bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting IL-6 by engineered Lactococcus lactis via surface-displayed affibody
Authors: Zahirović Abida , Berlec Aleš 
Published: July 2022

Abstract
Background
Dysregulated production of interleukin (IL)-6 is implicated in the pathology of inflammatory bowel disease (IBD). Neutralization of IL-6 in the gut by safe probiotic bacteria may help alleviate intestinal inflammation. Here, we developed Lactococcus lactis with potent and selective IL-6 binding activity by displaying IL-6-specific affibody on its surface.

Results
Anti-IL-6 affibody (designated as ZIL) was expressed in fusion with lactococcal secretion peptide Usp45 and anchoring protein AcmA. A high amount of ZIL fusion protein was detected on bacterial surface, and its functionality was validated by confocal microscopy and flow cytometry. Removal of IL-6 from the surrounding medium by the engineered L. lactis was evaluated using enzyme-linked immunosorbent assay. ZIL-displaying L. lactis sequestered recombinant human IL-6 from the solution in a concentration-dependent manner by up to 99% and showed no binding to other pro-inflammatory cytokines, thus proving to be highly specific for IL-6. The removal was equally efficient across different IL-6 concentrations (150–1200 pg/mL) that were found to be clinically relevant in IBD patients. The ability of engineered bacteria to capture IL-6 from cell culture supernatant was assessed using immunostimulated human monocytic cell lines (THP-1 and U-937) differentiated into macrophage-like cells. ZIL-displaying L. lactis reduced the content of IL-6 in the supernatants of both cell lines in a concentration-dependent manner by up to 94%. Dose response analysis showed that bacterial cell concentrations of 107 and 109 CFU/mL (colony forming units per mL) were required for half-maximal removal of recombinant and macrophage-derived IL-6, respectively.

Conclusion
The ability of ZIL-displaying L. lactis to bind pathological concentrations of IL-6 at common bacterial doses suggests physiological significance.
LINE-1 promotes tumorigenicity and exacerbates tumor progression via stimulating metabolism reprogramming in non-small cell lung cancer
Authors: Sun Zeguo , Zhang Rui , Zhang Xiao , Sun Yifei , Liu Pengpeng , Francoeur Nancy , Han Lei , Lam Wan Yee , Yi Zhengzi , Sebra Robert , Walsh Martin , Yu Jinpu , Zhang Weijia 
Published: July 2022

Abstract
Background
Long Interspersed Nuclear Element-1 (LINE-1, L1) is increasingly regarded as a genetic risk for lung cancer. Transcriptionally active LINE-1 forms a L1-gene chimeric transcript (LCTs), through somatic L1 retrotransposition (LRT) or L1 antisense promoter (L1-ASP) activation, to play an oncogenic role in cancer progression.

Methods
Here, we developed Retrotransposon-gene fusion estimation program (ReFuse), to identify and quantify LCTs in RNA sequencing data from TCGA lung cancer cohort (n = 1146) and a single cell RNA sequencing dataset then further validated those LCTs in an independent cohort (n = 134). We next examined the functional roles of a cancer specific LCT (L1-FGGY) in cell proliferation and tumor progression in LUSC cell lines and mice.

Results
The LCT events correspond with specific metabolic processes and mitochondrial functions and was associated with genomic instability, hypomethylation, tumor stage and tumor immune microenvironment (TIME). Functional analysis of a tumor specific and frequent LCT involving FGGY (L1-FGGY) reveal that the arachidonic acid (AA) metabolic pathway was activated by the loss of FGGY through the L1-FGGY chimeric transcript to promote tumor growth, which was effectively targeted by a combined use of an anti-HIV drug (NVR) and a metabolic inhibitor (ML355). Lastly, we identified a set of transcriptomic signatures to stratify the LUSC patients with a higher risk for poor outcomes who may benefit from treatments using NVR alone or combined with an anti-metabolism drug.

