectal cancer liver metastasis is also the leading cause of death in patients with colorectal cancer. In recent years, several studies have demonstrated that intestinal flora, especially Fusobacterium nucleatum, plays a crucial role in the development of colorectal cancer liver metastasis, so we hypothesized that long-term metronidazole use could effectively reduce the incidence of postoperative liver metastasis in colorectal cancer patients. Methods/design This study is a prospective, single-centre, randomized, double-blind controlled study in which 300 patients will be randomly assigned to the test group or the control group in a 1:1 allocation ratio. The aim of this trial is to demonstrate that long-term oral antibiotics can effectively reduce the incidence of postoperative liver metastasis in patients with colorectal cancer. Ethics and dissemination Ethics approval was obtained from the Ethics Committee at the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20210229). The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals. Trial registration Chinese Clinical Trial Registry ChiCTR2100046201. Registered on July 05, 2021.

Humification plays a significant role in converting phenolic pollutants and forming heterogeneous polymers, but few studies have been performed to investigate exolaccase-started humification (ESH). Herein, the influences of lignin precursors (LPs) on exolaccase-induced bisphenol A (BPA) removal and humification were explored. In particular, the architectural features and botanical effects of the formed humification products were also tested. ESH was extremely beneficial in boosting BPA removal in the presence of LPs. Compared with LP-free (58.49%), 100% of BPA was eliminated after the reaction with ESH for 72 h. Such a process was controlled by an exolaccase-caused random assembly of radicals, which generated a large number of hydrophobic polymers through nonspecific covalent binding of C–C and/or C–O. These humified polymers were extremely stable at pH 2.0–10.0 and −20 °C to 80 °C and displayed unique functions, i.e., scavenged 2,2-diphenyl-1-picrylhydrazyl/2,2′-azino-bis3-ethylbenzothiazoline-6-sulphonic acid radicals and exerted antioxidant capacities. More importantly, the functional polymers could act as auxin analogs to increase the germination index (>100%), plant biomass, and salt tolerance of radish seedlings. Our findings disclosed that ESH could not only be optimized to mitigate the ecological risks of phenolic pollutants and sequester organic carbon in environmental bioremediation, but the resulting abundant auxin analogs also contributed to agricultural productivity.

Abstract Background Long non-coding RNAs play an important role in the development of colorectal cancer (CRC), while many CRC-related lncRNAs have not yet been identified. Methods The relationship between the expression of LINC00955 (Long Intergenic Non-protein Coding RNA 955) and the prognosis of colorectal cancer patients was analyzed using the sequencing results of the TCGA database. LINC00955 expression levels were measured using qRT-PCR. The anti-proliferative activity of LINC00955 was evaluated using CRC cell lines in vitro and xenograft models in nude mice in vivo. The interaction of TRIM25-Sp1-DNMT3B-PHIP-CDK2 was analyzed by western blotting, protein degradation experiment, luciferase, RNA-IP, RNA pull-down assays and immunohistochemically analysis. The biological roles of LINC00955, tripartite motif containing 25 (TRIM25), Sp1 transcription factor (Sp1), DNA methyltransferase 3 beta (DNMT3B), pleckstrin homology domain interacting protein (PHIP), cyclin dependent kinase 2 (CDK2) in colorectal cancer cells were analyzed using ATP assays, Soft agar experiments and EdU assays. Results The present study showed that LINC00955 is downregulated in CRC tissues, and such downregulation is associated with poor prognosis of CRC patients. We found that LINC00955 can inhibit CRC cell growth both in vitro and in vivo. Evaluation of its mechanism of action showed that LINC00955 acts as a scaffold molecule that directly promotes the binding of TRIM25 to Sp1, and promotes ubiquitination and degradation of Sp1, thereby attenuating transcription and expression of DNMT3B. DNMT3B inhibition results in hypomethylation of the PHIP promoter, in turn increasing PHIP transcription and promoting ubiquitination and degradation of CDK2, ultimately leading to G0/G1 growth arrest and inhibition of CRC cell growth. Conclusions These findings indicate that downregulation of LINC00955 in CRC cells promotes tumor growth through the TRIM25/Sp1/DNMT3B/PHIP/CDK2 regulatory axis, suggesting that LINC00955 may be a potential target for the therapy of CRC.

