Publications by authors named "Jingjing Ji"

43 Publications

Effects of hypertension on the outcomes of COVID-19: a multicentre retrospective cohort study.

Ann Med 2021 12;53(1):770-776

Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Southern Medical University, Guangzhou, China.

Hypertension is thought to be a contributor to mortality in coronavirus disease 2019 patients; however, limited clinical data on the outcomes of COVID-19 in patients with hypertension are available. This study was designed to confirm whether hypertension affects the outcomes of COVID-19. A total of 983 patients with COVID-19 (female, 48%; male, 52%) were enrolled. Significantly higher odds of 60-day mortality ( = .017) were observed in the hypertensive group. In the hypertensive group, even after adjustment in multivariate analysis, the subgroup of patients 70 years old and older had higher 28-day mortality and total 60-day mortality rates than the other age subgroups (both < .05). A total of 297 (89%) COVID-19 patients with hypertension survived, and 35 (11%) died. In addition, compared with hypertensive patients who survived COVID-19, non-survivors had more pre-existing conditions, including cardiovascular diseases and stroke, higher blood pressure on admission, more severe inflammation, and more liver and kidney damage. Hypertension does not affect the outcome of COVID-19, which is different than the conclusions drawn in other studies. However, the 28-day mortality and total 60-day mortality rates of hypertensive patients (age ≥ 70) with COVID-19 were significantly elevated, and compared with the group of survivors, non-surviving COVID-19 patients with hypertension were older, had more basic diseases and had a more severe clinical condition.
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http://dx.doi.org/10.1080/07853890.2021.1931957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183539PMC
December 2021

The MYB family transcription factor TuODORANT1 from Triticum urartu and the homolog TaODORANT1 from Triticum aestivum inhibit seed storage protein synthesis in wheat.

Plant Biotechnol J 2021 May 5. Epub 2021 May 5.

State Key Laboratory of Plant Cell and Chromosome Engineering, National Center for Plant Gene Research, Institute of Genetics and Developmental Biology/Innovative Academy of Seed Design, Chinese Academy of Sciences, Beijing, China.

Seed storage proteins (SSPs) are determinants of wheat end-product quality. SSP synthesis is mainly regulated at the transcriptional level. Few transcriptional regulators of SSP synthesis have been identified in wheat and this study aims to identify novel SSP gene regulators. Here, the R2R3 MYB transcription factor TuODORANT1 from Triticum urartu was found to be preferentially expressed in the developing endosperm during grain filling. In common wheat (Triticum aestivum) overexpressing TuODORANT1, the transcription levels of all the SSP genes tested by RNA-Seq analysis were reduced by 49.71% throughout grain filling, which contributed to 13.38%-35.60% declines in the total SSP levels of mature grains. In in vitro assays, TuODORANT1 inhibited both the promoter activities and the transcription of SSP genes by 1- to 13-fold. The electrophoretic mobility shift assay (EMSA) and ChIP-qPCR analysis demonstrated that TuODORANT1 bound to the cis-elements 5'-T/CAACCA-3' and 5'-T/CAACT/AG-3' in SSP gene promoters both in vitro and in vivo. Similarly, the homolog TaODORANT1 in common wheat hindered both the promoter activities and the transcription of SSP genes by 1- to 112-fold in vitro. Knockdown of TaODORANT1 in common wheat led to 14.73%-232.78% increases in the transcription of the tested SSP genes, which contributed to 11.43%-19.35% elevation in the total SSP levels. Our data show that both TuODORANT1 and TaODORANT1 are repressors of SSP synthesis.
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http://dx.doi.org/10.1111/pbi.13604DOI Listing
May 2021

Neutrophil in Reverse Migration: Role in Sepsis.

Authors:
Jingjing Ji Jie Fan

Front Immunol 2021 15;12:656039. Epub 2021 Mar 15.

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. During the development and progression of sepsis, polymorphonuclear neutrophils (PMNs) are the most abundantly recruited innate immune cells at sites of infection, playing critical roles in the elimination of local infection and healing of the injury. PMN reverse migration (rM) describes the phenomenon in which PMNs migrate away from the inflammatory site back into the vasculature following the initial PMN infiltration. The functional role of PMN rM within inflammatory scenarios requires further exploration. Current evidence suggests that depending on the context, PMN rM can be both a protective response, by facilitating an efficient resolution to innate immune reaction, and also a tissue-damaging event. In this review, we provide an overview of current advancements in understanding the mechanism and roles of PMN rM in inflammation and sepsis. A comprehensive understanding of PMN rM may allow for the development of novel prophylactic and therapeutic strategies for sepsis.
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http://dx.doi.org/10.3389/fimmu.2021.656039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006006PMC
March 2021

A novel NAC family transcription factor SPR suppresses seed storage protein synthesis in wheat.

