Publications by authors named "Jun Fang"

487 Publications

A pilot human study on newly designed closure clips in endoscopic closure of giant gastrointestinal perforation using a continuous closing method.

Surg Endosc 2021 Jun 2. Epub 2021 Jun 2.

Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, 168 Changhai Rd, Shanghai, 200433, China.

Background: A large gastrointestinal perforation is a serious and even life-threatening clinical condition. Current endoscopic techniques for closing large gastrointestinal perforation have limitations. Building upon our recent findings in a porcine model, this pilot human study aimed to evaluate the safety, feasibility, and effectiveness of a novel endoscopic technique using newly designed closure clips for closure of giant gastrointestinal perforation.

Methods: A total of 18 patients who underwent endoscopic submucosal dissection (ESD) and developed giant gastrointestinal perforation > 2 cm in diameter were enrolled in this study. The newly designed closure clips, consisting of a sewing clip and knotter, were applied in endoscopic closure of the gastrointestinal perforations using a continuous suturing method. The safety, feasibility, and effectiveness were subsequently assessed in these patients.

Results: Endoscopic closure of the giant perforation was achieved in all patients. In evaluation of safety and effectiveness of this technique with the new closure clips and the continuous suturing method, no obvious intraoperative complications (e.g., bleeding, abdominal infection) occurred in the studied patients. Furthermore, on 1-month follow-up gastric endoscopy, all the patients showed complete closure of the gastrointestinal perforations, and no clinical signs of specific abnormalities or symptoms were observed.

Conclusion: This novel technique has been shown to be safe, effective, and feasible for the treatment of giant gastrointestinal perforation.
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http://dx.doi.org/10.1007/s00464-021-08564-1DOI Listing
June 2021

EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect.

J Pers Med 2021 May 28;11(6). Epub 2021 May 28.

Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.

For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers-isosorbide dinitrate (ISDN, Nitrol) and sildenafil citrate-strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.
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http://dx.doi.org/10.3390/jpm11060487DOI Listing
May 2021

Role of Two Plant Growth-Promoting Bacteria in Remediating Cadmium-Contaminated Soil Combined with (Lab.).

Plants (Basel) 2021 May 2;10(5). Epub 2021 May 2.

College of Bioscience and Biotechnology, College of Resource and Environment, Hunan Agricultural University, Changsha 410128, China.

spp. are energy plants and excellent candidates for phytoremediation approaches of metal(loid)s-contaminated soils, especially when combined with plant growth-promoting bacteria. Forty-one bacterial strains were isolated from the rhizosphere soils and roots tissue of five dominant plants ( Levl., Vaniot Houtt, L., Tenore, and Lab.) colonizing a cadmium (Cd)-contaminated mining area (Huayuan, Hunan, China). We subsequently tested their plant growth-promoting (PGP) traits (e.g., production of indole-3-acetic acid, siderophore, and 1-aminocyclopropane-1-carboxylate deaminase) and Cd tolerance. Among bacteria, two strains, TS8 and MR2, presented higher Cd tolerance and showed the best results regarding in vitro growth-promoting traits. In the subsequent pot experiments using soil spiked with 10 mg Cd·kg, we investigated the effects of TS8 and MR2 strains on soil Cd phytoremediation when combined with (Lab.). After sixty days of planting (Lab.), we found that TS8 increased plant height by 39.9%, dry weight of leaves by 99.1%, and the total Cd in the rhizosphere soil was reduced by 49.2%. Although MR2 had no significant effects on the efficiency of phytoremediation, it significantly enhanced the Cd translocation from the root to the aboveground tissues (translocation factor > 1). The combination of TS8 and (Lab.) may be an effective method to remediate Cd-contaminated soils, while the inoculation of MR2 may be used to enhance the phytoextraction potential of .
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http://dx.doi.org/10.3390/plants10050912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147505PMC
May 2021

Adropin-based dual treatment enhances the therapeutic potential of mesenchymal stem cells in rat myocardial infarction.

Cell Death Dis 2021 May 18;12(6):505. Epub 2021 May 18.

Department of Cardiology, Fujian Institute of Coronary Heart Disease, Fujian Heart Medical Center, Fujian Medical University Union Hospital, Fuzhou, PR China.

Both weak survival ability of stem cells and hostile microenvironment are dual dilemma for cell therapy. Adropin, a bioactive substance, has been demonstrated to be cytoprotective. We therefore hypothesized that adropin may produce dual protective effects on the therapeutic potential of stem cells in myocardial infarction by employing an adropin-based dual treatment of promoting stem cell survival in vitro and modifying microenvironment in vivo. In the current study, adropin (25 ng/ml) in vitro reduced hydrogen peroxide-induced apoptosis in rat bone marrow mesenchymal stem cells (MSCs) and improved MSCs survival with increased phosphorylation of Akt and extracellular regulated protein kinases (ERK) l/2. Adropin-induced cytoprotection was blocked by the inhibitors of Akt and ERK1/2. The left main coronary artery of rats was ligated for 3 or 28 days to induce myocardial infarction. Bromodeoxyuridine (BrdU)-labeled MSCs, which were in vitro pretreated with adropin, were in vivo intramyocardially injected after ischemia, following an intravenous injection of 0.2 mg/kg adropin (dual treatment). Compared with MSCs transplantation alone, the dual treatment with adropin reported a higher level of interleukin-10, a lower level of tumor necrosis factor-α and interleukin-1β in plasma at day 3, and higher left ventricular ejection fraction and expression of paracrine factors at day 28, with less myocardial fibrosis and higher capillary density, and produced more surviving BrdU-positive cells at day 3 and 28. In conclusion, our data evidence that adropin-based dual treatment may enhance the therapeutic potential of MSCs to repair myocardium through paracrine mechanism via the pro-survival pathways.
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http://dx.doi.org/10.1038/s41419-021-03610-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131743PMC
May 2021

The impact of probiotics on gut health via alternation of immune status of monogastric animals.

Anim Nutr 2021 Mar 26;7(1):24-30. Epub 2020 Dec 26.

College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha, 410128, China.