Coronary microvascular dysfunction (CMD) is a critical pathogenesis of cardiovascular diseases. Lower endothelial nitric oxide synthase (eNOS) phosphorylation leads to reduced endothelium-derived relaxing factor nitric oxide (NO) generation, causing and accelerating CMD. Endoplasmic reticulum stress (ER stress) has been shown to reduce NO production in umbilical vein endothelial cells. Oxidized low-density lipoprotein (ox-LDL) damages endothelial cell function. However, the relationship between ox-LDL and coronary microcirculation has yet to be assessed. Short-chain fatty acid (SCFA), a fermentation product of the gut microbiome, could improve endothelial-dependent vasodilation in human adipose arterioles, but the effect of SCFA on coronary microcirculation is unclear. In this study, we found ox-LDL stimulated expression of ER chaperone GRP78. Further, we activated downstream PERK/eIF2a, IRE1/JNK, and ATF6 signaling pathways, decreasing eNOS phosphorylation and NO production in human cardiac microvascular endothelial. Furthermore, SCFA-propionate can inhibit ox-LDL-induced eNOS phosphorylation reduction and raise NO production; the mechanism is related to the inhibition of ER stress and downstream signaling pathways PERK/eIF2a, IRE1/JNK, and ATF6. In summary, we demonstrate that ox-LDL induced CMD by activating ER stress, propionate can effectively counteract the adverse effects of ox-LDL and protect coronary microcirculation function via inhibiting ER stress.

Primary colorectal squamous cell carcinoma (CSCC) is a rare pathological subtype. Currently, clinical data with regards to its prognosis and treatment is limited, and there is no optimal treatment method. The case presented involves a proficient mismatch repair (pMMR) and microsatellite-stable (MSS) Colorectal cancer (CRC) patient with squamous cell carcinoma (SCC) located transversely in the colon. Based on the imaging assessment, the tumor infiltration depth is classified as T4. After receiving 4 cycles of neoadjuvant treatment with oxaliplatin and capecitabine (XELOX), the patients were evaluated for partial response (PR) in 2 cycles and stable disease (SD) in 4 cycles. The patient underwent a right hemicolectomy and received postoperative paclitaxel/cisplatin (TC) adjuvant chemotherapy. After 23 months, a systemic examination revealed abdominal metastasis. A needle biopsy was conducted on the detected abdominal metastases, with the resulting pathology indicating the presence of metastatic SCC. The individual exhibited expression of programmed cell death ligand 1 (PD-L1) and a mutation in the TP53 gene. Considering the patient’s disease recurrence based on medical history, a treatment plan was formulated. This involved Sintilimab plus Cetuximab and the combination of leucovorin, fluorouracil, and irinotecan (FOLFIRI) regimen. The patient received four cycles of treatment with an efficacy evaluation of SD- and seven cycles of treatment with an efficacy evaluation of SD+, which resulted in a progression-free survival (PFS) duration of 7 months. This case study presents the conventional XELOX chemotherapy protocol, which has shown limited effectiveness, and highlights the favorable results achieved by implementing the TC adjuvant chemotherapy regimen in individuals diagnosed with primary colonic SCC. Furthermore, combining immune checkpoint blockade (ICB) with other therapies for patients with advanced disease is anticipated to provide an extended duration of survival.

The use of solvent-free approach to manufacture antibacterial epoxy coatings with high renewable carbon content is of important for environmental sustainability and the diversity of antibacterial materials. Herein, an epoxy monomer with inherent antibacterial properties, eugenol-modified epoxidized soybean oil (EUESO) with totally natural carbon was synthesized from renewable epoxidized soybean oil (ESO) and eugenol via one-step solvent-free method. Then, EUESO was cured with DGEBA and 4, 4′-diaminodicyclohexylmethane (HDDM) to construct mechanically robust and anti-release antibacterial epoxy coatings. The influence of the weight ratio of EUESO on epoxy coating and comprehensive performance was systematically studied. According to DSC, TGA and bending test on the thermal and mechanical properties of the cured resins, all cured resins demonstrated high thermodynamic properties and high Tg. Meanwhile, in the dynamic shake test, all cured resins demonstrated a certain degree of killing effect on Escherichia coli (E. coli), with a maximum killing rate of 93.8% as the concentration of EUESO increased.

Rumexpatientia L. ×Rumextianshanicus A. Los (RRL), known as “protein grass” in China, was recognized as a new food ingredient in 2021. However, the cultivation and product development of RRL are still at an early stage, and no peptide research has been reported. In this study, two novel antioxidant peptides, LKPPF and LPFRP, were purified and identified from RRL and applied to H2O2-induced HepG2 cells to investigate their antioxidant properties. It was shown that 121 peptides were identified by ultrafiltration, gel filtration chromatography, and LC-MS/MS, while computer simulation and molecular docking indicated that LKPPF and LPFRP may have strong antioxidant properties. Both peptides were not cytotoxic to HepG2 cells at low concentrations and promoted cell growth, which effectively reduced the production of intracellular ROS and MDA, and increased cell viability and the enzymatic activities of SOD, GSH-Px, and CAT. Therefore, LKPPF and LPFRP, two peptides, possess strong antioxidant activity, which provides a theoretical basis for their potential as food additives or functional food supplements, but still need to be further investigated through animal models as well as cellular pathways.