Plant Biotechnol J 2021 May 4;19(5):992-1007. Epub 2021 Jan 4.

State Key Laboratory of Plant Cell and Chromosome Engineering, National Center for Plant Gene Research, Institute of Genetics and Developmental Biology/Innovation Academy of Seed Design, Chinese Academy of Sciences, Beijing, China.

The synthesis of seed storage protein (SSP) is mainly regulated at the transcriptional level. However, few transcriptional regulators of SSP synthesis have been characterized in common wheat (Triticum aestivum) owing to the complex genome. As the A genome donor of common wheat, Triticum urartu could be an elite model in wheat research considering its simple genome. Here, a novel NAC family transcription factor TuSPR from T. urartu was found preferentially expressed in developing endosperm during grain-filling stages. In common wheat transgenically overexpressing TuSPR, the content of total SSPs was reduced by c. 15.97% attributed to the transcription declines of SSP genes. Both in vitro and in vivo assays showed that TuSPR bound to the cis-element 5'-CANNTG-3' distributed in SSP gene promoters and suppressed the transcription. The homolog in common wheat TaSPR shared a conserved function with TuSPR on SSP synthesis suppression. The knock-down of TaSPR in common wheat resulted in 7.07%-20.34% increases in the total SSPs. Both TuSPR and TaSPR could be superior targets in genetic engineering to manipulate SSP content in wheat, and this work undoubtedly expands our knowledge of SSP gene regulation.
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http://dx.doi.org/10.1111/pbi.13524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131056PMC
May 2021

Early, low-dose, short-term methylprednisolone decreased the mortality in critical COVID-19 patients: A multicenter retrospective cohort study.

J Infect 2021 04 8;82(4):84-123. Epub 2020 Nov 8.

Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, China; Key Laboratory of Hot Zone Trauma Care and Tissue Repair of PLA, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, China; The First School of Clinical Medicine, Southern Medical University, Guangzhou, 510010, China. Electronic address:

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http://dx.doi.org/10.1016/j.jinf.2020.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649028PMC
April 2021

Clinical efficacy of intravenous immunoglobulin therapy in critical ill patients with COVID-19: a multicenter retrospective cohort study.

Clin Transl Immunology 2020 14;9(10):e1192. Epub 2020 Oct 14.

Department of Critical Care Medicine General Hospital of Southern Theater Command of PLA Guangzhou 510010 China.

Objective: Coronavirus disease 2019 (COVID-19) outbreak is a major challenge all over the world, without acknowledged treatment. Intravenous immunoglobulin (IVIG) has been recommended to treat critical coronavirus disease 2019 (COVID-19) patients in a few reviews, but the clinical study evidence on its efficacy in COVID-19 patients was lacking.

Methods: 325 patients with laboratory-confirmed critical COVID-19 were enrolled from 4 government-designated COVID-19 treatment centres in southern China from December 2019 to March 2020. The primary outcomes were 28- and 60-day mortality, and the secondary outcomes were the total length of in-hospital and the total duration of the disease. Subgroup analysis was carried out according to clinical classification of COVID-19, IVIG dosage and timing.

Results: In the enrolled 325 patients, 174 cases used IVIG and 151 cases did not. The 28-day mortality was improved with IVIG after adjusting confounding in overall cohort (0.0014), and the in-hospital and the total duration of disease were longer in the IVIG group ( < 0.001). Subgroup analysis showed that only in patients with critical type, IVIG could significantly reduce the 28-day mortality, decrease the inflammatory response and improve some organ functions (all  < 0.05); the application of IVIG in the early stage (admission ≤ 7 days) with a high dose (> 15 g per day) exhibited significant reduction in 60-day mortality in the critical-type patients.

Conclusion: Early administration of IVIG with high dose improves the prognosis of critical-type patients with COVID-19. This study provides important information on clinical application of IVIG in the treatment of SARS-CoV-2 infection, including patient selection and administration dosage and timing.
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http://dx.doi.org/10.1002/cti2.1192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557105PMC
October 2020

Glucocorticoid therapy does not delay viral clearance in COVID-19 patients.

Crit Care 2020 09 21;24(1):565. Epub 2020 Sep 21.

Department of Critical Care Medicine, General Hospital of Southern Theater Command of PLA, Guangzhou, 510010, China.

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http://dx.doi.org/10.1186/s13054-020-03287-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503440PMC
September 2020

Retrospective study of quadratus lumborum block for postoperative analgesia in patients undergoing percutaneous nephrolithotomy.

BMC Anesthesiol 2020 08 31;20(1):217. Epub 2020 Aug 31.

Department of Anesthesiology, Drum Tower Hospital Affiliated Nanjing University Medical School, Road 321#, Nanjing, Zhongshan, 210008, China.