The intestinal immune system is affected by various factors during its development, such as maternal antibodies, host genes, intestinal microbial composition and activity, and various stresses (such as weaning stress). Intestinal microbes may have an important impact on the development of the host immune system. Appropriate interventions such as probiotics may have a positive effect on intestinal immunity by regulating the composition and activity of intestinal microbes. Moreover, probiotics participate in the regulation of host health in many ways; for instance, by improving digestion and the absorption of nutrients, immune response, increasing the content of intestinal-beneficial microorganisms, and inhibiting intestinal-pathogenic bacteria, and they participate in regulating intestinal diseases in various ways. Probiotics are widely used as additives in livestock and the poultry industry and bring health benefits to hosts by improving intestinal microbes and growth performance, which provides more choices for promoting strong and efficient productivity.
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http://dx.doi.org/10.1016/j.aninu.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110871PMC
March 2021

Bioorthogonal catalytic patch.

Nat Nanotechnol 2021 May 10. Epub 2021 May 10.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, P. R. China.

Bioorthogonal catalysis mediated by transition metals has inspired a new subfield of artificial chemistry complementary to enzymatic reactions, enabling the selective labelling of biomolecules or in situ synthesis of bioactive agents via non-natural processes. However, the effective deployment of bioorthogonal catalysis in vivo remains challenging, mired by the safety concerns of metal toxicity or complicated procedures to administer catalysts. Here, we describe a bioorthogonal catalytic device comprising a microneedle array patch integrated with Pd nanoparticles deposited on TiO nanosheets. This device is robust and removable, and can mediate the local conversion of caged substrates into their active states in high-level living systems. In particular, we show that such a patch can promote the activation of a prodrug at subcutaneous tumour sites, restoring its parent drug's therapeutic anticancer properties. This in situ applied device potentiates local treatment efficacy and eliminates off-target prodrug activation and dose-dependent side effects in healthy organs or distant tissues.
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http://dx.doi.org/10.1038/s41565-021-00910-7DOI Listing
May 2021

Metabolic reprogramming of macrophages and its involvement in inflammatory diseases.

EXCLI J 2021 11;20:628-641. Epub 2021 Mar 11.

Department of Toxicology, School of Public Health, Anhui Medical University, and Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, No 81 Meishan Road, Hefei 230032, China.

Macrophages are critical effector cells of the innate immune system. The presence of microbes or the stimulation by inflammatory factors triggers the metabolic reprogramming of macrophages or macrophage polarization into two phenotypes: the classically activated macrophages (M1) displaying a pro-inflammatory phenotype and the alternatively activated macrophages (M2) having anti-inflammatory functions. The imbalance between the two phenotypes has been linked with various pathological states, such as fibrosis, hepatitis, colitis, and tumor progression. An avenue of potential therapeutic strategies based on macrophage polarization has emerged. Therefore, it is essential to understand the mechanisms of macrophage polarization. In this review, we focus on the macrophage polarization process and discuss the stimuli-dependent conversion into M1 and M2 phenotypes. We also present the metabolic patterns supporting their specific functions. The factors and signaling cascades involved in intra-class switching are also detailed. Finally, the role of macrophage polarization in disease progression is discussed.
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http://dx.doi.org/10.17179/excli2020-3053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056050PMC
March 2021

Epigallocatechin Gallate Can Protect Mice From Acute Stress Induced by LPS While Stabilizing Gut Microbes and Serum Metabolites Levels.

Front Immunol 2021 1;12:640305. Epub 2021 Apr 1.

College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha, China.

Epigallocatechin gallate (EGCG) has potent biological activity as well as strong antioxidant and anti-inflammatory effects. This study aims to explore the protective effect of EGCG on LPS-induced acute injury. We randomly divided 18 mice into three groups: CON, LPS, and EGCG-LPS. We gave the EGCG-LPS group gavage treatment with EGCG on day 8-15 and an intraperitoneal injection of LPS on day 16 to induce acute injury. The results showed that, compared with the LPS group, the bodyweight of the mice in the EGCG-LPS group increased significantly and effectively inhibited the morphological damage of the jejunum and liver. We measured liver tissue and found that the EGCG gavage treatment significantly inhibited the pro-inflammatory factors () and oxidation indicators (MPO, NO, ALT, and AST) levels increase. The microbiological results showed that the EGCG gavage treatment reshaped the disturbance done to the intestinal microbial community in the mice by LPS, reversed the changes in the abundance ratio of /, and significantly reduced the abundance of . Finally, the serum metabolomics results showed that, when compared with the LPS group, the gavage treatment of EGCG significantly increased the concentration of sphingomyelin (d17:1/17:0), sphingomyelin (d16:1/20:0), and significantly reduced the content of trans-Hexadec-2-enoyl carnitine, and so on. Therefore, we believe that EGCG can protect mice from acute stress induced by LPS while stabilizing gut microbes in general, improving the metabolism of sphingolipids, and inhibiting the content of harmful metabolites.
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http://dx.doi.org/10.3389/fimmu.2021.640305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047319PMC
April 2021

Circular RNA hsa_circ_0000700 promotes cell proliferation and migration in Esophageal Squamous Cell Carcinoma by sponging miR-1229.

J Cancer 2021 5;12(9):2610-2623. Epub 2021 Mar 5.

Department of Radiotherapy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China.

Accumulating evidence has demonstrated that circular RNAs (circRNAs) are involved in the pathogenesis of cancer, including that of esophageal squamous cell carcinoma (ESCC). The current study aimed to investigate the role of hsa_circ_0000700 in ESCC. hsa_circ_0000700, miR-1229, and related functional gene expression was measured by RT-qPCR. To characterize the functions of hsa_circ_0000700 and miR-1229, ESCC cells were infected with hsa_circ_0000700-specific siRNA, miR-1229 mimics, and an inhibitor alone or in combination. Cell Counting Kit-8 (CCK8), colony formation, EdU, flow cytometry, and Transwell assays were employed to evaluate cell proliferation, apoptosis, and migration. Luciferase reporter and RNA immunoprecipitation assays were used to confirm the targeting relationship between hsa_circ_0000700 and miR-1229. Finally, a competing endogenous RNAs (ceRNA) network was built for hsa_circ_0000700, and miR-1229 targets were analyzed by bioinformatics. circ_0000700 expression was significantly upregulated in ESCC cell lines. Actinomycin D and RNase R treatment confirmed that circ_0000700 was more stable than its linear CDH9 mRNA form. Moreover, a cytoplasmic and nuclear fractionation assay suggested that circ_0000700 was mainly distributed in the cytoplasm of ECA-109 and TE-1 cells. , the proliferative and migratory capacities of ECA-109 and TE-1 cells were inhibited by knocking down circ_0000700 expression. Additionally, miR-1229 silencing reversed the circ_0000700-specific siRNA-induced attenuation of malignant phenotypes. Mechanistically, circ_0000700 was identified as a sponge of miR-1229 and could activate PRRG4, REEP5, and PSMB5 indirectly to promote ESCC progression. In summary, our results suggest that hsa_circ_0000700 functions as an oncogenic factor by sponging miR-1229 in ESCC.
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http://dx.doi.org/10.7150/jca.47112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040728PMC
March 2021

Anti-inflammatory and antibacterial activities of P. petiolosa (Christ) Ching ethyl acetate extract against S. aureus in mice.

