Differential characteristics of chemical composition, fermentation metabolites and antioxidant effects of polysaccharides from Eurotium Cristatum and Fu-brick tea.

Fu-brick tea (FBT) is predominately fermented by Eurotium Cristatum, FBT polysaccharides (FTPs) and Eurotium Cristatum extracellular polysaccharides (ECPs) are the main active substances in FBT and Eurotium Cristatum, respectively. FTPs was shown to exhibit higher levels of uronic acids, proteins, and polyphenols as compared to ECPs (p < 0.05), contributing to the superior antioxidant activity observed in FTPs. Additionally, FTPs had better water solubility and thermal stability than ECPs. Interestingly, in vitro digestive simulation revealed that FTPs and ECPs resist digestion in the stomach and small intestine. Excitingly, utilizing in vitro fermentation with feces from healthy individuals and type 2 diabetes mellitus (T2DM) patients demonstrated that FTPs and ECPs promote the production of SCFAs. Still, FTPs resulted in greater SCFAs contents than ECPs (p < 0.05). Moreover, FTPs and ECPs fermentation by T2DM patients' fecal microbiota affected different metabolomic pathways. Our findings suggested that FTPs holds great promise for application in functional foods.

Evaluating the global prevalence of insomnia during pregnancy through standardized questionnaires and diagnostic criteria: a systematic review and meta-analysis.

Introduction: Insomnia during pregnancy presents significant medical care challenges and heightens the risk of adverse outcomes for both pregnant women and fetuses. This study undertook a meta-analysis to assess the global prevalence of insomnia during pregnancy, examining both the overall prevalence and regional variations. Method: The aim of this study was to perform a meta-analysis of articles indexed in PubMed, Embase, and Web of Science from the inception of these databases up to February 29, 2024. The study systematically reviewed the global prevalence of gestational insomnia and explored potential moderating factors, encompassing research type, publication date, regional influences, maternal age, pregnancy status, depressive symptoms, and anxiety symptoms. Result: Forty-four studies, encompassing a total of 47,399,513 participants, were included in the analysis. The overall prevalence of insomnia symptoms during pregnancy was 43.9%. Regional factors and depression emerged as the main factors affecting insomnia, with Europe (53.6%) surpassing North America (41.0%), followed by South America (50.6%) and Asia (40.7%). High depression rates (56.2%) correlated with increased insomnia prevalence compared to low depression rates (39.8%). The type of research and publication date showed no significant impact on the prevalence of insomnia symptoms. Conclusion: The meta-analysis results indicated that the prevalence of insomnia symptoms was higher during pregnancy, especially among pregnant women who were in a highly depressed state or located in the European region. Systematic review registration: PROSPERO, identifier CRD42018104460.

Intracellular Polysaccharides of Eurotium cristatum Exhibited Anticolitis Effects in Association with Gut Tryptophan Metabolism.

This study is to investigate the protective effects of Eurotium cristatum intracellular polysaccharides (ECIP) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC). The oral administration of ECIP could downregulate the disease activity index (DAI) and ameliorate the colonic shortening, immune stress, and damage caused by DSS. In addition, ECIP treatment increased the colonic contents of SCFAs including acetic, propionic, and butyric acids in UC mice. Targeted and untargeted metabolic analysis suggested that ECIP dramatically altered the tryptophan metabolism in the feces of UC mice and promoted the conversion of tryptophan into indole metabolites including indolepyruvate and indole-3-acetic acid (IAA) and indolealdehyde (IAId). Moreover, ECIP observably increased the content of colonic IL-22 and stimulated the relative concentration and relative expression of tight junction molecules in mRNA and proteins levels. Conclusively, consumption of ECIP can improve colon damage and its related effects of UC by promoting the production of IAA and IAId to reinforce intestinal barriers.

Consumption of dietary turmeric promotes fat browning and thermogenesis in association with gut microbiota regulation in high-fat diet-fed mice.