Conclusions
This study is the first to characterize the role of L1 in metabolic reprogramming of lung cancer and provide rationale for L1-specifc prognosis and potential for a therapeutic strategy for treating lung cancer.

Trial registration
Study on the mechanisms of the mobile element L1-FGGY promoting the proliferation, invasion and immune escape of lung squamous cell carcinoma through the 12-LOX/Wnt pathway, Ek2020111. Registered 27 March 2020 ‐ Retrospectively registered.
Circulating growth differentiation factor 15 levels and apolipoprotein B to apolipoprotein A1 ratio in coronary artery disease patients with type 2 diabetes mellitus
Authors: Mei Yufeng , Zhao Zhiming , Lyu Yongnan , Li Yan 
Published: July 2022

Abstract
Background
Clinical investigations have found that there was a close association between T2DM and adverse cardiovascular events, with possible mechanisms included inflammation, apoptosis, and lipid metabolism disorders. High serum GDF-15 concentration and the apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) are involved in the above-mentioned mechanisms and are thought to be related to the occurrence of adverse cardiovascular events. However, it remains unclear whether circulating GDF-15 levels and the ApoB/ApoA1 ratio are related to T2DM patients with CAD.

Methods
T2DM patients with or without CAD were eligible for this study. According to the inclusion and exclusion criteria, 502 T2DM patients were enrolled between January 2021 and December 2021 and were then divided into T2DM group (n = 249) and CAD group (n = 253). The ApoB, ApoA1 and GDF-15 concentrations were measured at hospital admission and the ApoB/ApoA1 ratio was then calculated.

Results
Compared with T2DM group, serum GDF-15 levels and ApoB/ApoA1 ratio increased in CAD group. Furthermore, a positive relationship between the occurrence of CAD in diabetic population and circulating GDF-15 concentrations and ApoB/ApoA1 ratio was observed in logistic regression analysis (p < 0.01). Restrictive cubic spline analysis after adjusted for multiple risky variables showed that serum GDF-15 or ApoB/ApoA1 ratio correlated positively with CAD.

Conclusions
Circulating GDF-15 levels and serum ApoB/ApoA1 ratio vary in CAD group and T2DM group. ApoB/ApoA1 and GDF-15 may be helpful for predicting the occurrence of CAD in patients with T2DM.
The associations between serum high-density lipoprotein cholesterol levels and malignant behavior in pancreatic neuroendocrine neoplasms
Authors: Quan Li , Liu Yongkang , Cui Wenjing , Wang Xinru , Zhang Weixiao , Wang Zhongqiu , Guo Chuangen , Lu Chao , Hu Feixiang , Chen Xiao 
Published: July 2022

Abstract
Background
The role of serum high-density lipoprotein cholesterol (HDL-c) in tumorigenesis are observed in several endocrine-related cancers. However, its role in pancreatic neuroendocrine neoplasms (PNENs) has not been understood. In the current study, the relationship between HDL-c levels and malignant behavior in PNENs was explored.

Methods
One hundred ninety-seven patients with histopathology confirmed PNENs were included. PNENs were divided into three grades (G1, G2 and G3) as 2017 WHO classification based on ki67 index and mitosis count. The demographic data, clinical information, tumor morphological and pathological features (organs invasion, lymph node metastasis, vascular invasion and perineural invasion), and serum tumor biomarkers were collected. The relationships between HDL-c levels and malignant behaviors in PNENs were analyzed using logistic regression analysis. Models were also developed for the identification of high grade PNENs.