Pak J Pharm Sci 2020 Sep;33(5):2047-2052

Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, Sichuan, P.R. China.

P. petiolosa as a typical Chinese herbal medicine has been generally utilized as Chinese native medicine formulation for treatment of chronic bronchitis, bronchial asthma and pneumoconiosis. The objective of this study was to evaluate the anti-inflammatory and antibacterial activities of P. petiolosa ethyl acetate extract (PPEAE) against S. aureus in mice. The air-dried leaves were extracted with ethyl acetate, mice were infected pneumonia by S. aureus. Colonization of S. aureus in lung tissue was calculated by plate colony count. The number of white blood cells (WBC) in blood was measured by blood cell automatic analyzer. The histopathological analysis of hematoxylin-eosin staining (H&E) of lung tissue was observed under microscope. Real-time PCR assay was employed to determine the relative mRNA expression of HO-1, iNOS and TNF-α. The results showed that, compared with control, after treated with PPEAE the wet/dry (W/D) weight ratio of mice lung tissue (decreased from 5.371 to 4.9) and the number of white blood cells (WBC) (decreased by 3.13×10/mL) decreased dramatically. The number of S. aureus was significantly reduced (from 1.93×105 CFU/mL to 26×103 CFU/mL) in lung tissue after treated with PPEAE. Furthermore, H&E staining showed that PPEAE obviously relieved the inflammation of lung tissue of infected mice. Meanwhile, real-time PCR results indicated that PPEAE down regulated the expression of inflammatory iNOS, TNF-α mRNA and up regulated the expression of anti-inflammatory HO-1 mRNA. In summary, this study revealed that application of crude product PPEAE had prominent antibacterial activity against S. aureus. PPEAE significantly reduced the biomass of S. aureus in lung tissue and effectively relieved the inflammation of S. aureus-induced pneumonia.
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September 2020

Frost Resistance and Pore Structure of Concrete Incorporated with Rubber Aggregates and Nano-SiO.

Materials (Basel) 2021 Mar 2;14(5). Epub 2021 Mar 2.

School of Civil Engineering and Architecture, Xinxiang University, Xinxiang 453003, China.

This paper aims to develop frost-resistant concretes, and investigate their pore structures and freeze-thaw damage mechanism. The frost-resistant concrete mixtures are designed by using rubber particles and nano-SiO to partially replace sands. The chord lengths, specific surface areas, contents and spacing coefficients of the pores in the designed concretes are measured and analyzed. The results show that concrete mixture incorporated with 5% silanized rubber and 3% nanosilica shows good synergetic effect by considering both mass loss and relative dynamic modulus of elasticity (RDME). The freeze-thaw damage degree of the concrete could be reduced by adding high elastic rubber particles, due to filling and constraining pores, and resulting in better uniform pore distribution and smaller pore spacing coefficient. Furthermore, the correlations between frost resistance and pore are analyzed and proposed.
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http://dx.doi.org/10.3390/ma14051170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958853PMC
March 2021

Functional analyses unveil the involvement of moso bamboo (Phyllostachys edulis) group I and II NIN-LIKE PROTEINS in nitrate signaling regulation.

Plant Sci 2021 May 25;306:110862. Epub 2021 Feb 25.

Basic Forestry and Proteomics Research Center, College of Forestry, Fujian Agriculture and Forestry University, Fuzhou, 350002, China. Electronic address:

For rapid growth, moso bamboo (Phyllostachys edulis) requires large amounts of nutrients. Nitrate is an indispensable molecular signal to regulate nitrogen absorption and assimilation, which are regulated by group III NIN-LIKE PROTEINs (NLPs). However, no Phyllostachys edulis NLP (PeNLP) has been characterized. Here, eight PeNLPs were identified, which showed dynamic expression patterns in bamboo tissues. Nitrate did not affect PeNLP mRNA levels, and PeNLP1, -2, -5, -6, -7, and -8 successfully restored nitrate signaling in Arabidopsis atnlp7-1 protoplasts through recovering AtNiR and AtNRT2.1 expression. Four group I and II PeNLPs (PeNLP1, -2, -5, and -8) interacted with the nitrate-responsive cis-element of PeNiR. Moreover, nitrate triggered the nuclear retention of PeNLP8. PeNLP8 overexpression in Arabidopsis significantly increased the primary root length, lateral root number, leaf area, and dry and wet weight of the transgenic plants, and PeNLP8 expression rescued the root architectural defect phenotype of atnlp7-1 mutants. Interestingly, PeNLP8 overexpression dramatically reduced nitrate content but elevated total amino acid content in Arabidopsis. Overall, the present study unveiled the potential involvement of group I and II NLPs in nitrate signaling regulation and provided genetic resources for engineering plants with high nitrogen use efficiency.
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http://dx.doi.org/10.1016/j.plantsci.2021.110862DOI Listing
May 2021

Unraveling the role of Intralipid in suppressing off-target delivery and augmenting the therapeutic effects of anticancer nanomedicines.

Acta Biomater 2021 05 24;126:372-383. Epub 2021 Mar 24.

Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan. Electronic address:

Intralipid, a clinically used lipid emulsion, was reportedly utilized as one strategy to suppress off-target delivery of anticancer nanomedicines; Intralipid also effectively improved drug delivery to tumors and produced better therapeutic effects. However, the mechanisms involved-the why and how-in Intralipid's facilitation of delivery of nanomedicines to tumors have not yet been reported in detail. In this study, we investigated Intralipid and discovered the beneficial effects of Intralipid pretreatment when using three anticancer nanomedicines, including the clinically approved drug doxorubicin (Doxil). Intralipid pretreatment induced a 40% reduction in liver uptake of a polymeric nanoprobe used in photodynamic therapy as well as a 1.5-fold-increased nanomedicine accumulation in tumors. This increased accumulation consequently led to significantly better therapeutic effects, and this finding was validated by using Doxil. As an interesting result, Intralipid pretreatment significantly prolonged the plasma half-life of nanomedicines in normal healthy mice but not in tumor-bearing mice, which suggests that tumors become an alternative route of nanomedicine delivery when liver delivery is suppressed. Also, we found markedly increased tumor blood flow, as measured by fluorescence angiography, and significantly lower blood viscosity after Intralipid pretreatment. All our results together indicate that Intralipid treatment not only suppressed off-target nanomedicine delivery by the reticuloendothelial system, but more important, it enhanced nanomedicine delivery to tumors by improving tumor blood flow, which is key to satisfactory drug delivery via the enhanced permeability and retention effect. Significantly better therapeutic outcomes were thus achieved by the strategy of combining utilization of nanomedicines and Intralipid pretreatment. STATEMENT OF SIGNIFICANCE: Off-target delivery to organs such as the liver and obstructed tumor blood flow as is often seen in advanced cancers are major barriers to the therapeutic efficacy of anticancer nanomedicines. Intralipid has been shown effective for suppressing nanomedicine accumulation in the liver, resulting in improved anticancer effects. Unraveling the mechanisms involved in this process will be greatly helpful for the clinical application of anticancer nanomedicines. We reported here that Intralipid could also significantly increase tumor delivery of nanomedicine, which is beneficial for improving tumor blood flow and lowering blood viscosity. To our knowledge, this is the first study to investigate the role of Intralipid in this regard. This knowledge provides a solid rationale for the use of Intralipid in combination with anticancer nanomedicines.
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http://dx.doi.org/10.1016/j.actbio.2021.03.044DOI Listing
May 2021

MiR-21-3p Promotes Hepatocellular Carcinoma Progression SMAD7/YAP1 Regulation.

Front Oncol 2021 8;11:642030. Epub 2021 Mar 8.

Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Background: Hepatocellular carcinoma (HCC) remains a major global health burden due to its high prevalence and mortality. Emerging evidence reveals that microRNA (miRNA) plays a vital role in cancer pathogenesis and is widely involved in the regulation of signaling pathways their targeting of downstream genes. MiR-21-3p, a liver-enriched miRNA, and SMAD7, the negative regulator of the TGF- signaling pathway, likely exert a vital influence on HCC progression.

Aims: Here, we explore the role of the miR-21-3p-SMAD7/YAP1 axis on HCC pathogenesis.

Methods: MiRNA microarray analysis was performed for miRNA screening. The dual-luciferase assay was adopted for target verification. Expression of miRNA and related genes were quantified qRT-PCR, western blotting, and immunohistochemical staining. Flow cytometry and the transwell migration assay were used to detail cell apoptosis, invasion and metastases. Rat models were established to explore the role of the miR-21-3p-SMAD7/YAP1 axis in hepatocarcinogenesis. Bioinformatics analysis was conducted for exploring genes of clinical significance.

Results: MiR-21-3p levels were found to be significantly elevated in hepatocellular carcinoma and indicate poor overall survival. High miR-21-3p levels were associated with advanced tumor stages ( = 0.029), in particular T staging ( = 0.026). Low SMAD7/high YAP1 levels were confirmed in both HCC and rat models with advanced liver fibrosis and cirrhosis. Besides, SMAD7 was demonstrated to be the direct target of miR-21-3p. The effect of MiR-21-3p on tumor phenotypes and YAP1 upregulation could be partly reversed the restoration of SMAD7 expression in HCC cell lines. Overexpression of YAP1 after miR-21-3p upregulation promoted expression of nuclear transcription effector connective tissue growth factor. Co-survival analysis indicated that lower miR-21-3p/higher SMAD7 ( = 0.0494) and lower miR-21-3p/lower YAP1 ( = 0.0379) group patients had better overall survival rates. Gene Set Variation Analysis revealed that gene sets related to miR-21-3p and SMAD7 were significantly associated with the TGF-β signaling pathway in HCC.

Conclusion: MiR-21-3p promotes migration and invasion of HCC cells and upregulation of YAP1 expression direct inhibition of SMAD7, underscoring a major epigenetic mechanism in the pathogenesis of HCC.
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http://dx.doi.org/10.3389/fonc.2021.642030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982593PMC
March 2021

Dual function of clock component OsLHY sets critical day length for photoperiodic flowering in rice.

Plant Biotechnol J 2021 Mar 19. Epub 2021 Mar 19.

State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Rice Research Institute, Sichuan Agricultural University, Chengdu, China.

Circadian clock, an endogenous time-setting mechanism, allows plants to adapt to unstable photoperiod conditions and induces flowering with proper timing. In Arabidopsis, the central clock oscillator was formed by a series of interlocked transcriptional feedback loops, but little is known in rice so far. By MutMap technique, we identified the candidate gene OsLHY from a later flowering mutant lem1 and further confirmed it through genetic complementation, RNA interference knockdown, and CRISPR/Cas9-knockout. Global transcriptome profiling and expression analyses revealed that OsLHY might be a vital circadian rhythm component. Interestingly, oslhy flowered later under ≥12 h day length but headed earlier under ≤11 h day length. qRT-PCR results exhibited that OsLHY might function through OsGI-Hd1 pathway. Subsequent one-hybrid assays in yeast, DNA affinity purification qPCR, and electrophoretic mobility shift assays confirmed OsLHY could directly bind to the CBS element in OsGI promoter. Moreover, the critical day length (CDL) for function reversal of OsLHY in oslhy (11-12 h) was prolonged in the double mutant oslhy osgi (about 13.5 h), indicating that the CDL set by OsLHY was OsGI dependent. Additionally, the dual function of OsLHY entirely relied on Hd1, as the double mutant oslhy hd1 showed the same heading date with hd1 under about 11.5, 13.5, and 14 h day lengths. Together, OsLHY could fine-tune the CDL by directly regulating OsGI, and Hd1 acts as the final effector of CDL downstream of OsLHY. Our study illustrates a new regulatory mechanism between the circadian clock and photoperiodic flowering.
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http://dx.doi.org/10.1111/pbi.13580DOI Listing
March 2021

Skeletal muscle regeneration via the chemical induction and expansion of myogenic stem cells in situ or in vitro.

Nat Biomed Eng 2021 Mar 18. Epub 2021 Mar 18.

Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA, USA.