This study was designed to verify the anti-obesity effect of dietary turmeric powder (TP) as a traditional cooking spice and its underlying mechanism. The HFD-fed C57BL/6J mice were supplemented with or without TP (8%) for 12 weeks. The results indicated that the glucolipid metabolism disorder of high-fat diet (HFD)-fed mice was significantly ameliorated through the supplementation of TP. The consumption of TP also induced beige-fat development and brown adipose tissue (BAT)-derived nonshivering thermogenesis in HFD-fed obese mice. 16S rDNA-based microbiota or targeted metabolomics analysis indicated that TP ameliorated the intestinal microbiota dysbiosis and microbial metabolism abnormality caused by HFD, reflected by dramatically increasing the relative abundance of Muribaculaceae, Candidatus_Saccharimonas, and Bifidobacterium and production of short-chain fatty acids (SCFAs) and succinate. Interestingly, TP-induced BAT thermogenesis and iWAT browning were highly correlated with the reconstruction of the gut microbiome and formation of SCFAs and succinate. Collectively, these findings manifest beneficial actions of TP on the promotion of adipose browning and thermogenesis in association with gut microbiota reconstruction, and our findings may provide a promising way for preventing obesity.

Cardiac adverse events associated with lacosamide: a disproportionality analysis of the FAERS database.

Lacosamide was the first approved third-generation antiepileptic drug. However, real-world data regarding its adverse cardiac reactions in large samples still need to be completed. We evaluated the cardiac safety profile of lacosamide using the Food and Drug Administration Adverse Event Reporting System (FAERS). We performed disproportionality analysis computing reporting odds ratio (ROR) as a quantitative metric to assess the signal of lacosamide-related cardiac adverse events (AEs) from 2013 Q1 to 2022 Q4. The signal was considered significant when the lower limit of the 95% confidence interval (CI) of the ROR exceeded 1, and ≥ 5 AEs were reported. Serious and nonserious cases were compared by statistical analysis, and signals were further prioritized using a rating scale. A total of 812 cardiac AEs associated with lacosamide were identified, and 92 signals were detected, of which 17 AEs were significantly associated signals. The median time-to-onset (TTO) for moderate priority signals was 10 days, whereas for weak priority signals, it was 54 days. Notably, all cardiac AEs exhibited an early failing pattern, indicating the risk gradually decreasing. Based on the comprehensive analysis of the FAERS database and prioritization of cardiac AE signals, our research enhances the awareness among healthcare professionals regarding cardiac AEs associated with lacosamide.

Synthesis of a pH/temperature bi-response gallic acid magnetic imprinted polymer for extracting natural product from Galla chinensis.

A pH/temperature bi-responsive gallic acid magnetic imprinted polymer (PTBG-MIP) was synthesized on a Fe3O4@SiO2@KH570 carrier using methacrylic acid (MAA), p-Vinylphenylboronic acid (p-VPBA), and N-isopropyl-acrylamide (NIPAAm) as complex functional monomers. The density functional theory (DFT) was employed to optimize the molar ratio of multi-functional monomers-template complex, which proved to be an effective tool for predicting complex configuration based on electrostatic potential (ESP) analysis and the lowest binding energy. DFT calculation and analysis determined the optimized molar ratio of 2:1:1:1 for GA-MAA-NIPAAm-p-VPBA, which showed good agreement with experimental results. The PTBG-MIP-4 obtained under the optimized conditions exhibited high pH- and temperature- dependence in rebinding the template, displaying a maximum adsorption capacity (Qe) of 62.26 mg g-1 and a highest selection factor (α) of 5.217. Additionally, the PTBG-MIP-4 exhibited exceptional physicochemical properties encompassing magnetization characteristics, morphology, surface sites distribution, and adsorption performance. The application efficiency of this imprinted composite in the extraction and purification of gallic acid from Galla chinensis was remarkably demonstrated.

Modified Hongteng Baijiang decoction enema improves sequelae of pelvic inflammatory disease by regulating the LIF/JAK2/STAT3 pathway and gut microbiota.