Background: The postoperative analgesic effect of transmuscular quadratus lumborum block (QLB-TM) in patients following lower abdominal surgeries has been identified; however, the efficacy of QLB using the lateral approach (QLB-L) is still in debate. Therefore, this retrospective study was conducted to investigate the effect of a single-shot block with QLB-L on postoperative analgesia for patients undergoing percutaneous nephrolithotomy (PCNL).

Methods: The medical information of the patients undergoing PCNL was retrieved from the electronic charter system (Medisystem, Suzhou, China) in our Nanjing Drum Tower Hospital during the period of Jan/2019 to Jun/2019. Among the total of 57 patients, there are 17, 18, and 22 patients subjected to QLB-L, QLB-TM, or routine treatment, respectively. The primary observational parameter was to assess postoperative pain with visual analog scales (VAS) at rest 30 min after extubation, 24 h, and 48 h after surgery, respectively. The secondary observatory endpoints, including the consumption of intraoperative opioids, the cumulative dose of non-steroid anti-inflammatory drugs (NSAIDs) and the incidence of adverse events related to postoperative analgesia, were evaluated as well.

Results: The static VAS score at 24 h after surgery and the intraoperative consumption of sufentanil were significantly lower in patients receiving either intervention of QLB-L or QLB-TM as compared with those receiving routine treatment. However, one shot of QLB had no impact on VAS scores at 30 min post-extubation, 48 h after PCNL procedure compared with the patients receiving routine treatment. The percentage of non-ambulatory patients within 24 h post-PCNL was significantly higher in the QLB-TM group compared with the routine treatment group (P = 0.04). There were no significant differences in the incidence of postoperative nausea and vomit (PONV), itches, respiratory depression, the time for the first defecation, and the length of hospital stay (LOS) among the three groups.

Conclusions: QLB-L procedure may exert as equivalent as QLB-TM in terms of abrogating postoperative pain within 24 h post-surgery and decreasing intraoperative sufentanil consumption in patients undergoing PCNL procedure as well. The caution should be taken to avoid lower extremities weakness in the patients after QLB-TM within the first 24 h post-PCNL procedure.
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http://dx.doi.org/10.1186/s12871-020-01134-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457541PMC
August 2020

First Report of Purple Spot on Dandelion in China Caused by Alternaria tenuissima.

Plant Dis 2020 Aug 21. Epub 2020 Aug 21.

NO.600 Changjiang Street Xiangfang DistrictHarbin, China, 150030;

Dandelion (Taraxacum mongolicum) is a perennial herb of the family Asteraceae, with a high edible and medicinal value and widely grown at medium and low altitudes in China. In July 2019, purple spot of dandelion was found in a field near Harbin City, Heilongjiang province, China. The disease incidence regionally reached 95% in fields with yield losses between 10 and 20%, seriously reducing the economic and food value of dandelion. Multiple, irregular brown spots were first observed on the leaves of this plant- that later developed into circular or near-circular purple spots with raised centers, or purple lesions along the veins. When the leaf spots coalesced, the value of the commodity was lost. To isolate the pathogen, 5 × 5 mm pieces of leaf tissue from the margins of lesions were surface disinfected in 75% alcohol, rinsed in distilled water, and incubated on potato dextrose agar (PDA) plates at 28℃ until sporulation. Using single-spore isolation, a pure culture (YY-1) was obtained with abundant grayish white hyphae that later turned olive green. The underside of the colonies were brown. Conidia were typically obclavate, had a short beak with 1 to 6, but usually 3, transverse septa, and up to 3 longitudinal septa. The transverse septum was thicker and the wall of the conidium appeared brick-like. Conidia were pale brown, catenulate, and measured from 25 to 42 μm long by 6 to 10 μm wide. YY-1 was identified as Alternaria sp. based on morphological characteristics (Simmons 2007). Molecular identification was performed to detect the fungal species, and included the Internal Transcribed Spacer (ITS), translation elongation factor 1-alpha (EF1), actin gene (ACT), plasma membrane ATPase gene (ATP), and the calmodulin gene (CAL), which were respectively amplified with primers ITS4/ITS5 (Guo et al. 2012), EF1-728F/EF1-986R (Carbone and Kohn 1999), ACT-512F/ACT-783R (Carbone and Kohn 1999), and ATPDF1/ATPDR1 and CALDF1/CALDR1 (Lawrence 2013) (GenBank Accession Nos. MN746334, MT627208, MT627209, MT558864, MT558865). The species of Alternaria could not be confirmed by sequencing the above genes, as described previously (Zheng et al. 2015). Hence, a partial coding sequence of the histone 3 gene (GenBank Accession No. MN744235) was amplified using primers H3-1a/H3-1b (Zheng et al. 2015) and it shared 98.09% sequence identity with A. tenuissima (KP267543). The ITS sequence (MN746334) was 99.81% similar to the reference sequences of A. tenuissima (KT223327) in GenBank. A Maximum-likelihood tree was then reconstructed based on the ITS, CAL, and ATP sequences by MEGA7, which showed that YY-1 was most closely related to A. tenuissima. Therefore, YY-1 was identified as A. tenuissima based on its morphological and molecular characteristics. To perform Koch's postulates, 20 healthy leaves from greenhouse-grown dandelion were inoculated with 5-μL drops of a conidial suspension (1 x 105 conidia/ml) of isolate YY-1. Sterile water was used as a control. The inoculated plants were placed in a growth chamber at 28℃ and 80 to 90% relative humidity. After 10 days, similar symptoms were observed on plants inoculated with YY-1, while control plants did not produce symptoms. The pathogen was reisolated from the inoculated leaves and identified by morphological and molecular methods as A. tenuissima. To our knowledge, this is the first report of A. tenuissima causing purple spot on T. mongolicum in China.
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http://dx.doi.org/10.1094/PDIS-05-20-1037-PDNDOI Listing
August 2020