Muscle loss and impairment resulting from traumatic injury can be alleviated by therapies using muscle stem cells. However, collecting sufficient numbers of autologous myogenic stem cells and expanding them efficiently has been challenging. Here we show that myogenic stem cells (predominantly Pax7 cells)-which were selectively expanded from readily obtainable dermal fibroblasts or skeletal muscle stem cells using a specific cocktail of small molecules and transplanted into muscle injuries in adult, aged or dystrophic mice-led to functional muscle regeneration in the three animal models. We also show that sustained release of the small-molecule cocktail in situ through polymer nanoparticles led to muscle repair by inducing robust activation and expansion of resident satellite cells. Chemically induced stem cell expansion in vitro and in situ may prove to be advantageous for stem cell therapies that aim to regenerate skeletal muscle and other tissues.
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http://dx.doi.org/10.1038/s41551-021-00696-yDOI Listing
March 2021

Injectable Drug-Releasing Microporous Annealed Particle Scaffolds for Treating Myocardial Infarction.

Adv Funct Mater 2020 Oct 6;30(43). Epub 2020 Sep 6.

Department of Bioengineering, University of California, Los Angeles, CA 90095, USA.

Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drug-releasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug-loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.
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http://dx.doi.org/10.1002/adfm.202004307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942842PMC
October 2020

Tumor Environment-Responsive Hyaluronan Conjugated Zinc Protoporphyrin for Targeted Anticancer Photodynamic Therapy.

J Pers Med 2021 Feb 17;11(2). Epub 2021 Feb 17.

Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 4-22-1, Nishi-ku, Kumamoto 860-0082, Japan.

Targeted tumor accumulation, tumor environment responsive drug release, and effective internalization are critical issues being considered in developing anticancer nanomedicine. In this context, we synthesized a tumor environment-responsive nanoprobe for anticancer photodynamic therapy (PDT) that is a hyaluronan conjugated zinc protoporphyrin via an ester bond (HA-es-ZnPP), and we examined its anticancer PDT effect both in vitro and in vivo. HA-es-ZnPP exhibits high water-solubility and forms micelles of ~40 nm in aqueous solutions. HA-es-ZnPP shows fluorescence quenching without apparent O generation under light irradiation because of micelle formation. However, O was extensively generated when the micelle is disrupted, and ZnPP is released. Compared to native ZnPP, HA-es-ZnPP showed lower but comparable intracellular uptake and cytotoxicity in cultured mouse C26 colon cancer cells; more importantly, light irradiation resulted in 10-time increased cytotoxicity, which is the PDT effect. In a mouse sarcoma S180 solid tumor model, HA-es-ZnPP as polymeric micelles exhibited a prolonged systemic circulation time and the consequent tumor-selective accumulation based on the enhanced permeability and retention (EPR) effect was evidenced. Consequently, a remarkable anticancer PDT effect was achieved using HA-es-ZnPP and a xenon light source, without apparent side effects. These findings suggest the potential of HA-es-ZnPP as a candidate anticancer nanomedicine for PDT.
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http://dx.doi.org/10.3390/jpm11020136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922489PMC
February 2021

Effect of Deep Versus Moderate Neuromuscular Block on Pain After Laparoscopic Colorectal Surgery: A Randomized Clinical Trial.

Dis Colon Rectum 2021 Apr;64(4):475-483

The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.

Background: Anesthesia with deep neuromuscular block for laparoscopic surgery may result in less postoperative pain with lower intra-abdominal pressure. However, results in the existing literature are controversial.

Objective: The study aimed to evaluate the effect of deep neuromuscular block on postoperative pain at rest and during coughing after laparoscopic colorectal surgery.

Design: The design is a parallel-group, randomized clinical trial.

Settings: The study was conducted at a tertiary care center.

Patients: Patients undergoing laparoscopic resection of colorectal tumors were included.

Interventions: Patients were randomly assigned to either a deep (posttetanic count 1 to 2) or moderate (train-of-four 1 to 2) neuromuscular group.

Main Outcome Measures: The coprimary efficacy outcomes were numeric rating scale scores of the postoperative pain at rest and during coughing after surgery.

Results: Pain was lower in the deep neuromuscular block group at rest and during coughing at 1, 6, 24, and 48 hours after surgery (median difference of 2 points and 1 point at 1 h; p < 0.001 at each time point). The deep neuromuscular block group displayed a significantly lower number of bolus attempts by the patient (4 in the deep group vs 9 in the moderate group; p < 0.001) and boluses delivered (4 in the deep group vs 9 in the moderate group; p < 0.001) on postoperative day 1. The number of rescue analgesics was lower in the deep group on postoperative day 2 (p < 0.001). The deep neuromuscular block group showed a lower frequency of postoperative nausea and vomiting (p = 0.02) and lower intraoperative intra-abdominal pressure (p < 0.001).

Limitations: This was a single-center study.

Conclusions: Deep neuromuscular block resulted in better pain relief and lower opioid consumption and use of rescue analgesics after laparoscopic colorectal surgery. Deep neuromuscular block was associated with less postoperative nausea and vomiting and facilitated the use of lower intra-abdominal pressure in laparoscopic surgery. See Video Abstract at http://links.lww.com/DCR/B458.