OBJECTIVE: The sequelae of pelvic inflammatory disease (SPID) are major causes of secondary infertility. Modified Hongteng Baijiang decoction (MHTBD) has produced positive results in the treatment of patients with chronic pelvic inflammatory disease; however, its role in SPID remains elusive. Therefore, this study clarified the role of MHTBD in SPID pathogenesis. METHODS: The main components in MHTBD were analyzed by using liquid chromatography‒mass spectrometry (LC/MS). An SPID rat model was established, and the rats were treated with different doses of MHTBD (0.504 g of raw drug/kg, 1.008 g of raw drug/kg, and 2.016 g of raw drug/kg). Endometrial pinopodes were observed via scanning electron microscopy, endometrial thickness and inflammatory cell infiltration were assessed via HE staining, and the expression of estrogen receptor (ER), progesterone receptor (PR), integrin ß3 (ITGB3), and CD31 in the endometrium was detected by using immunohistochemistry. Western blot analysis was used to detect the protein expression of LIF, JAK2, p-JAK2, STAT3, and p-STAT3 in the endometrium. Moreover, the changes in the gut microbiota were analyzed via 16S rRNA sequencing. RESULTS: MHTBD improved endometrial receptivity, attenuated endometrial pathologic damage, reduced inflammatory cell infiltration, decreased ER and PR expression in the endometrium, and promoted the expression of LIF, p-JAK2, and p-STAT3 in the endometrium (p < .05) in SPID rats. Additionally, MHTBD treatment affected the composition of the gut microbiota in SPID rats. Furthermore, MHTBD attenuated endometrial receptivity and pathological damage in SPID rats by promoting the LIF/JAK2/STAT3 pathway. CONCLUSION: MHTBD attenuates SPID in rats by promoting the LIF/JAK2/STAT3 pathway and improving the composition of the gut microbiota. MHTBD may be a valuable drug for SPID therapy.

Self-assembled copper-based nanoparticles for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma.

As an emerging cancer treatment strategy, reactive oxygen species-based tumor catalytic therapies face enormous challenges due to hypoxia and the overexpression of glutathione (GSH) in the tumor microenvironment. Herein, a self-assembled copper-based nanoplatform, TCCHA, was designed for enzyme-like catalysis-enhanced chemodynamic/photodynamic/antiangiogenic tritherapy against hepatocellular carcinoma. TCCHA was fabricated from Cu2+, 3,3'-dithiobis (propionohydrazide), and photosensitizer chlorine e6 via a facile one-pot self-assembly strategy, after which an aldehyde hyaluronic acid was coated, followed by loading of the antivascular drug AL3818. The obtained TCCHA nanoparticles exhibited pH/GSH dual-responsive drug release behaviors and multienzymatic activities, including Fenton, glutathione peroxidase-, and catalase-like activities. TCCHA, a redox homeostasis disruptor, promotes ⋅OH generation and GSH depletion, thus increasing the efficacy of chemodynamic therapy. TCCHA, which has catalase-like activity, can also reinforce the efficacy of photodynamic therapy by amplifying O2 production. In vivo, TCCHA efficiently inhibited tumor angiogenesis and suppressed tumor growth without apparent systemic toxicity. Overall, this study presents a facile strategy for the preparation of multienzyme-like nanoparticles, and TCCHA nanoparticles display great potential for enzyme catalysis-enhanced chemodynamic/photodynamic/antiangiogenic triple therapy against cancer.

Dynamic changes on sensory property, nutritional quality and metabolic profiles of green kernel black beans during Eurotium cristatum-based solid-state fermentation.

Eurotium cristatum, a unique probiotic in Fu brick tea, is widely used in food processing to enhance added values. Here, green kernel black beans (GKBBs) were solid-fermented with E. cristatum and dynamic changes in flavour, chemical composition and metabolites during fermentation were investigated. As results, E. cristatum fermentation altered aroma profiles and sensory attributes of GKBBs, especially reduced sourness. After fermentation, total polyphenolic and flavonoid contents in GKBBs were elevated, while polysaccharides, soluble proteins and short-chain fatty acids contents were decreased. E. cristatum fermentation also induced biotransformation of glycosidic isoflavones into sapogenic isoflavones. During fermentation, dynamic changes in levels of 17 amino acids were observed, in which 3 branched-chain amino acids were increased. Non-targeted metabolomics identified 51 differential compounds and 10 related metabolic pathways involved in E. cristatum fermentation of GKBBs. This study lays foundation for the development of green kernel black bean-based functional food products with E. cristatum fermentation.

Iguratimod ameliorates antibody-mediated rejection after renal transplant by modulating the Th17/Treg paradigm.