Identification and genetic analysis of EMS-mutagenized wheat mutants conferring lesion-mimic premature aging.

BMC Genet 2020 08 17;21(1):88. Epub 2020 Aug 17.

Institute of Crop Science, Chinese Academy of Agricultural Sciences, Beijing, 10081, China.

Background: Lesion-mimic and premature aging (lmpa) mutant lmpa1 was identified from the ethyl methane sulfonate (EMS) mutant library in the bread wheat variety Keda 527 (KD527) background. To reveal the genetic basis of lmpa1 mutant, phenotypic observations and analyses of chlorophyll content and photosynthesis were carried out in lmpa1, KD527 and their F and F derivatives. Further, bulked segregation analysis (BSA) in combination with a 660 K SNP array were conducted on the F segregation population of lmpa1/Chinese spring (CS) to locate the lmpa1 gene.

Results: Most agronomic traits of lmpa1 were similar to those of KD527 before lesion-like spots appeared. Genetic analysis indicated that the F plants from the crossing of lmpa1 and KD527 exhibited the lmpa phenotype and the F progenies showed a segregation of normal (wild type, WT) and lmpa, with the ratios of lmpa: WT = 124:36(χ = 1.008 < =3.841), indicating that lmpa is a dominant mutation. The combination of BSA and the SNP array analysis of CS, lmpa1 and lmpa1/CS F WT pool (50 plants) and lmpa pool (50 plants) showed that polymorphic SNPs were enriched on chromosome 5A, within a region of 30-40 Mb, indicating that the wheat premature aging gene Lmpa1 was probably located on the short arm of chromosome 5A.

Conclusions: EMS-mutagenized mutant lmpa1 deriving from elite wheat line KD527 conferred lmpa. Lmpa phenotype of lmpa1 mutant is controlled by a single dominant allele designated as Lmpa1, which affected wheat growth and development and reduced the thousand grain weight (tgw) of single plant in wheat. The gene Lmpa1 was tentatively located within the region of 30-40 Mb near to the short arm of chromosome 5A.
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http://dx.doi.org/10.1186/s12863-020-00891-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430028PMC
August 2020

Intraoperative venous air embolism in the non-cardiac surgery-the role of perioperative echocardiography in a case series report.

Ann Transl Med 2020 Jun;8(12):798

Department of Anesthesia, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China.

Venous air embolism (VAE) is commonly one of the iatrogenic complications associated with divergent high-risk surgeries. In this case-series report, we presented a series of VAE cases in our institute during the last 6 consecutive years. There were total of nine cases suspected to be VAE according the clinical symptom and signs, of which seven cases were definitively diagnosed VAE using transthoracic echocardiography (TTE). We also reported two presumptive cases of paradoxical VAE during hepatectomy in this case series, furthermore, the cause, complications and hazards secondary to paradoxical VAE were discussed as well. All cases had an uneventful recovery from VAE with the assistance of TTE as well as other therapeutic management of VAE, except one neurosurgical patient died from postoperative hemorrhagic stroke per se. Therefore, VAE or paradoxical air embolism can occur during various non-cardiac operations and the significance of perioperative ultrasound should be emphasized in the treatment of VAE.
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http://dx.doi.org/10.21037/atm-20-497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333140PMC
June 2020

Protective effects of rolipram on endotoxic cardiac dysfunction via inhibition of the inflammatory response in cardiac fibroblasts.

BMC Cardiovasc Disord 2020 05 24;20(1):242. Epub 2020 May 24.

Guangdong Provincial Key Laboratory of Proteomics; School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.