Abstract Introduction The optimal preoperative preparation for elective colorectal cancer surgery has been debated in academic circles for decades. Previously, several expert teams have conducted studies on whether preoperative mechanical bowel preparation and oral antibiotics can effectively reduce the incidence of postoperative complications, such as surgical site infections and anastomotic leakage. Most of the results of these studies have suggested that preoperative mechanical bowel preparation for elective colon surgery has no significant effect on the occurrence of surgical site infections and anastomotic leakage. Methods/design This study will examine whether oral antibiotic bowel preparation (OABP) influences the incidence of anastomotic leakage after surgery in a prospective, multicentre, randomized controlled trial that will enrol 1500 patients who require colon surgery. The primary endpoint, incidence of anastomotic leakage, is based on 2.3% in the OABP ± mechanical bowel preparation (MBP) group in the study by Morris et al. Patients will be randomized (1:1) into two groups: the test group will be given antibiotics (both neomycin 1 g and metronidazole 0.9 g) the day before surgery, and the control group will not receive any special intestinal preparation before surgery, including oral antibiotics or mechanical intestinal preparation. All study-related clinical data, such as general patient information, past medical history, laboratory examination, imaging results, and surgery details, will be recorded before surgery and during the time of hospitalization. The occurrence of postoperative fistulas, including anastomotic leakage, will be recorded as the main severe postoperative adverse event and will represent the primary endpoint. Ethics and dissemination Ethics approval was obtained from the Chinese Ethics Committee of Registering Clinical Trials (ChiECRCT20200173). The results of this study will be disseminated at several research conferences and as published articles in peer-reviewed journals. Protocol was revised on November 22, 2021, version 4.0. Trial registration ChiCTR2000035550 . Registered on 13 Aug 2020.

Objective To explore the expression and distribution of runt-related transcription factor (RUNX) family in lesions of psoriasis vulgaris (PV), and analyze the correlation between its levels and markers of proliferation, apoptosis and immunity. Methods The transcript levels of RUNX1, 2 and 3 were analyzed in normal skin from 14 healthy controls (HC) and lesions from 17 patients with PV by gene array from a published database. The protein levels and distribution of RUNX1, 2, and 3 were examined by immunohistochemistry (IHC) in normal skin from 11 HC and lesions from 11 patients with chronic eczema (CE) and 12 patients with PV. The correlation between RUNX and other genes in the gene array was analyzed by R, and GO enrichment analysis was performed. Results Compared with HC, the transcript levels of RUNX1 were down-regulated (HC: 0.61±0.06, PV: 0.54±0.02, P

BackgroundProximal gastrectomy has gradually gained more attention due to its superiority in retaining the function of part of the stomach. The inevitable loss of the antireflux barrier and postoperative complications resulting from proximal gastrectomy can severely affect the quality of life. Continuous improvements in digestive tract reconstruction after proximal gastrectomy have yielded the development of a variety of methods with antireflux functions. Recently, our center attempted the left-open single-flap technique and initiated a multicenter, prospective, randomized controlled trial for patients undergoing proximal gastrectomy to reduce the difficulty of surgical anastomosis and the incidence of perioperative complications compared with the double-flap technique. These findings will provide more evidence-based medical research for the development of clinical guidelines.Methods/designThis study is a prospective, multicenter, randomized controlled clinical trial. We plan to recruit 250 patients who are eligible for proximal gastrectomy. After informed consent is obtained, patients will be randomly assigned to the trial group (left-open single-flap technique) and the control group (double-flap technique) in a 1:1 allocation ratio.DiscussionIncreasingly, clinical studies have focused on the improvement of reconstruction modalities after proximal gastrectomy. Among these methods, the double-flap technique is a clinically effective method. The purpose of this study is to establish a prospective randomized controlled trial to compare the efficacy of the left-open single-flap technique versus the double-flap technique after proximal gastrectomy, aiming to provide more evidence-based medical studies for digestive tract reconstruction in proximal gastrectomy.Clinical Trial RegistrationClinicalTrials.gov, identifier [NCT05418920].