BACKGROUND: Iguratimod (IGU) is widely used in clinical practice due to its stable anti-inflammatory effects. Our previous studies have confirmed that the proportion of Th17/Treg balance in patients taking IGU altered significantly. This study aims to explore the role of IGU in antibody-mediated rejection (ABMR) and its potential mechanisms. METHODS: We conducted bioinformatics analysis of sequencing data from the GEO database to analyze the abundance of immune cell infiltration in transplanted kidney tissues. In vivo, IGU was intervened in a mice secondary skin transplantation model and a mice kidney transplantation ABMR model, and histological morphology of the grafts were examined by pathological staining, while relevant indicators were determined through qRT-PCR, immunohistochemistry, and enzyme-linked immunosorbent assay, observed T cell differentiation by flow cytometry, and preliminarily assessed the immunosuppressive effect of IGU. In vitro, we established Th17 and Treg cell induction and stimulation differentiation culture systems and added IGU for intervention to explore its effects on their differentiation. RESULTS: Through bioinformatics analysis, we found that Th17 and Treg may play important roles in the occurrence and development of ABMR. In vivo, we found that IGU could effectively reduce the damage caused by ABMR to the grafts, alleviate the infiltration of inflammatory cells in the graft tissues, and reduce the deposition of C4d in the grafts. Moreover, it is also found that IGU regulated the differentiation of Th17 and Treg cells in the spleen and peripheral blood and reduced the expression of IL-17A in the grafts and serum. In addition, same changes were observed in the induction and differentiation culture system of Th17 and Treg cells in vitro after the addition of IGU. CONCLUSION: IGU can inhibit the progression of ABMR by regulating the differentiation of Th17 and Treg cells, providing novel insights for optimizing clinical immunosuppressive treatment regimens.

Semaphorin 7A impairs barrier function in cultured human corneal epithelial cells in a manner dependent on nuclear factor-kappa B.

AIM: To evaluate the role of semaphorin 7A (Sema7A) and its associated regulatory mechanisms in modulating the barrier function of cultured human corneal epithelial cells (HCEs). METHODS: Barrier models of HCEs were treated with recombinant human Sema7A at concentrations of 0, 125, 250, or 500 ng/mL for 24, 48, or 72h in vitro. Transepithelial electrical resistance (TEER) as well as Dextran-fluorescein isothiocyanate (FITC) permeability assays were conducted to assess barrier function. To quantify tight junctions (TJs) such as occludin and zonula occludens-1 (ZO-1) at the mRNA level, reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed. Immunoblotting was used to examine the activity of the nuclear factor-kappa B (NF-κB) signaling pathway and the production of TJs proteins. Immunofluorescence analyses were employed to localize the TJs. Enzyme-linked immunosorbent assay (ELISA) and RT-PCR were utilized to observe changes in interleukin (IL)-1ß levels. To investigate the role of NF-κB signaling activation and IL-1ß in Sema7A's anti-barrier mechanism, we employed 0.1 µmol/L IκB kinase 2 (IKK2) inhibitor IV or 500 ng/mL IL-1 receptor (IL-1R) antagonist. RESULTS: Treatment with Sema7A resulted in decreased TEER and increased permeability of Dextran-FITC in HCEs through down-regulating mRNA and protein levels of TJs in a time- and dose-dependent manner, as well as altering the localization of TJs. Furthermore, Sema7A stimulated the activation of inhibitor of kappa B alpha (IκBα) and expression of IL-1ß. The anti-barrier function of Sema7A was significantly suppressed by treatment with IKK2 inhibitor IV or IL-1R antagonists. CONCLUSION: Sema7A disrupts barrier function through its influence on NF-κB-mediated expression of TJ proteins, as well as the expression of IL-1ß. These findings suggest that Sema7A could be a potential therapeutic target for the diseases in corneal epithelium.

FBXO32-mediated degradation of PTEN promotes lung adenocarcinoma progression.

FBXO32, a member of the F-box protein family, is known to play both oncogenic and tumor-suppressive roles in different cancers. However, the functions and the molecular mechanisms regulated by FBXO32 in lung adenocarcinoma (LUAD) remain unclear. Here, we report that FBXO32 is overexpressed in LUAD compared with normal lung tissues, and high expression of FBXO32 correlates with poor prognosis in LUAD patients. Firstly, we observed with a series of functional experiments that FBXO32 alters the cell cycle and promotes the invasion and metastasis of LUAD cells. We further corroborate our findings using in vivo mouse models of metastasis and confirmed that FBXO32 positively regulates LUAD tumor metastasis. Using a proteomic-based approach combined with computational analyses, we found a positive correlation between FBXO32 and the PI3K/AKT/mTOR pathway, and identified PTEN as a FBXO32 interactor. More important, FBXO32 binds PTEN via its C-terminal substrate binding domain and we also validated PTEN as a bona fide FBXO32 substrate. Finally, we demonstrated that FBXO32 promotes EMT and regulates the cell cycle by targeting PTEN for proteasomal-dependent degradation. In summary, our study highlights the role of FBXO32 in promoting the PI3K/AKT/mTOR pathway via PTEN degradation, thereby fostering lung adenocarcinoma progression.