Background: Cardiac fibroblasts, regarded as the immunomodulatory hub of the heart, have been thought to play an important role during sepsis-induced cardiomyopathy (SIC). However, the detailed molecular mechanism and targeted therapies for SIC are still lacking. Therefore, we sought to investigate the likely protective effects of rolipram, an anti-inflammatory drug, on lipopolysaccharide (LPS)-stimulated inflammatory responses in cardiac fibroblasts and on cardiac dysfunction in endotoxic mice.

Method: Cardiac fibroblasts were isolated and stimulated with 1 μg/ml LPS for 6 h, and 10 μmol/l rolipram was administered for 1 h before LPS stimulation. mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) in fibroblasts and their protein concentrations in supernatant were measured with real-time PCR (rt-PCR) and enzyme-linked immunosorbent assay, respectively. The expression of dual specificity phosphatase 1 (DUSP1), an endogenous negative regulator that inactivates MAPK-mediated inflammatory pathways, was also measured by rt-PCR and western blotting. DUSP1-targeted small interfering RNA (siRNA) was used to examine the specific role of DUSP1. To evaluate the role of rolipram in vivo, an endotoxic mouse model was established by intraperitoneal injection of 15 mg/kg LPS, and 10 mg/kg rolipram was intraperitoneally injected 1 h before LPS injection. mRNA and protein levels of inflammatory cytokines and DUSP1 in heart, inflammatory cell infiltration and cardiac function were all examined at 6 h after LPS injection.

Results: The results showed that LPS could increase the expression and secretion of inflammatory cytokines and decrease the transcription and expression of DUSP1 in cardiac fibroblasts. However, rolipram pretreatment significantly reversed the LPS-induced downregulation of DUSP1 and inhibited LPS-induced upregulation and secretion of TNF-α and IL-6 but not IL-1β. Moreover, DUSP1-targeted siRNA experiments indicated that the protective effect of rolipram on inflammatory response was specific dependent on DUSP1 expression. Moreover, rolipram could further reduce inflammatory cell infiltration scores as shown by pathological analysis and increase the ejection fraction (EF) detected with echocardiography in the hearts of endotoxic mice.

Conclusions: Rolipram could improve endotoxin-induced cardiac dysfunction by upregulating DUSP1 expression to inhibit the inflammatory response in cardiac fibroblasts, which may be a potential treatment for SIC.
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http://dx.doi.org/10.1186/s12872-020-01529-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247226PMC
May 2020

MSCs Contribute to the Conversion of Ly6C Monocytes into Ly6C Subsets under AMI.

Stem Cells Int 2020 13;2020:2460158. Epub 2020 Jan 13.

Department of Cardiology, Zhongda Hospital Affiliated with Southeast University, Lishui Branch, China.

Background: Ly6C monocytes are inflammatory cells that accumulate in an infarcted myocardium, and Ly6C monocytes are believed to be reparative and curb myocardial remodeling. NR4A1 is a novel target for modulating the inflammatory phenotype of monocytes during atherogenesis.

Objectives: We aimed to investigate whether MSCs can contribute to the heterogeneity of Ly6C monocytes differentiated into Ly6C monocytes and whether this regulation is related to nuclear receptor NR4A1.

Methods: Ly6C monocytes were first cocultured with MSCs. C57BL/6 mice and C57BL/6 wild-type mice were then used to construct AMI models, and survival functions in the two groups were further compared. Ly6C monocytes in circulation and in MI tissue of C57BL/6 AMI mice with or without MSC transplantation were determined by flow cytometry at day 1 and day 3. NR4A1 expression was further determined by Western blot. Apoptosis of cardiac myocytes in the infarct border zone at day 3 and day 7 was identified by TUNEL kits. Angiogenesis in the AMI heart at day 7 and day 21 was determined through immunohistochemistry by CD31.

Results: We first demonstrated that the percentage of Ly6C monocytes increased greatly after 3 days of coculture with MSCs (12.8% ± 3.77% vs. 3.69% ± 0.74%, < 0.001). The expression of NR4A1 in Ly6C monocytes was also significantly elevated at that time (1.81 ± 0.46 vs. 0.43 ± 0.09, < 0.001). Following AMI, the percentage of circulating Ly6C monocytes in C57BL/6 mice was significantly lower than that in C57BL/6 wild-type mice (4.36% ± 1.27% vs. 12.17% ± 3.81%, < 0.001). The survival rate of C57BL/6 mice (25%) was significantly lower than that of C57BL/6 wild-type mice (56.3%) after AMI ( = 4.343, = 0.037). After MSCs were transplanted, we observed a significant increase in Ly6C monocytes both in circulation (16.7% ± 3.67% vs. 3.22% ± 0.44%, < 0.001) and in the MI heart (3.31% ± 0.69% vs. 0.42% ± 0.21%, < 0.001) of C57BL/6 mice. Western blot analysis further showed that the expression level of NR4A1 in the MI hearts of C57BL/6 mice increased significantly under MSC transplantation (0.39 ± 0.10 vs. 0.11 ± 0.04, < 0.001). We also found significantly decreased TUNEL cardiac myocytes (15.45% ± 4.42% vs. 22.78% ± 6.40%, < 0.001) in mice with high expression levels of NR4A1 compared to mice with low expression levels. Meanwhile, we further identified increased capillary density in the infarct zones of mice with high expression levels of NR4A1 (0.193 ± 0.036 vs. 0.075 ± 0.019, < 0.001) compared to mice with low expression levels 21 days after AMI.