Efecto Del Bloqueo Neuromuscular Profundo Versus Moderado En El Dolor, Despus De La Ciruga Colorrectal Laparoscpica Un Ensayo Clnico Aleatorizado: ANTECEDENTES:La anestesia con bloqueo neuromuscular profunda para cirugía laparoscópica, puede resultar con menor dolor postoperatorio y con menos presión intraabdominal. Sin embargo, los resultados en la literatura existente son controvertidos.OBJETIVO:El objetivo del estudio, fue evaluar el efecto del bloqueo neuromuscular profundo en dolor postoperatorio de reposo y con la tos, después de cirugía colorrectal laparoscópica.DISEÑO:Ensayo clínico aleatorizado de grupos paralelos.AJUSTE:El estudio se realizó en un centro de atención terciaria.PACIENTES:Se incluyeron pacientes sometidos a resección laparoscópica de tumores colorrectales.INTERVENCIONES:Los pacientes fueron aleatorizados a un grupo neuromuscular profundo (recuento posttetánico 1 a 2) o moderado (tren de cuatro 1 a 2).PRINCIPALES MEDIDAS DE RESULTADO:Los resultados coprimarios de eficacia, fueron las puntuaciones numéricas en la escala de calificación del dolor postoperatorio en reposo y durante la tos, después de la cirugía.RESULTADOS:El dolor fue menor en el grupo de bloqueo neuromuscular profundo en reposo y durante la tos, en 1, 6, 24, 48 horas después de la cirugía, (diferencia de mediana de 2 puntos y 1 punto respectivamente en 1 hora; p <0,001 en cada punto de tiempo). El grupo de bloqueo neuromuscular profundo, mostró un número significativamente menor de intentos de bolo por parte del paciente, (4 en el grupo profundo versus 9 del grupo moderado, p <0,001) y de bolos administrados (4 en el grupo profundo versus 9 en el grupo moderado, p <0,001) en el primer día postoperatorio. El número de analgésicos de rescate, fue menor en el grupo profundo en el segundo día postoperatorio (p <0,001). El grupo de bloqueo neuromuscular profundo, mostró una menor frecuencia de náuseas y vómitos postoperatorios (p = 0,02) y una menor presión intraoperatoria e intraabdominal (p <0,001).LIMITACIONES:Este estudio fue un estudio de un solo centro.CONCLUSIONES:El bloqueo neuromuscular profundo, resultó en mayor alivio del dolor y menor consumo de opioides y uso de analgésicos de rescate, después de la cirugía colorrectal laparoscópica. El bloqueo neuromuscular profundo, se asoció con menos náuseas y vómitos posoperatorios y facilitó el uso de una presión intraabdominal más baja, en la cirugía laparoscópica. Consulte Video Resumen en http://links.lww.com/DCR/B458.
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http://dx.doi.org/10.1097/DCR.0000000000001854DOI Listing
April 2021

Early reoccurrence of traumatic posterior atlantoaxial dislocation without fracture: A case report.

World J Clin Cases 2021 Feb;9(6):1461-1468

Department of Orthopedics, Yidu Central Hospital, Weifang Medical University, Qingzhou 262500, Shandong Province, China.

Background: In general, atlantoaxial dislocation is rare due to the stability of the C1-C2 complex. Traumatic atlantoaxial dislocations are usually anterior and accompanied by odontoid fractures. Posterior atlantoaxial dislocations are rare, and complete posterior dislocation without associated fracture is even more rare. A case of early recurrence of posterior atlantoaxial dislocation without fracture being in therapy of first closed reduction and then open reduction has not been previously reported.

Case Summary: A 45-year-old female presented with traumatic posterior atlantoaxial dislocation (TPAD) of C1-C2 without associated fractures, and Frankel Grade B spinal cord function. She was successfully managed by immediate closed reduction under skull traction. Unexpectedly, 17 d later, re-dislocation was discovered. On day 28, closed reduction was performed as before but failed. Then, open reduction and posterior internal fixation with autologous iliac bone grafts was performed. By 6 mo after surgery, atlantoaxial joint fusion was achieved, and neurological function had recovered to Frankel Grade E. At 12 mo follow-up, she had lost only 15° of cervical rotation, and atlantoaxial complex instability in joint flexing and extending were no longer observed under fluoroscopy.

Conclusion: Early assessment of transverse ligament is critical for TPAD without fracture avoiding re-dislocation after closed reduction.
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http://dx.doi.org/10.12998/wjcc.v9.i6.1461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896674PMC
February 2021

Revisiting bone morphogenetic protein-2 knuckle epitope and redesigning the epitope-derived peptides.

J Pept Sci 2021 Jun 22;27(6):e3309. Epub 2021 Feb 22.

Department of Orthopedics, Yidu Central Hospital Affiliated to Weifang Medical University, Weifang, China.

The bone morphogenetic protein-2 (BMP2) plays a crucial role in bone formation, growth and regeneration, which adopts a conformational wrist epitope and a linear knuckle epitope to interact with its type-I (BRI) and type-II (BRII) receptors, respectively. In this study, we systematically examine the BRII-recognition site of BMP2 at structural, energetic and dynamic levels and accurately locate hotspots of the recognition at BMP2-BRII complex interface. It is revealed that the traditional knuckle epitope (BMP2 residue range 73-92) do fully match the identified hotspots; the BMP2-recognition site includes the C-terminal region of traditional knuckle epitope as well as its flanked β-strands. In addition, the protein context of full-length BMP2 is also responsible for the recognition by addressing conformational constraint on the native epitope segment. Therefore, we herein redefine the knuckle epitope to BMP2 residue range 84-102, which has a similar sequence length but is slid along the protein sequence by ~10 residues as compared to traditional knuckle epitope. The redefined one is also a linear epitope that is natively a double-stranded β-sheet with two asymmetric arms as compared to the natively single β-strand of the traditional version, although their sequences are partially overlapped to each other. It is revealed that the redefined epitope-derived peptide LN exhibits an improved affinity by >3-fold relative to the traditional epitope-derived peptide KL . Even so, the LN peptide still cannot fully represent the BMP2 recognition event by BRII that has been reported to have a nanomolar affinity. We further introduce a disulfide bond across the two arms of double-stranded β-sheet to constrain the free LN peptide conformation, which mimics the conformational constraint addressed by protein context. Consequently, several cyclic peptides are redesigned, in which the LN (cyc89-101) is determined to exhibit a sub-micromolar affinity; this value is ~5-fold higher than its linear counterpart. Structural analysis also reveals that the cyclic peptide can interact with BRII in a similar binding mode with the redefined knuckle epitope region in full-length BMP2 protein.
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http://dx.doi.org/10.1002/psc.3309DOI Listing
June 2021

Potential role of Lactobacillus plantarum in colitis induced by dextran sulfate sodium through altering gut microbiota and host metabolism in murine model.

Sci China Life Sci 2021 Feb 10. Epub 2021 Feb 10.

College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha, 410128, China.