Exploring the therapeutic effect of Pen Yan Kang Fu Decoction on SPID rats based on LIF/JAK2/STAT3 signaling pathway.

Tubal inflammation, endometritis, and uterine adhesions due to post-pelvic inflammatory disease (SPID) are important causes of infertility. Chronic endometritis (CE) belongs to SPID, which seriously affects women's reproductive health, quality of life, and family harmony, and is a hot and difficult problem in clinical research. The efficacy of Pen Yan Kang Fu Decoction (PYKFD) has been verified in long-term clinical practice for chronic endometritis infertility caused by the SPID. Numerous studies have confirmed that the LIF/JAK2/STAT3 signaling pathway is important in embryo implantation and development, and endometritis infertility is close to LIF/JAK2/STAT3. In vivo results showed that PYKFD increased endometrial receptivity, repaired uterine tissue damage, and regulates the expression of endometrial receptivity-related factors ER (estrogen receptor), PR (progesterone receptor), CD31, and integrin αvß3, and induced the transduction of LIF/JAK2/STAT3 signaling pathway. PYKFD can also regulate the expression of IL-6. The results of in vitro experiments showed that PYKFD regulates the behavior of rat endometrial epithelial cells (REECs) involving LIF. In conclusion, PYKFD can improve endometrial receptivity and promote endometrial repair by LIF/JAK2/STAT3 signaling pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-024-03981-0.

Unlocking PD-1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression.

In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8+ T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8+/CD4+ T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.

Phthalate metabolites and sex steroid hormones in relation to obesity in US adults: NHANES 2013-2016.

Background: Obesity and metabolic syndrome pose significant health challenges in the United States (US), with connections to disruptions in sex hormone regulation. The increasing prevalence of obesity and metabolic syndrome might be associated with exposure to phthalates (PAEs). Further exploration of the impact of PAEs on obesity is crucial, particularly from a sex hormone perspective. Methods: A total of 7780 adult participants in the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2016 were included in the study. Principal component analysis (PCA) coupled with multinomial logistic regression was employed to elucidate the association between urinary PAEs metabolite concentrations and the likelihood of obesity. Weighted quartiles sum (WQS) regression was utilized to consolidate the impact of mixed PAEs exposure on sex hormone levels (total testosterone (TT), estradiol and sex hormone-binding globulin (SHBG)). We also delved into machine learning models to accurately discern obesity status and identify the key variables contributing most to these models. Results: Principal Component 1 (PC1), characterized by mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) as major contributors, exhibited a negative association with obesity. Conversely, PC2, with monocarboxyononyl phthalate (MCNP), monocarboxyoctyl phthalate (MCOP), and mono(3-carboxypropyl) phthalate (MCPP) as major contributors, showed a positive association with obesity. Mixed exposure to PAEs was associated with decreased TT levels and increased estradiol and SHBG. During the exploration of the interrelations among obesity, sex hormones, and PAEs, models based on Random Forest (RF) and eXtreme Gradient Boosting (XGBoost) algorithms demonstrated the best classification efficacy. In both models, sex hormones exhibited the highest variable importance, and certain phthalate metabolites made significant contributions to the model's performance. Conclusions: Individuals with obesity exhibit lower levels of TT and SHBG, accompanied by elevated estradiol levels. Exposure to PAEs disrupts sex hormone levels, contributing to an increased risk of obesity in US adults. In the exploration of the interrelationships among these three factors, the RF and XGBoost algorithm models demonstrated superior performance, with sex hormones displaying higher variable importance.

Nonextractable Polyphenols from Fu Brick Tea Alleviates Ulcerative Colitis by Controlling Colon Microbiota-Targeted Release to Inhibit Intestinal Inflammation in Mice.