Conclusions: MSCs can control the heterogeneity of Ly6C monocyte differentiation into Ly6C monocytes and further reduce inflammation after AMI. The underlying mechanism might be that MSCs contribute to the increased expression of NR4A1 in Ly6C monocytes.
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http://dx.doi.org/10.1155/2020/2460158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201476PMC
January 2020

Comprehensive analysis of the SLC16A gene family in pancreatic cancer via integrated bioinformatics.

Sci Rep 2020 04 30;10(1):7315. Epub 2020 Apr 30.

Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.

SLC16A family members play crucial roles in tumorigenesis and tumor progression. However, the exact role of distinct members in the SLC16A family in human pancreatic cancer remains unclear. Integrated bioinformatics analysis for the identification of therapeutic targets for certain cancers based on transcriptomics, proteomics and high-throughput sequencing could help us obtain novel information and understand potential underlying molecular mechanisms. In the present study, we investigated SLC16A family members in pancreatic cancer through accumulated data from GEO (Gene Expression Omnibus), TCGA (The Cancer Genome Atlas) and other available databases. The expression profile, clinical application significance and prognostic value of the SLC16A family for patients with pancreatic cancer were explored. SLC16A1, SLC16A3 and SLC16A13 exhibited biomarker potential for prognosis, and we further identified their related genes and regulatory networks, revealing core molecular pathways that require further investigation for pancreatic cancer.
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http://dx.doi.org/10.1038/s41598-020-64356-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193566PMC
April 2020

Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production.

Exp Mol Med 2020 04 28;52(4):702-712. Epub 2020 Apr 28.

Department of Anesthesia, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.

To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogen-activated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4 and Tg-CAST mice but not in LYZ/Capn4 mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.
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http://dx.doi.org/10.1038/s12276-020-0426-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210976PMC
April 2020

The multifaceted roles of long noncoding RNAs in pancreatic cancer: an update on what we know.

Cancer Cell Int 2020 5;20:41. Epub 2020 Feb 5.

1Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 XueFu Avenue, Harbin, 150086 People's Republic of China.

Pancreatic cancer (PC) is one of the leading causes of cancer-related deaths worldwide. Due to the shortage of effective biomarkers for predicting survival and diagnosing PC, the underlying mechanism is still intensively investigated but poorly understood. Long noncoding RNAs (lncRNAs) provide biological functional diversity and complexity in protein regulatory networks. Scientific studies have revealed the emerging functions and regulatory roles of lncRNAs in PC behaviors. It is worth noting that some in-depth studies have revealed that lncRNAs are significantly associated with the initiation and progression of PC. As lncRNAs have good properties for both diagnostic and prognostic prediction due to their translation potential, we herein address the current understanding of the multifaceted roles of lncRNAs as regulators in the molecular mechanism of PC. We also discuss the possibility of using lncRNAs as survival biomarkers and their contributions to the development of targeted therapies based on the literature. The present review, based on what we know about current research findings, may help us better understand the roles of lncRNAs in PC.
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http://dx.doi.org/10.1186/s12935-020-1126-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003405PMC
February 2020

An Early Neutrophil Recruitment into the Infectious Site Is Critical for Bacterial Lipoprotein Tolerance-Afforded Protection against Microbial Sepsis.

J Immunol 2020 01 4;204(2):408-417. Epub 2019 Dec 4.

Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China;

Bacterial lipoprotein (BLP)-induced tolerance represents an essential regulatory mechanism during bacterial infection and has been shown to protect against microbial sepsis. This protection is generally attributed to BLP-tolerized monocytes/macrophages characterized by hyporesponsiveness in producing inflammatory cytokines and, simultaneously, an augmented antimicrobial activity. However, the contribution of polymorphonuclear neutrophils (PMNs), another major player in innate immunity against bacterial infection, to BLP tolerance-afforded protection against microbial sepsis has not been identified. In this study, we report that induction of BLP tolerance protected mice against cecal ligation and puncture-induced polymicrobial sepsis, with significantly improved survival. Importantly, BLP tolerization via i.p. injection triggered an early PMN recruitment even before bacterial infection and promoted further PMN influx into the infectious site (i.e., the peritoneal cavity upon cecal ligation and puncture-associated septic challenge). Notably, this early PMN influx was mediated by BLP tolerization-induced PMN chemoattractant CXCL2-formed concentration gradient between the circulation and peritoneal cavity. Critically, blockage of PMN influx with the CXCR2 antagonist SB225002 abolished BLP tolerance-afforded protection and rendered BLP-tolerized mice more vulnerable to microbial infection with impaired bacterial clearance and increased overall mortality. Thus, our results highlight that an early recruitment of PMNs in the infectious site, as an important cellular mechanism, contributes to BLP tolerance-afforded protection against microbial sepsis.
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http://dx.doi.org/10.4049/jimmunol.1801602DOI Listing
January 2020