BackgroundAppropriate gastrointestinal reconstruction after proximal gastrectomy can effectively reduce the incidence of postoperative complications in patients with proximal early gastric cancer. However, there is still great controversy about the choice of digestive tract reconstruction after proximal gastrectomy, and there is no clinical consensus on the choice of digestive tract reconstruction after proximal gastrectomy. Currently, there is a lack of large-sample, prospective, randomized controlled studies to compare the efficacy of Kamikawa, double-tract reconstruction, and tube-like stomach reconstruction after proximal gastrectomy.Methods/designThis study will investigate the efficacy of three reconstruction methods after proximal gastrectomy in a prospective, multicenter, randomized controlled trial, which will enroll 180 patients with proximal early gastric cancer. Patients will be randomly divided into three groups: Group A (Kamikawa, n = 60), Group B (double-tract reconstruction, n = 60), and Group C (tube-like stomach, n = 60). The general information, past medical history, laboratory findings, imaging findings, and surgical procedures of the patients will be recorded and analyzed. The incidence of reflux esophagitis will be recorded as the primary endpoint. The incidence of anastomotic leakage, anastomotic stenosis, operative time and intraoperative blood loss will be recorded as secondary endpoints.DiscussionThis study will establish a large-sample, prospective, randomized controlled trial to compare the efficacy of Kamikawa, double-tract reconstruction, and tube-like stomach reconstruction after proximal gastrectomy.Trial registrationThis study was approved by the Chinese Clinical Trial Registry and registered on April 30, 2021. The registration number is ChiCTR2100045975.

Microabscess of neutrophils in epidermis is one of the histological hallmarks of psoriasis. The axis of neutrophil–keratinocyte has been thought to play a critical role in the pathogenesis of psoriasis. However, the features and mechanism of interaction between the two cell types remain largely unknown. Herein, we found that blood neutrophils were increased in psoriasis patients, positively correlated with disease severity and highly expressed CD66b, but not CD11b and CD62L compared to healthy controls. Keratinocytes expressed high levels of psoriasis-related inflammatory mediators by direct and indirect interaction with neutrophils isolated from psoriasis patients and healthy controls. The capacity of neutrophils in provoking keratinocytes inflammatory response was comparable between the two groups and is dependent on IL-17A produced by itself. Neutrophils isolated from psoriasis patients displayed more transcriptome changes related to integrin and increased migration capacity toward keratinocytes with high CD11b expression on cell surface. Of interest, neutrophils were more susceptible to keratinocyte stimulation than to fibroblasts and human umbilical vein endothelial cells (HUVECs) in terms of CD11b expression and the production of ROS and NETs. In conclusion, neutrophils from psoriasis patients gain a strong capacity of IL-17A production and integrins expression that possibly facilitates their abilities to promote production of psoriasis-related inflammatory mediators and migration, a phenomenon likely induced by their interaction with keratinocytes but not with fibroblasts. These findings provide a proof-of-concept that development of new drugs targeting migration of neutrophils could be a more specific and safe solution to treat psoriasis.

Brevilaterins, antimicrobial peptides produced by Brevibacillus laterosporus, are regarded as excellent food preservatives and are popular as antimicrobial applications. Recent research has uncovered their potent cytotoxic effects against diverse cancer cells, thereby underscoring the pressing need for more extensive and intensive investigations into this use. In this study, we explored their novel function in inducing cytotoxicity to cancer cells and systematically investigated the mechanism of action of Brevilaterin B/C (BB/BC) in vivo. Proliferation, membrane permeability, and apoptotic rate were evaluated using CCK-8 assay, LDH assay, and Annexin V-FITC/PI kits. ROS levels and mitochondrial membrane potential were detected using the fluorescent probe DCFH-DA and JC-1. Our results demonstrated that both BB and BC at concentrations of 4–6 µg/mL significantly inhibited the proliferation and migration of gastric cancer cells BGC-823. Treatment with 4 µg/mL of BB/BC rapidly increased LDH levels in the supernatant of BGC-823 cells, leading to further investigation of the mechanism of apoptosis. We found that the apoptotic rate of BGC-823 cells significantly increased upon treatment with BB/BC, demonstrating their potent induction of apoptosis. BB/BC-induced ROS production in BGC-823 cells impaired their growth and induced apoptosis, indicating a close association between apoptosis and ROS elevation. Additionally, JC-1 aggregates rapidly accumulated after treatment with 4 µg/mL of BB/BC, suggesting changes in mitochondrial membrane potential and early apoptosis. Taken together, our findings revealed that BB and BC exhibit significant anticancer effects against gastric cancer cells, highlighting the promising potential of Brevilaterins as anticancer agents.