Results
The levels of serum HDL-c in G2/G3 tumor were significantly lower than that in G1 tumor (P = 0.031). However, no such difference was found between G3 and G1/G2. The proportions of low HDL-c (≤ 0.9 mmol/L) were higher in high-grade PNENs (G2/G3 or G3) than those in low-grade (G1 or G1/G2) (29.0 vs 15.2%, P = 0.032; 37.0 vs 20.5%, P = 0.023). The risk of G2/G3 tumors in patients with high serum HDL-c levels was decreased (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.12–0.99). Similarly, the risk of G3 PNENs increased in patients with low HDL-c levels (OR = 2.51, 95%CI:1.12–5.60). HDL-c level was also associated with a high ki67 index (> 55%) (OR = 0.10, 95%CI: 0.02–0.51) and neuroendocrine carcinoma G3 (OR = 0.21, 95%CI: 0.06–0.80). The area under the curve (AUC) of HDL-c + tumor size + age was 0.85 (95% CI: 0.79–0.91) in identifying G2/G3 PNENs, and HDL-c (> 0.9 mmol/L) + tumor size + age had an AUC of 0.77 (95% CI: 0.70–0.84) in identifying G3 PNENs. HDL-c level was associated with lymph node metastasis (OR = 0.24, 95%CI:0.08–0.99).

Conclusion
Serum HDL-c levels were significantly associated with malignant behaviors in PNENs, in particular to tumor grade and lymph node metastasis.
Rod-like hybrid nanomaterial with tumor targeting and pH-responsive for cancer chemo/photothermal synergistic therapy
Authors: Wang Shaochen , Zhou Qiaoqiao , Yu Shuling , Zhao Shuang , Shi Jiahua , Yuan Jintao 
Published: July 2022

AbstractThe development of chemo/photothermal nanotherapeutic systems with excellent photothermal performance, stable drug loading, tumor targeting and strong membrane penetration still remains a challenge. To address this problem, herein a rod-like nanocomposite system (AuNR@FA-PR/PEG) forming from folic acid (FA) terminated carboxylated cyclodextrin (CD) pseudopolyrotaxane (FA-PR) and polyethylene glycol (PEG) modifying gold nanorods (AuNR) was reported. Cisplatin (CDDP) was loaded in AuNR@FA-PR/PEG via coordination bonds to prepare a rod-like pH-responsive nanosystem (AuNR@FA-PR/PEG/CDDP) with chemotherapy/photothermal therapy. The rod-like morphology of AuNR@FA-PR/PEG was characterized by transmission electron microscope. In vitro drug release experiments showed the pH-responsive of AuNR@FA-PR/PEG/CDDP. In vivo real-time imaging assays proved AuNR@FA-PR/PEG/CDDP could rapidly enrich in the tumor area and stay for a long time because of folate targeting and their rod-like morphology. In vivo photothermal imaging assays showed AuNR@FA-PR/PEG/CDDP excellent photothermal performance, the average temperature of tumor region could reach 63.5 °C after 10 min irradiation. In vitro and in vivo experiments also demonstrated that the combined therapy of chemotherapy and photothermal therapy had an outstandingly synergistic effect and improved the therapeutic efficacy comparing with chemotherapy and photothermal therapy alone. Therefore, the prepared rod-like AuNR@FA-PR/PEG/CDDP will provide a new strategy for the effective treatment of cancer.
pH-sensitive packaging of cationic particles by an anionic block copolymer shell
Authors: Solomun Jana I. , Martin Liam , Mapfumo Prosper , Moek Elisabeth , Amro Elias , Becker Friedrich , Tuempel Stefan , Hoeppener Stephanie , Rudolph K. Lenhard , Traeger Anja 
Published: July 2022