This study was designed to elucidate the colon microbiota-targeted release of nonextractable bound polyphenols (NEPs) derived from Fu brick tea and to further identify the possible anti-inflammatory mechanism in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. 1.5% DSS drinking water-induced C57BL/6J mice were fed rodent chow supplemented with or without 8% NEPs or dietary fibers (DFs) for 37 days. The bound p-hydroxybenzoic acid and quercetin in NEPs were liberated up to 590.5 ± 70.6 and 470.5 ± 51.6 mg/g by in vitro human gut microbiota-simulated fermentation, and released into the colon of the mice supplemented with NEPs by 4.4- and 1.5-fold higher than that of the mice supplemented without NEPs, respectively (p < 0.05). Supplementation with NEPs also enhanced the colonic microbiota-dependent production of SCFAs in vitro and in vivo (p < 0.05). Interestingly, Ingestion of NEPs in DSS-induced mice altered the gut microbiota composition, reflected by a dramatic increase in the relative abundance of Dubosiella and Enterorhabdus and a decrease in the relative abundance of Alistipes and Romboutsia (p < 0.05). Consumption of NEPs was demonstrated to be more effective in alleviating colonic inflammation and UC symptoms than DFs alone in DSS-treated mice (p < 0.05), in which the protective effects of NEPs against UC were highly correlated with the reconstruction of the gut microbiome, formation of SCFAs, and release of bound polyphenols. These findings suggest that NEPs as macromolecular carriers exhibit targeted delivery of bound polyphenols into the mouse colon to regulate gut microbiota and alleviate inflammation.

An innovative antibody fusion protein targeting PD-L1, VEGF and TGF-ß with enhanced antitumor efficacies.

Immunosuppressive pathways in the tumor microenvironment (TME) are inextricably linked to tumor progression. Mono-therapeutics of immune checkpoint inhibitors (ICIs, e.g. antibodies against programmed cell death protein-1/programmed cell death ligand-1, PD-1/PD-L1) is prone to immune escape while combination therapeutics tends to cause high toxicity and side effects. Therefore, using multi-functional molecules to target multiple pathways simultaneously is becoming a new strategy for cancer therapies. Here, we developed a trifunctional fusion protein, DR30206, composed of Bevacizumab (an antibody against VEGF), and a variable domain of heavy chain of heavy chain antibody (VHH) against PD-L1 and the extracellular domain (ECD) protein of TGF-ß receptor II (TGF-ß RII), which are fused to the N- and C-terminus of Bevacizumab, respectively. The original intention of DR30206 design was to enhance the immune responses pairs by targeting PD-L1 while inhibiting VEGF and TGF-ß in the TME. Our data demonstrated that DR30206 exhibits high antigen-binding affinities and efficient blocking capabilities, the principal drivers of efficacy in antibody therapy. Furthermore, the capability of eliciting antibody-dependent cellular cytotoxicity (ADCC) and mixed lymphocyte reaction (MLR) provides a greater possibility to enhance the immune response. Finally, in vivo experiments showed that the antitumor activity of DR30206 was superior to those of monoclonal antibody of PD-L1 or VEGF, PD-L1 and TGF-ß bispecific antibody or the combination inhibition of PD-L1 and VEGF. Our findings suggest there is a great potential for DR30206 to become a therapeutic for the treatment of multiple cancer types, especially lung cancer, colon adenocarcinoma and breast carcinoma.

Dietary Inflammatory Index and diabetic retinopathy risk in US adults: findings from NHANES (2005-2008).