Cytokines like IL-17A have been consistently found to be elevated in psoriatic lesional skin, and therapeutic antibodies to IL-17 have demonstrated efficacy in treating psoriatic skin and joint disease. However, results about the circulating cytokines in psoriasis patients remained controversial. Anticytokine autoantibodies (ACAAs) were detected in various autoimmune diseases but remained largely unknown in psoriasis. We aimed to investigate the serum levels of cytokines and ACAAs in psoriasis patients. The study included 44 biologics-naive psoriasis patients and 40 healthy controls. Serum cytokines and the corresponding autoantibodies were measured by multiplex bead-based technology. The bioactivity of serum IL-17A was determined by IL-8 production in primary keratinocytes. Herein, we found serum levels of IL-12B (median: 6.16 vs. 9.03, p=0.0194) and Th17 cytokines (IL-17A: median: 0.32 vs. 1.05, p=0.0026; IL-22: median: 4.41 vs. 4.41, p=0.0120) were increased in psoriasis patients. More interestingly, bioactive IL-17A was identified in a proportion of patients and positively correlated with disease severity. A few of cytokines were closely associated with each other and formed into a distinct panel in psoriasis. Of 13 anticytokine antibodies, anti-IL-22 was moderately lower (median: 262.8 vs.190.5, p=0.0418), and anti-IL-15 was slightly higher (median: 25.5 vs. 30.5, p=0.0069) in psoriasis than controls. None of ACAAs was related to disease severity. Consequently, the ratios of antibodies to cytokines varied with the pattern of cytokines. In summary, our finding suggested that the levels of circulating bioactive IL-17A were associated with disease activity in psoriasis patients. In contrast, the titers of ACAAs were not significantly altered nor correlated with disease severity. However, the functionality of ACAAs remains to be further demonstrated in vitro in future studies.

Probiotics are being used in diets to improve the quality of chicken meat. The aim of the study was to investigate the effects of dietary supplementation with Brevibacillus laterosporus S62-9 microbial agent on the meat quality, amino acids, and volatile compounds of chicken. The experiment was carried out with 160 1-day-old Arbor Acres male broiler chickens, rearing for 42 d. The chickens were randomly divided into two groups of 8 replicates each, with 10 chickens in each group. No supplement was added to the basal diet in the control group and Brevibacillus laterosporus S62-9 microbial agent was added to the diet of the experimental group. At the end of the experiment, the meat quality, meat chemical composition, amino acid composition, and volatile compounds of chicken were determined. The results showed that pH (p < 0.05), pressing loss (p < 0.05), cooking loss (p < 0.05), and shear force (p < 0.01) were notably decreased, the percentage of breast meat (p < 0.01), protein content (p < 0.05) were visibly increased, and remarkable changes were observed in the amino acid composition (change in seven amino acids) and volatile compounds profile (an increase of about 20-fold in the contents of 1-octen-3-ol and hexanal). In summary, it was found that Brevibacillus laterosporus S62-9 microbial agent can be used as a novel and effective feed supplement to improve the nutritional quality and flavor characteristics of broilers.

Objective To investigate the potential correlation between the Arg188His (rs3218536) polymorphism of X-ray repair cross-complementing 2 ( XRCC2 ) and colorectal cancer (CRC) risk, as the association remains unclear. Methods The CNKI, PubMed, EMBASE and Cochrane library databases were systematically searched for relevant studies published up to July 2021. Data were extracted from included studies, and analysed for pooled or subgroup odds ratios (ORs) with 95% confidence intervals (CIs) using STATA 12.0 software. Results Seven published studies were included. Pooled analysis revealed that the XRCC2 Arg188His polymorphism was associated with increased CRC risk (His versus Arg: OR 1.14, 95% CI 1.01, 1.29). Trial Sequential Analysis to test the power of the results showed that they were unreliable and the meta-analysis required additional studies. Conclusion The current meta-analysis suggests that the XRCC2 Arg188His polymorphism may be a risk factor for CRC.

Psoriasis is a common inflammatory skin disease resulting from an interplay of keratinocytes and immune cells. Previous studies have identified an essential role of autophagy in the maintenance of epidermal homeostasis including proliferation and differentiation. However, much less is known about the role of autophagy-related proteins in the cutaneous immune response. Herein, we showed that ULK1, the key autophagic initiator, and its phosphorylation at Ser556 were distinctively decreased in the epidermis from lesional skin of psoriasis patients. Topical application of SBI0206965, a selective ULK1 inhibitor, significantly attenuated epidermal hyperplasia, infiltration of neutrophils, and transcripts of the psoriasis-related markers in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD). In vitro, ULK1 impairment by siRNA and SBI0206965 arrested cell proliferation and promoted apoptosis of keratinocytes but had a marginal effect on the expression of proinflammatory mediators under steady status. Surprisingly, SBI0206965 blocked the production of chemokines and cytokines in keratinocytes stimulated by neutrophils. Of interest, the pro-apoptotic and anti-inflammatory effects of ULK1 inhibition cannot be fully replicated by autophagic inhibitors. Our findings suggest a self-regulatory process by downregulating ULK1 to maintain the immune homeostasis of psoriatic skin via regulating keratinocytes and their crosstalk with neutrophils, possibly through both autophagy-dependent and independent mechanisms. ULK1 might be a potential target for preventing or treating psoriasis.