AbstractCationic non-viral vectors show great potential to introduce genetic material into cells, due to their ability to transport large amounts of genetic material and their high synthetic versatility. However, designing materials that are effective without showing toxic effects or undergoing non-specific interactions when applied systemically remains a challenge. The introduction of shielding polymers such as polyethylene glycol (PEG) can enhance biocompatibility and circulation time, however, often impairs transfection efficiency. Herein, a multicomponent polymer system is introduced, based on cationic and hydrophobic particles (P(nBMA46-co-MMA47-co-DMAEMA90), (PBMD)) with high delivery performance and a pH-responsive block copolymer (poly((N-acryloylmorpholine)-b-(2-(carboxy)ethyl acrylamide)) (P(NAM72-b-CEAm74), PNC)) as shielding system, with PNAM as alternative to PEG. The pH-sensitive polymer design promotes biocompatibility and excellent stability at extracellular conditions (pH 7.4) and also allows endosomal escape and thus high transfection efficiency under acidic conditions. PNC shielded particles are below 200 nm in diameter and showed stable pDNA complexation. Further, interaction with human erythrocytes at extracellular conditions (pH 7.4) was prevented, while acidic conditions (pH 6) enabled membrane leakage. The particles demonstrate transfection in adherent (HEK293T) as well as difficult-to-transfect suspension cells (K-562), with comparable or superior efficiency compared to commercial linear poly(ethylenimine) (LPEI). Besides, the toxicity of PNC-shielded particles was significantly minimized, in particular in K-562 cells and erythrocytes. In addition, a pilot in vivo experiment on bone marrow blood cells of mice that were injected with PNC-shielded particles, revealed slightly enhanced cell transfection in comparison to naked pDNA. This study demonstrates the applicability of cationic hydrophobic polymers for transfection of adherent and suspension cells in culture as well as in vivo by co-formulation with pH-responsive shielding polymers, without substantially compromising transfection performance.
Graphical Abstract
Protective role of small extracellular vesicles derived from HUVECs treated with AGEs in diabetic vascular calcification
Authors: Guo Bei , Shan Su-Kang , Xu Feng , Lin Xiao , Li Fu-Xing-zi , Wang Yi , Xu Qiu-Shuang , Zheng Ming-Hui , Lei Li-Min , Li Chang-Chun , Zhou Zhi-Ang , Ullah Muhammad Hasnain Ehsan , Wu Feng , Liao Xiao-Bo , Yuan Ling-Qing 
Published: July 2022

AbstractThe pathogenesis of vascular calcification in diabetic patients remains elusive. As an effective information transmitter, small extracellular vesicles (sEVs) carry abundant microRNAs (miRNAs) that regulate the physiological and pathological states of recipient cells. In the present study, significant up-regulation of miR-126-5p was observed in sEVs isolated from human umbilical vein endothelial cells (HUVECs) stimulated with advanced glycation end-products (A-EC/sEVs). Intriguingly, these sEVs suppressed the osteogenic differentiation of vascular smooth muscle cells (VSMCs) by targeting BMPR1B, which encodes the receptor for BMP, thereby blocking the smad1/5/9 signalling pathway. In addition, knocking down miR-126-5p in HUVECs significantly diminished the anti-calcification effect of A-EC/sEVs in a mouse model of type 2 diabetes. Overall, miR-126-5p is highly enriched in sEVs derived from AGEs stimulated HUVECs and can target BMPR1B to negatively regulate the trans-differentiation of VSMCs both in vitro and in vivo.
Graphical Abstract
Light triggered release of a triple action porphyrin-cisplatin conjugate evokes stronger immunogenic cell death for chemotherapy, photodynamic therapy and cancer immunotherapy
Authors: Song Haiqin , Cai Zhenghao , Li Juyi , Xiao Haihua , Qi Ruogu , Zheng Minhua 
Published: July 2022