BACKGROUND: Inflammation is associated with the pathophysiology of diabetic retinopathy (DR). Within the framework of complete dietary patterns, the Dietary Inflammatory Index (DII) was formulated to evaluate the inflammatory properties inherent in a diet. The main purpose of the current study was to assess the relationship between DII and DR using National Health and Nutrition Examination Survey (NHANES). METHODS: The original sample size included 1,148 diabetes patients out of 2005-2008 NHANES surveys. Twenty-four-hour dietary consumptions were used to calculate the DII scores. Demographic characteristics and retina examinations were collected for the comparison between DR and non-DR groups in diabetes patients. The relationship between DII and DR was analyzed by a logistic regression model. RESULTS: 227 subjects (110 non-DR and 117 DR) were selected in the analyses by using undersampling method to balance the sample size. Compared with non-DR group, DR group had higher DII values (1.14 ± 0.29 vs. 1.49 ± 0.21, p = 0.32), higher levels of HbA1c (6.8 ± 1.1% vs. 7.7 ± 2.6%, p < 0.001), longer duration of diabetes (6.52 ± 12 years vs. 14 ± 11 years, p < 0.001). The odds rate (OR) of DII for DR from the logistic regression was 1.38 (95%CI 1.06-1.81, p < 0.001). HbA1c, diabetes duration and obesity were important influencing factors, and their ORs were 1.81 (95% CI:1.31-2.50), 1.12 (95%CI:1.04-1.20), 4.01 (95%CI:1.12-14.32), respectively. In addition, the most important dietary indices for DR were different across males and females. CONCLUSIONS: The current study demonstrates that a higher DII is associated with an increased risk of DR in US adults. Considering diet as a modifiable factor, limiting pro-inflammatory diets or encouraging an anti-inflammatory diet may be a promising and cost-effective method in the management of DR.

Identification of Increased Grain Length 1 (IGL1), a novel gene encoded by a major QTL for modulating grain length in rice.

KEY MESSAGE: A novel quantitative trait locus qIGL1, which performed a positive function in regulating grain length in rice, was cloned by the map-based cloning approach; further studies revealed that it corresponded to LOC_Os03g30530, and the IGL1 appeared to contribute to lengthening and widening of the cells on the surface of grain hulls. Grain length is a prominent determinant for grain weight and appearance quality of rice. In this study, we conducted quantitative trait locus mapping to determine a genomic interval responsible for a long-grain phenotype observed in a japonica cultivar HD385. This led to the identification of a novel QTL for grain length on chromosome 3, named qIGL1 (for Increased Grain Length 1); the HD385 (Handao 385)-derived allele showed enhancement effects on grain length, and such an allele as well as NIP (Nipponbare)-derived allele was designated qigl1 HD385 and qIGL1NIP, respectively. Genetic analysis revealed that the qigl1HD385 allele displayed semidominant effects on grain length. Fine mapping further narrowed down the qIGL1 to an ~ 70.8-kb region containing 9 open reading frames (ORFs). A comprehensive analysis indicated that LOC_Os03g30530, which corresponded to ORF6 and carried base substitutions and deletions in HD385 relative to NIP, thereby causing changes or losses of amino-acid residues, was the true gene for qIGL1. Comparison of grain traits between a pair of near-isogenic lines (NILs), termed NIL-igl1HD385 and NIL-IGL1NIP, discovered that introduction of the igl1HD385 into the NIP background significantly resulted in the elevations of grain length and 1000-grain weight. Closer inspection of grain surfaces revealed that the cell length and width in the longitudinal direction were significantly longer and greater, respectively, in NIL-igl1HD385 line compared with in NIL-IGL1NIP line. Hence, our studies identified a new semidominant natural allele contributing to the increase of grain length and further shed light on the regulatory mechanisms of grain length.

Preparation of rutin imprinted monolith (RIM) by using porogen containing ion liquid [BMIM]PF6 and its molecular recognition.

A [BMIM]PF6 ion liquid (IL)-assisted synthesis of a rutin imprinted monolith (RIM) was carried out in an in-situ polymerization method. Bi-functional monomers and a ternary porogen containing IL was used for the RIM preparation and a L9(33) orthogonal factor design performed. Scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR) and N2 adsorption method was for structural characterization of the RIMs. The monolith was directly used as stationary phase in liquid chromatography to test the retention selectivity, adsorption capacity and extraction application. The optimized porogen consists of 900 µL DMF, 144 µL ACN and 216 µL IL. The monolith RIM-13 obtained under the optimized conditions possessed improved adsorption performance, with a dynamic adsorption capacity of 6.695 mg/g, an imprinting efficiency of 4.841 and a selectivity α value of 4.821. Additionally, this monolith had also higher specific surface area, pore volume and permeability than that obtained without IL and the homogeneity of the imprint sites could be improved by using IL. When the RIM-13 was applied to the separation and purification of rutin from tartary buckwheat, a rutin product with a purity higher than 92 % can be obtained by one cycle. This molecular imprint solid-phase extraction (MI-SPE) is of potency to be applied to preparative-scale separation of other natural products.