Transcribed ultraconserved regions (T-UCRs) are a new type of long non-coding RNA, and the UCR has 481 segments longer than 200 base pairs that are 100% conserved between humans, rats, and mice. T-UCRs involved in colorectal cancer (CRC) have not been studied in detail. We performed T-UCR microarray analysis and found that uc.77- was significantly downregulated in CRC tissues and cell lines. Ectopic expression of uc.77- significantly inhibited the proliferation of CRC cells in vitro and the growth of xenograft tumors in nude mice in vivo. Mechanistic studies showed that uc.77- competed with FBXW8 mRNA for binding to microRNA (miR)-4676-5p through a competing endogenous RNA mechanism and inhibited the proliferation of CRC cells by negatively regulating CDK4. The present findings highlight the role of the uc.77-/miR-4676-5p/FBXW8 axis in CRC and identify uc.77- as a potential novel target for the treatment of CRC.

Magnetic Resonance Imaging (MRI) is an indispensable tool in the diagnosis of brain diseases due to painlessness and safety. Nevertheless, Rician noise is inevitably injected during the image acquisition process, which leads to poor observation and interferes with the treatment. Owing to the complexity of Rician noise, using the elimination method of Gaussian to remove it does not perform well. Therefore, the feature fusion and attention network (FFA-DMRI) is proposed to separate noise from observed MRI. Inspired by the attention-guided CNN network (ADNet) and Convolutional block attention module (CBAM), a spatial attention mechanism has been specially designed to obtain the area of interest in MRI. Furthermore, the feature fusion block concatenates local with global information, which makes full use of the multilevel structure and boosts the expressive ability of network. The comprehensive experiments on Alzheimer’s disease neuroimaging initiative dataset (ADNI) have demonstrated high effectiveness of FFA-DMRI with maintaining the crucial brain details. Moreover, in terms of visual inspections, the denoising results are also consistent with human perception.

The subjective cognitive decline (SCD) may last for decades prior to the onset of dementia and has been proposed as a risk population for development to amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Disruptions of functional connectivity and causal connectivity (CC) in the salience network (SN) are generally perceived as prominent hallmarks of the preclinical AD. Nevertheless, the alterations in anterior SN (aSN), and posterior SN (pSN) remain unclear. Here, we hypothesized that both the functional connectivity (FC) and CC of the SN subnetworks, comprising aSN and pSN, were distinct disruptive in the SCD and aMCI. We utilized resting-state functional magnetic resonance imaging to investigate the altered FC and CC of the SN subnetworks in 28 healthy controls, 23 SCD subjects, and 29 aMCI subjects. In terms of altered patterns of FC in SN subnetworks, aSN connected to the whole brain was significantly increased in the left orbital superior frontal gyrus, left insula lobule, right caudate lobule, and left rolandic operculum gyrus (ROG), whereas decreased FC was found in the left cerebellum superior lobule and left middle temporal gyrus when compared with the HC group. Notably, no prominent statistical differences were obtained in pSN. For altered patterns of CC in SN subnetworks, compared to the HC group, the aberrant connections in aMCI group were separately involved in the right cerebellum inferior lobule (CIL), right supplementary motor area (SMA), and left ROG, whereas the SCD group exhibited more regions of aberrant connection, comprising the right superior parietal lobule, right CIL, left inferior parietal lobule, left post-central gyrus (PG), and right angular gyrus. Especially, SCD group showed increased CC in the right CIL and left PG, whereas the aMCI group showed decreased CC in the left pre-cuneus, corpus callosum, and right SMA when compared to the SCD group. Collectively, our results suggest that analyzing the altered FC and CC observed in SN subnetworks, served as impressible neuroimaging biomarkers, may supply novel insights for designing preclinical interventions in the preclinical stages of AD.