AbstractPhotodynamic therapy (PDT) has emerged as an attractive therapeutic approach which can elicit immunogenic cell death (ICD). However, current ICD inducers are still very limited as the representative ICD induces of photosensitizers can only evoke insufficient ICD to achieve unsatisfactory cancer immunotherapy. Herein, we demonstrated the use of a triple action cationic porphyrin-cisplatin conjugate (Pt-1) for drug delivery by a reactive oxygen species (ROS) sensitive polymer as nanoparticles (NP@Pt-1) for combined chemotherapy, PDT and immunotherapy. This unique triple action Pt-1 contains both chemotherapeutic Pt drugs and Porphyrin as a photosensitizer to generate ROS for PDT. Moreover, the ROS generated by Pt-1 can on the one hand degrade polymer carriers to release Pt-1 for chemotherapy and PDT. On the other hand, the ROS generated by Pt-1 subsequently triggered the ICD cascade for immunotherapy. Taken together, we demonstrated that NP@Pt-1 were the most effective and worked in a triple way. This study could provide us with new insight into the development of nanomedicine for chemotherapy, PDT as well as cancer immunotherapy.
PLA-lignin nanofibers as antioxidant biomaterials for cartilage regeneration and osteoarthritis treatment
Authors: Liang Ruiming , Yang Xingchen , Yew Pek Yin Michelle , Sugiarto Sigit , Zhu Qiang , Zhao Jinmin , Loh Xian Jun , Zheng Li , Kai Dan 
Published: July 2022

AbstractBackgroundOsteoarthritis (OA) is common musculoskeletal disorders associated with overgeneration of free radicals, and it causes joint pain, inflammation, and cartilage degradation. Lignin as a natural antioxidant biopolymer has shown its great potential for biomedical applications. In this work, we developed a series of lignin-based nanofibers as antioxidative scaffolds for cartilage tissue engineering.ResultsThe nanofibers were engineered by grafting poly(lactic acid) (PLA) into lignin via ring-opening polymerization and followed by electrospinning. Varying the lignin content in the system was able to adjust the physiochemical properties of the resulting nanofibers, including fiber diameters, mechanical and viscoelastic properties, and antioxidant activity. In vitro study demonstrated that the PLA-lignin nanofibers could protect bone marrow-derived mesenchymal stem/stromal cells (BMSCs) from oxidative stress and promote the chondrogenic differentiation. Moreover, the animal study showed that the lignin nanofibers could promote cartilage regeneration and repair cartilage defects within 6 weeks of implantation.ConclusionOur study indicated that lignin-based nanofibers could serve as an antioxidant tissue engineering scaffold and facilitate the cartilage regrowth for OA treatment.Graphical Abstract
Radiodynamic therapy with CsI(na)@MgO nanoparticles and 5-aminolevulinic acid
Authors: Jiang Fangchao , Lee Chaebin , Zhang Weizhong , Jiang Wen , Cao Zhengwei , Chong Harrison Byron , Yang Wei , Zhan Shuyue , Li Jianwen , Teng Yong , Li Zibo , Xie Jin 
Published: July 2022

Abstract
Background
Radiodynamic therapy (RDT) holds the potential to overcome the shallow tissue penetration issue associated with conventional photodynamic therapy (PDT). To this end, complex and sometimes toxic scintillator–photosensitizer nanoconjugates are often used, posing barriers for large-scale manufacturing and regulatory approval.

Methods
Herein, we report a streamlined RDT strategy based on CsI(Na)@MgO nanoparticles and 5-aminolevulinic acid (5-ALA). 5-ALA is a clinically approved photosensitizer, converted to protoporphyrin IX (PpIX) in cancer cells’ mitochondria. CsI(Na)@MgO nanoparticles produce strong ~ 410 nm X-ray luminescence, which matches the Soret band of PpIX. We hypothesize that the CsI(Na)@MgO-and-5-ALA combination can mediate RDT wherein mitochondria-targeted PDT synergizes with DNA-targeted irradiation for efficient cancer cell killing. Because scintillator nanoparticles and photosensitizer are administered separately, the approach forgoes issues such as self-quenching or uncontrolled release of photosensitizers.

Results
When tested in vitro with 4T1 cells, the CsI(Na)@MgO and 5-ALA combination elevated radiation-induced reactive oxygen species (ROS), enhancing damages to mitochondria, DNA, and lipids, eventually reducing cell proliferation and clonogenicity. When tested in vivo in 4T1 models, RDT with the CsI(Na)@MgO and 5-ALA combination significantly improved tumor suppression and animal survival relative to radiation therapy (RT) alone. After treatment, the scintillator nanoparticles, made of low-toxic alkali and halide elements, were efficiently excreted, causing no detectable harm to the hosts.