Inflammatory bowel disease (IBD) is a chronic lifelong disease characterized by inflammation of the gastrointestinal tract. Although more and more treatment options serve IBD, there is still no cure. It is important to find an effective treatment for IBD. This study aims to investigate whether Lactobacillus plantarum (L. plantarum) could alleviate colitis induced by dextran sulfate sodium (DSS). Following the DSS challenge, L. plantarum on DSS-mediated inflammatory colon lesions in mice, and L. plantarum therapy heightened the relative abundance of the colon-resident Actinobacteria. Analysis of serum metabolomics also indicated that the content of MG (18:4 (6Z, 9Z, 12Z, 15Z)/0:0/0:0) was increased in response to L. plantarum therapy, and this was also the case for indolepyruvate and 1-hydroxyibuprofen. However, 13-oxooctadecadienoic acid (13-oxoODE) and indolylacryloylglycine content fell following the DSS challenge. Based on these results, the study elucidates the mitigatory effects of L. plantarum in colitis, which depend on its regulation of the colonic microbial community and its modification of serum metabolites. The results revealed that L. plantarum mitigated inflammatory colon lesions, reprogrammed the microbial community and altered the level of serum metabolites in a murine model challenged with DSS. The study may present a potential therapeutic strategy for colitis.
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http://dx.doi.org/10.1007/s11427-020-1835-4DOI Listing
February 2021

MiR-34a reverses radiation resistance on ECA-109 cells by inhibiting PI3K/AKT/mTOR signal pathway through downregulating the expression of SIRT1.

Int J Radiat Biol 2021 2;97(4):452-463. Epub 2021 Feb 2.

Department of Radiation Oncology, Hangzhou City, China.

Background: Radiotherapy is an effective treatment for esophageal squamous cell carcinoma (ESCC). However, many ESCC patients relapsed after receiving radiotherapy due to the inherent resistance. The function of miR-34a and SIRT1, as well as the correlation between miR-34a and SIRT1 has been widely claimed in multiple types of malignant tumors. This study aimed to investigate the effects of miR-34a on radiation resistance against ESCC and the underlying mechanism.

Methods: In this study, CCK8, flow cytometry, wounding healing assays, and cell clone formation assay were used to determine the in vitro anti-tumor effects of radiation on radiation-resistant ESCC cell line (rECA-109). The luciferase activity and Western Blot assays were used to investigate the relationship among miR-34a, SIRT1, and the anti-radiation resistant effects. The xenograft experiments were used to verify the important function of miR-34a and SIRT1 in radiation resistance against ESCC. The apoptosis state of tumor tissues was evaluated by TUNEL assay.

Results: The introduction of miR-34a significantly induced the cell death and apoptosis of rECA-109 and inhibit the migration of rECA-109 treated by radiation. The anti-tumor effect was accompanied by the downregulation of SIRT1 and the inhibition of PI3K/AKT/mTOR signal pathway. The radiation resistance on rECA-109 cells was reversed by silencing SIRT1, accompanied by the PI3K/AKT/mTOR signal pathway inhibited. In vivo experiments revealed that the radiation resistance on ESCC was reversed by the introduction of miR-34a, the effect of which was promoted by the activation of SIRT1.

Conclusion: Our results showed that miR-34a could reverse the radiation resistance on rECA-109 cells by downregulating the expression of SIRT1through inhibiting the PI3K-AKT-mTOR signal pathway.
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http://dx.doi.org/10.1080/09553002.2021.1866225DOI Listing
February 2021

Characterization of Glass Insulating Thick Films with Ag Conductors for Multilayer Packages.

Materials (Basel) 2021 Jan 21;14(3). Epub 2021 Jan 21.

College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing 211106, China.

In this paper, an insulating film was successfully prepared by sintering 35 wt % CaO-15 wt % AlO-10 wt % BO-40 wt % SiO glass at 875 °C. After sintering, the main component of the insulating film was glass-ceramics. The main crystal phase was CaAlSiO, and the crystallization activation energy was 189.76 kJ/mol. After preparing the insulating film, its color turned yellow, and the diffusion of Ag was found by XPS and XRD data. When the temperature increased to 875 °C, the color of the insulating film became lighter, and the silver content decreased. The adhesion of the multilayer structure could reach 875 N. The dielectric constant of the insulating film in the multilayer structure was approximately 5, and the dielectric loss was 0.0011. After sintering, the dielectric strength of the insulating film could reach 13.11 kV/mm, which fully meets the requirements of a complex packaging structure.
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http://dx.doi.org/10.3390/ma14030494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864519PMC
January 2021

The Protective Role of Probiotics against Colorectal Cancer.

Oxid Med Cell Longev 2020 9;2020:8884583. Epub 2020 Dec 9.

College of Bioscience and Biotechnology, Hunan Agricultural University, Hunan Provincial Engineering Research Center of Applied Microbial Resources Development for Livestock and Poultry, Changsha, Hunan 410128, China.

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide and a major global public health problem. With the rapid development of the economy, the incidence of CRC has increased linearly. Accumulating evidence indicates that changes in the gut microenvironment, such as undesirable changes in the microbiota composition, provide favorable conditions for intestinal inflammation and shaping the tumor growth environment, whereas administration of certain probiotics can reverse this situation to a certain extent. This review summarizes the roles of probiotics in the regulation of CRC, such as enhancing the immune barrier, regulating the intestinal immune state, inhibiting pathogenic enzyme activity, regulating CRC cell proliferation and apoptosis, regulating redox homeostasis, and reprograming intestinal microbial composition. Abundant studies have provided a theoretical foundation for the roles of probiotics in CRC prevention and treatment, but their mechanisms of action remain to be investigated, and further clinical trials are warranted for the application of probiotics in the target population.
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http://dx.doi.org/10.1155/2020/8884583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803265PMC
December 2020

Nano-designed carbon monoxide donor SMA/CORM2 exhibits protective effect against acetaminophen induced liver injury through macrophage reprograming and promoting liver regeneration.

J Control Release 2021 Mar 19;331:350-363. Epub 2021 Jan 19.

Department of Toxicology, School of Public Health, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China; Key Laboratory of Environmental Toxicology of Anhui Higher Education Institutes, School of Public Health, Anhui Medical University, Hefei 230022, China; Faculty of Pharmaceutical Science, Sojo University, Ikeda 4-22-1, Kumamoto 860-0082, Japan. Electronic address:

Acetaminophen (APAP) induced liver injury is the most common drug-induced liver injury, accounting for the top cause of acute liver failure in the United State, however the therapeutic options for it is very limited. Excess generation of reactive oxygen species (ROS) and the subsequent inflammatory responses are the major factors of the liver injury. Carbon monoxide (CO) is an important gaseous molecule with versatile functions including anti-oxidation and anti-inflammation, and we previous reported the therapeutic potential of a nano-designed CO donor SMA/CORM2 in a dextran sulphate sodium (DSS) induced mouse colitis model. In this context, we investigated the effect of SMA/CORM2 in an APAP-induced mouse acute liver injury model and tackled the mechanisms involved. We found upregulation of heme oxygenase-1 (HO-1, endogenous CO generating enzyme) and the dynamic changes of macrophage polarization (pro-inflammatory M1/anti-inflammatory M2), which played important roles in the process of live injury. SMA/CORM2 treatment remarkably increased the CO levels in the liver and circulation, by which oxidative stresses in the liver were significantly reduced, and more importantly, it remarkably suppressed the expression of M1 macrophages but alternatively increased M2 polarization. Consequently the liver injury was significantly ameliorated, and the proliferation and regeneration were greatly promoted through the Pi3k/Akt/mTOR signaling pathway. The shift of macrophage polarization accompanied with the downregulated hypoxia-inducible factor-1α (HIF-1α) level. These findings suggested CO released from SMA/CORM2 manipulated the macrophage reprogramming toward M2 phenotype by inhibiting HIF-1α, which subsequently protected liver against inflammatory injury and benefited tissue repair. Moreover, compared to native CORM2, SMA/CORM2 exhibited superior bioavailability and protective effect. We thus anticipate the application of SMA/CORM2 as a therapeutic regimen for APAP induced liver injury as well as other inflammatory diseases and disorders.
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http://dx.doi.org/10.1016/j.jconrel.2021.01.025DOI Listing
March 2021

Pathways involved in pony body size development.

BMC Genomics 2021 Jan 18;22(1):58. Epub 2021 Jan 18.

College of Life Sciences, Inner Mongolia Agricultural University, No. 306 Zhaowuda Road, Hohhot, 010018, China.

Background: The mechanism of body growth in mammals is poorly understood. Here, we investigated the regulatory networks involved in body growth through transcriptomic analysis of pituitary and epiphyseal tissues of smaller sized Debao ponies and Mongolian horses at the juvenile and adult stages.

Results: We found that growth hormone receptor (GHR) was expressed at low levels in long bones, although growth hormone (GH) was highly expressed in Debao ponies compared with Mongolian horses. Moreover, significant downregulated of the GHR pathway components m-RAS and ATF3 was found in juvenile ponies, which slowed the proliferation of bone osteocytes. However, WNT2 and PLCβ2 were obviously upregulated in juvenile Debao ponies, which led to premature mineralization of the bone extracellular matrix. Furthermore, we found that the WNT/Ca pathway may be responsible for regulating body growth. GHR was demonstrated by q-PCR and Western blot analyses to be expressed at low levels in long bones of Debao ponies. Treatment with WNT antagonistI decreased the expression of WNT pathway components (P < 0.05) in vitro. Transduction of ATDC5 cells with a GHR-RNAi lentiviral vector decreased the expression of the GHR pathway components (P < 0.05). Additionally, the expression of the IGF-1 gene in the liver was lower in Debao ponies than in Mongolian horses at the juvenile and adult stages. Detection of plasma hormone concentrations showed that Debao ponies expressed higher levels of IGF-1 as juveniles and higher levels of GH as adults than Mongolian horses, indicating that the hormone regulation in Debao ponies differs from that in Mongolian horses.

Conclusion: Our work provides insights into the genetic regulation of short stature growth in mammals and can provide useful information for the development of therapeutic strategies for small size.
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http://dx.doi.org/10.1186/s12864-020-07323-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814589PMC
January 2021

Polymer-conjugated glucosamine complexed with boric acid shows tumor-selective accumulation and simultaneous inhibition of glycolysis.

Biomaterials 2021 02 26;269:120631. Epub 2020 Dec 26.

Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan and Department of Molecular Pathology, Division of Health Sciences, And Graduate School of Medicine, Osaka University, Osaka, Japan; BioDynamics Research Foundation, Kumamoto, 862-0954, Japan; Tohoku University, Sendai, Japan. Electronic address:

We synthesized unique water-soluble synthetic-polymer, styrene-maleic acid copolymer (SMA) conjugated glucosamine (SG); which formed a stable complex with boric acid (BA). This complex had a mean particle size of 15 nm by light scattering, and single peak in gel permeation chromatography. The particles were taken up by tumor cells five times faster than free BA in vitro and liberated BA at acidic tumor pH (5-7). Liberated BA inhibited glycolysis and resulted in tumor suppression in vivo. Intravenously injected SGB-complex did bind with albumin, and plasma half-life was about 8 h in mice, and accumulated to tumor tissues about 10 times more than in normal organs. IC of SGB-complex for HeLa cells under pO of 6-9% was about 20 μg/ml (free BA equivalent), 150 times more potent than free BA. Neutron irradiation of human oral cancer cells with SGB-complex resulted in 16 times greater cell-killing than that without SGB-complex. In vivo antitumor effect was evaluated after neutron irradiation only once in SCC VII tumor bearing mice and significant tumor suppression was confirmed. These results indicate that SGB-complex is a unique multifunctional anticancer agent with much more potent activity under low pO conditions as in large advanced cancers.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120631DOI Listing
February 2021

Factors affecting the dynamics and heterogeneity of the EPR effect: pathophysiological and pathoanatomic features, drug formulations and physicochemical factors.

Expert Opin Drug Deliv 2021 Jan 29:1-14. Epub 2021 Jan 29.

Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.

Introduction: The enhanced permeability and retention (EPR) effect serves as the foundation of anticancer nanomedicine design. EPR effect-based drug delivery is an effective strategy for most solid tumors. However, the degree of efficacy depends on the pathophysiological conditions of tumors, drug formulations, and other factors.

Areas Covered: Vascular mediators including nitric oxide, bradykinin , and prostaglandins are vital for facilitating and maintaining EPR effect dynamics. Progression to large, advanced cancers may induce activated blood coagulation cascades, which lead to thrombus formation in tumor vasculature. Rapidly growing tumors cause obstructed or suppressed blood flow in tumor vasculature related to embolism or occluded blood vessels. The resulting limited tumor blood flow leads to less drug delivered to tumors, i.e. no or poor EPR effect. High stromal content also suppresses vascular permeability and drug diffusion. Restoring obstructed tumor blood flow and improving tumor vascular permeability via vascular mediators will improve drug delivery and the EPR effect. Physicochemical features of nanomedicines also influence therapeutic outcomes and are vital for the EPR effect.

Expert Opinion: The tumor microenvironment, especially tumor blood flow, is critical for a potent EPR effect. A rational strategy for circumventing EPR effect barriers must include restoring tumor blood flow.
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http://dx.doi.org/10.1080/17425247.2021.1874916DOI Listing
January 2021