Alzheimer’s disease (AD), which most commonly occurs in the elder, is a chronic neurodegenerative disease with no agreed drugs or treatment protocols at present. Amnestic mild cognitive impairment (aMCI), earlier than AD onset and later than subjective cognitive decline (SCD) onset, has a serious probability of converting into AD. The SCD, which can last for decades, subjectively complains of decline impairment in memory. Distinct altered patterns of default mode network (DMN) subnetworks connected to the whole brain are perceived as prominent hallmarks of the early stages of AD. Nevertheless, the aberrant phase position connectivity (PPC) connected to the whole brain in DMN subnetworks remains unknown. Here, we hypothesized that there exist distinct variations of PPC in DMN subnetworks connected to the whole brain for patients with SCD and aMCI, which might be acted as discriminatory neuroimaging biomarkers. We recruited 27 healthy controls (HC), 20 SCD and 28 aMCI subjects, respectively, to explore aberrant patterns of PPC in DMN subnetworks connected to the whole brain. In anterior DMN (aDMN), SCD group exhibited aberrant PPC in the regions of right superior cerebellum lobule (SCL), right superior frontal gyrus of medial part (SFGMP), and left fusiform gyrus (FG) in comparison of HC group, by contrast, no prominent difference was found in aMCI group. It is important to note that aMCI group showed increased PPC in the right SFGMP in comparison with SCD group. For posterior DMN (pDMN), SCD group showed decreased PPC in the left superior parietal lobule (SPL) and right superior frontal gyrus (SFG) compared to HC group. It is noteworthy that aMCI group showed decreased PPC in the left middle frontal gyrus of orbital part (MFGOP) and right SFG compared to HC group, yet increased PPC was found in the left superior temporal gyrus of temporal pole (STGTP). Additionally, aMCI group exhibited decreased PPC in the left MFGOP compared to SCD group. Collectively, our results have shown that the aberrant regions of PPC observed in DMN are related to cognitive function, and it might also be served as impressible neuroimaging biomarkers for timely intervention before AD occurs.

Aristolochic acid (AA) is known as a potent mutagen that induces significant cytotoxic and mutagenic effects on renal tubular epithelial cells. Clinically, the persistent injury of AA results in the infiltration of inflammatory cells, epithelial-to-mesenchymal transition (EMT), and renal tubulointerstitial fibrosis. There are no truly effective pharmaceuticals. In this study, we investigated the potential role of the extract of Sedum sarmentosum Bunge (SSB), a traditional Chinese herbal medicine, on rat tubuloepithelial (NRK-52E) cells after AA injury in vitro. Evidence revealed that AA induced mitochondrial-pathway–mediated cellular apoptosis, accompanied by cell proliferation in a feedback mechanism. Treatment with SSB also induced cells to enter early apoptosis, but inhibited cell proliferation. In cultured NRK-52E cells, AA induced the imbalance of MMP-2/TIMP-2 and promoted EMT and ECM accumulation. SSB treatment significantly alleviated AA-induced NRK-52E cells fibrosis-like appearance, inhibited the induction of EMT, and deposition of ECM. SSB also decreased the activity of the NF-κB signaling pathway, resulting in down-regulated expression of NF-κB–controlled chemokines and pro-inflammatory cytokines, including MCP-1, MIF, and M-CSF, which may regulate the macrophage-mediated inflammatory reaction during renal fibrosis in vivo. Therefore, these findings suggest that SSB exerts protective effects against AA-induced tubular epithelial cells injury through suppressing the synthesis of inflammatory factors, EMT, and ECM production. Keywords:: aristolochic acid, epithelial-to-mesenchymal transition, renal fibrosis, Sedum sarmentosum Bunge, inflammation

Background and objective The appearance of highly effective and low toxic drugs enables an increasing number of advanced non-small cell lung cancer (NSCLC) patients to receive third-line therapy. No other standard choice for third-line therapy aside from erlotinib is possible. This study respectively explores the efficacy and safety of single chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and doublet chemotherapy in advanced NSCLC third-line treatment. Methods This study included 115 NSCLC patients in the stage IIIb or IV who were retrospectively reviewed to investigate the differences of survival time between different treatments. Univariate and multivariate analyses were conducted based on the Kaplan-Meier method and Cox proportional-hazards model. Results The median progression free survival (PFS) values in the single agent, EGFR-TKIs and doublet groups were 2.30, 3.17 and 2.37 months, respectively (P=0.045). The median overall survival from the initiation of the third-line treatment were 8.00, 10.40 and 7.87 months in the three groups (P=0.110). The rates of stage III-IV toxicities were 33.3%, 18.2% and 68.8% (P