Conclusions
Our studies show that separately administering CsI(Na)@MgO nanoparticles and 5-ALA represents a safe and streamlined RDT approach with potential in clinical translation.

Graphical Abstract
Antibacterial metal nanoclusters
Authors: Zheng Youkun , Wei Min , Wu Haibin , Li Fangyuan , Ling Daishun 
Published: July 2022

AbstractCombating bacterial infections is one of the most important applications of nanomedicine. In the past two decades, significant efforts have been committed to tune physicochemical properties of nanomaterials for the development of various novel nanoantibiotics. Among which, metal nanoclusters (NCs) with well-defined ultrasmall size and adjustable surface chemistry are emerging as the next-generation high performance nanoantibiotics. Metal NCs can penetrate bacterial cell envelope more easily than conventional nanomaterials due to their ultrasmall size. Meanwhile, the abundant active sites of the metal NCs help to catalyze the bacterial intracellular biochemical processes, resulting in enhanced antibacterial properties. In this review, we discuss the recent developments in metal NCs as a new generation of antimicrobial agents. Based on a brief introduction to the characteristics of metal NCs, we highlight the general working mechanisms by which metal NCs combating the bacterial infections. We also emphasize central roles of core size, element composition, oxidation state, and surface chemistry of metal NCs in their antimicrobial efficacy. Finally, we present a perspective on the remaining challenges and future developments of metal NCs for antibacterial therapeutics.
Graphical Abstract
Malting barley carbon dots-mediated oxidative stress promotes insulin resistance in mice via NF-κB pathway and MAPK cascade
Authors: Zhang Boya , Yu Lidong , Zhu Ruijiao , Wei Xiangjuan , Fan Xingpei , Hu Hailong , Yang Daqian , Du Haining , Zhao Meimei , Li Li , Oh Yuri , Feng Yujie , Gu Ning 
Published: July 2022

Abstract
Background
Food-borne carbon dots (CDs) are widely generated during food processing and are inevitably ingested by humans causing toxicity. However, the toxic effects of food-borne CDs on the blood glucose metabolism are unknown.

Results
In this study, we brewed beer via a representative strategy and extracted the melting-barley CDs (MBCDs) to explore the toxic effects on blood glucose in mice. We found the accumulation of fluorescent labeled MBCDs in various organs and oral administration of MBCDs can cause visceral toxicity, manifested as liver damage. Mice were orally administered MBCDs (5 and 25 mg/kg) for 16 weeks, and increased levels of fasting blood glucose were observed in both MBCDs-treated groups. Transcriptomic analyses revealed that MBCDs activate oxidative stress, inflammatory responses, the MAPK cascade, and PI3K/Akt signaling in mice livers. Mechanistically, MBCDs exposure-induced reactive oxygen species (ROS) overproduction activates the nuclear factor-κB (NF-κB) signaling pathway and MAPK cascade, thereby promoting phosphorylated insulin receptor substrate (IRS)-1 at Ser307 and inducing insulin resistance (IR). Meanwhile, the IR promoted gluconeogenesis, which enhanced MBCDs-induced hyperglycemia of mice. Importantly, inhibition of the ROS significantly attenuated the MBCDs-induced inflammatory response and MAPK cascade, thereby alleviating IR and hyperglycemia in mice.

Conclusion
In summary, this study revealed that MBCDs promote ROS overproduction and thus induced IR, resulting in imbalance of glucose homeostasis in mice. More importantly, this study was further assessed to reveal an imperative emphasis on the reevaluation of dietary and environmental CDs exposure, and has important implications for T2DM prevention research.

Graphical Abstract