Background and objective At present clinical researches has proven that the chemotherapeutic effect on advanced non-small cell lung cancer (NSCLC) has gotten to plateau. Biotherapy combined with chemotherapy could improve curative effect on advanced NSCLC obviously. The project is aiming at exploring the killing effect and the mechanism of rmhTNF-alpha in combination with gemcitabine on human lung adenocarcinoma cell line A549. Methods CCK-8 was used to detect the inhibition ratio of rmhTNF-alpha and gemcitabine cell line A549; cell curve of growth was used to illustrate the influence of rmhTNF-alpha and gemcitabine on the proliferation of A549; FCM was used to detect the cell cycle and the apoptosis ratio of cell line A549 treated with either rmhTNF-alpha or gemcitabine or those combined. The change in cellular morphology and cell ultra-micromorphology was observed by light microscope and transmission electron microscope respectively. Results The result of CCK-8 and cell curve of growth demonstrated that rmhTNF-? not only inhibited the proliferation of A549, but also enhanced the killing effect of gemcitabine; FCM showed that rmhTNF-? promoted S cell cycle arrest and reduced proportion of G2/M cell arrest; also showed different apoptosis ratio was most significant in the group of rmhTNF-? combination with gemcitabine; the changes of morphology was observed obviously by light microscope and transmission electron microscope. Conclusion rmhTNF-alpha enhances the the killing effect of gemcitabine on human lung adenocarcinoma cells A549 by inducing apoptosis and promoting cell cycle arrest.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a specific cell-surface receptor for oxidized-low-density lipoprotein (ox-LDL). The impact of high-density lipoprotein (HDL) on endoplasmic reticulum (ER) stress-mediated alteration of the LOX-1 level in hepatocytes remains unclear. We aimed to investigate the impact on LOX-1 expression by tunicamycin (TM)-induced ER stress and to determine the effect of HDL on TM-affected LOX-1 expression in hepatic L02 cells. Overexpression or silencing of related cellular genes was conducted in TM-treated cells. mRNA expression was evaluated using real-time polymerase chain reaction (PCR). Protein expression was analyzed by western blot and immunocytochemistry. Lipid uptake was examined by DiI-ox-LDL, followed by flow cytometric analysis. The results showed that TM induced the upregulation of ER chaperone GRP78, downregulation of LOX-1 expression, and lipid uptake. Knock down of IRE1 or XBP-1 effectively restored LOX-1 expression and improved lipid uptake in TM-treated cells. HDL treatment prevented the negative impact on LOX-1 expression and lipid uptake induced by TM. Additionally, 1-10 μg/mL HDL significantly reduced the GRP78, IRE1, and XBP-1 expression levels in TM-treated cells. Our findings reveal that HDL could prevent the TM-induced reduction of LOX-1 expression via inhibiting the IRE1/XBP-1 pathway, suggesting a new mechanism for beneficial roles of HDL in improving lipid metabolism.

Introduction: Functional traits of desert plants exhibit remarkable responsiveness, adaptability and plasticity to environmental heterogeneity. Methods: In this study, we measured six crucial plant functional traits (leaf carbon, leaf nitrogen, leaf phosphorus, leaf thickness, chlorophyll concentration, and plant height) and employed exemplar analysis to elucidate the effects of soil environmental heterogeneity on intraspecific traits variation in the high-moisture-salinity and low-moisture-salinity habitats of the Ebinur LakeWetland National Nature Reserve. Results: The results showed that (1) The soil moisture and electrical conductivity heterogeneity showed significant differences between the two moisture-salinity habitats. Moreover, soil nutrient in high moisture-salinity habitat exhibited higher heterogeneity than in low moisture-salinity habitat. The order of intraspecific trait variation among different life forms was herbs > shrubs > trees in both the soil moisture-salinity habitats. (2) At the community level, intraspecific variation of leaf carbon, nitrogen, plant height and chlorophyll content in high moisture-salinity habitat was higher than that in low moisture-salinity habitat, while the opposite was true for leaf thickness and leaf phosphorus content. (3) Our findings revealed a positive impact of soil heterogeneity on intraspecific traits variation. In high moisture-salinity habitat, the heterogeneity of soil organic carbon had the highest explanatory power for intraspecific traits variation, reaching up to 20.22%, followed by soil total nitrogen (9.55%) and soil total phosphorus (3.49%). By comparison, in low-moisture-salinity habitat, the heterogeneity of soil moisture alone contributes the highest explanatory power for intraspecific traits variation in community-level, reaching up to 13.89%, followed by the heterogeneity of soil total nitrogen (3.76%). Discussion: This study emphasizes the differences in soil heterogeneity and intraspecific trait variation among plant life forms under various soil moisture-salinity habitats and confirms the significant promoting effect of soil heterogeneity on intraspecific trait variation of desert plant. Our findings provide valuable theoretical basis and reference for predicting plant adaptation strategies under environmental change scenarios. [ABSTRACT FROM AUTHOR]