Exfoliation and Sensitization of 2D Carbon Nitride for Photoelectrochemical Biosensing under Red Light.

Chemistry 2019 Dec 4;25(68):15680-15686. Epub 2019 Nov 4.

Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, School of Chemistry and Chemical Engineering, Medical School, Southeast University, Nanjing, 211189, P.R. China.

Two-dimensional carbon nitride (CN) has drawn increasing attention as a conjugated metal-free polymer for photoelectrochemical (PEC) biosensing. However, CN only absorbs ultraviolet and very limited visible light (λ<460 nm), which poses potential risks for biomolecules and also cannot pass through tissue for in vivo detection. Herein, simultaneous exfoliation and functionalization of CN nanosheets (CNNS) with copper phthalocyanine (TsCuPc) simply by mechanical milling, thanks to the delicate π-π interaction between them, is reported. Moreover, due to energy-level matching, an effective donor-acceptor (D-A) interaction with much-improved photocurrent under irradiation with red light (λ>630 nm) was observed for the as-prepared CNNS-TsCuPc. As an example, dopamine in blood was detected by using red light by a CNNS-TsCuPc photoelectrode with uncompromised linear range and detection limit, as well high selectivity. As one of the few successful demonstrations of red-light-responsive PEC sensing systems, this work takes a first step toward future in vivo applications by enriching the optoelectronic properties of CN with task-specific antenna molecules via D-A interaction.
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http://dx.doi.org/10.1002/chem.201904076DOI Listing
December 2019

The improved assembly of 7DL chromosome provides insight into the structure and evolution of bread wheat.

Plant Biotechnol J 2020 03 18;18(3):732-742. Epub 2019 Sep 18.

State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy and Yangling Branch of China Wheat Improvement Center, Northwest A&F University, Yangling, Shaanxi, China.

Wheat is one of the most important staple crops worldwide and also an excellent model species for crop evolution and polyploidization studies. The breakthrough of sequencing the bread wheat genome and progenitor genomes lays the foundation to decipher the complexity of wheat origin and evolutionary process as well as the genetic consequences of polyploidization. In this study, we sequenced 3286 BACs from chromosome 7DL of bread wheat cv. Chinese Spring and integrated the unmapped contigs from IWGSC v1 and available PacBio sequences to close gaps present in the 7DL assembly. In total, 8043 out of 12 825 gaps, representing 3 491 264 bp, were closed. We then used the improved assembly of 7DL to perform comparative genomic analysis of bread wheat (Ta7DL) and its D donor, Aegilops tauschii (At7DL), to identify domestication signatures. Results showed a strong syntenic relationship between Ta7DL and At7DL, although some small rearrangements were detected at the distal regions. A total of 53 genes appear to be lost genes during wheat polyploidization, with 23% (12 genes) as RGA (disease resistance gene analogue). Furthermore, 86 positively selected genes (PSGs) were identified, considered to be domestication-related candidates. Finally, overlapping of QTLs obtained from GWAS analysis and PSGs indicated that TraesCS7D02G321000 may be one of the domestication genes involved in grain morphology. This study provides comparative information on the sequence, structure and organization between bread wheat and Ae. tauschii from the perspective of the 7DL chromosome, which contribute to better understanding of the evolution of wheat, and supports wheat crop improvement.
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http://dx.doi.org/10.1111/pbi.13240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004910PMC
March 2020

MicroRNA-124: An emerging therapeutic target in cancer.

Cancer Med 2019 09 6;8(12):5638-5650. Epub 2019 Aug 6.

Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

MicroRNAs (miRNAs) are noncoding single-stranded RNAs, approximately 20-24 nucleotides in length, known as powerful posttranscriptional regulators. miRNAs play important regulatory roles in cellular processes by changing messenger RNA expression and are widely involved in human diseases, including tumors. It has been reported in the literature that miRNAs have a precise role in cell proliferation, programmed cell death, differentiation, and expression of coding genes. MicroRNA-124 (miR-124) has reduced exparession in various human neoplasms and is believed to be related to the occurrence, development, and prognosis of malignant tumors. In our review, we focus on the specific molecular functions of miR-124 and the downstream gene targets in major cancers, which provide preclinical evidence for the treatment of human cancer. Although some obstacles exist, miR-124 is still attracting intensive research focus as a promising and effective anticancer weapon.
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http://dx.doi.org/10.1002/cam4.2489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745873PMC
September 2019

Sequencing of a Wild Apple (Malus baccata) Genome Unravels the Differences Between Cultivated and Wild Apple Species Regarding Disease Resistance and Cold Tolerance.

G3 (Bethesda) 2019 Jul;9(7):2051-2060

College of Life Sciences, Northwest A&F University, Yangling 712100, Shannxi, China.

Malus baccata is one of four wild apple species that can hybridize with the cultivated apple species (Malus domestica). It is widely used in high-latitude apple-producing areas as a rootstock and breeding resource because of its disease resistance, and cold tolerance. A lack of a reference genome has limited the application of M. baccata for apple breeding. We present a draft reference genome for M. baccata. The assembled sequence consisting of 665 Mb, with a scaffold N50 value of 452 kb, included transposable elements (413 Mb) and 46,114 high-quality protein-coding genes. According to a genetic map derived from 390 sibling lines, 72% of the assembly and 85% of the putative genes were anchored to 17 linkage groups. Many of the M. baccata genes under positive selection pressure were associated with plant-pathogen interaction pathways. We identified 2,345 Transcription factor-encoding genes in 58 families in the M. baccata genome. Genes related to disease defense and cold tolerance were also identified. A total of 462 putative nucleotide-binding site (NBS)-leucine-rich-repeat (LRR) genes, 177 Receptor-like kinase (RLK) and 51 receptor-like proteins (RLP) genes were identified in this genome assembly. The M. baccata genome contained 3978 cold-regulated genes, and 50% of these gene promoter containing DREB motif which can be induced by CBF gene. We herein present the first M. baccata genome assembly, which may be useful for exploring genetic variations in diverse apple germplasm, and for facilitating marker-assisted breeding of new apple cultivars exhibiting resistance to disease and cold stress.
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http://dx.doi.org/10.1534/g3.119.400245DOI Listing
July 2019

Sequencing of a Wild Apple () Genome Unravels the Differences Between Cultivated and Wild Apple Species Regarding Disease Resistance and Cold Tolerance.

G3 (Bethesda) 2019 07 9;9(7):2051-2060. Epub 2019 Jul 9.

College of Life Sciences, Northwest A&F University, Yangling 712100, Shannxi, China

is one of four wild apple species that can hybridize with the cultivated apple species (). It is widely used in high-latitude apple-producing areas as a rootstock and breeding resource because of its disease resistance, and cold tolerance. A lack of a reference genome has limited the application of for apple breeding. We present a draft reference genome for The assembled sequence consisting of 665 Mb, with a scaffold N50 value of 452 kb, included transposable elements (413 Mb) and 46,114 high-quality protein-coding genes. According to a genetic map derived from 390 sibling lines, 72% of the assembly and 85% of the putative genes were anchored to 17 linkage groups. Many of the genes under positive selection pressure were associated with plant-pathogen interaction pathways. We identified 2,345 Transcription factor-encoding genes in 58 families in the genome. Genes related to disease defense and cold tolerance were also identified. A total of 462 putative nucleotide-binding site (NBS)-leucine-rich-repeat (LRR) genes, 177 Receptor-like kinase (RLK) and 51 receptor-like proteins (RLP) genes were identified in this genome assembly. The genome contained 3978 cold-regulated genes, and 50% of these gene promoter containing DREB motif which can be induced by gene. We herein present the first genome assembly, which may be useful for exploring genetic variations in diverse apple germplasm, and for facilitating marker-assisted breeding of new apple cultivars exhibiting resistance to disease and cold stress.
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http://dx.doi.org/10.1534/g3.119.400245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643876PMC
July 2019

Fusobacterium nucleatum, the communication with colorectal cancer.

Biomed Pharmacother 2019 Aug 18;116:108988. Epub 2019 May 18.

Department of Pathology, The Second Affiliated Hospital of Harbin Medical University, 150080, Harbin, China. Electronic address:

Colorectal cancer (CRC) is the fourth most common cancer in 2018 with poor prognosis. Fusobacterium nucleatum (F.n), an anaerobe, is found to be enriched in both stools and tumor tissues of CRC patients. As surveys show, tumor initiates before the collection of F.n. In return, F.n helps cancer cells to build up tumor microenvironment and benefit for their chemo-resistant. The elements constituted the tumor environment, including neutrophils, macrophages and lymphocytes, contribute to the existing of tumor cells respectively. However, the integrated and interactive roles of those elements are poorly investigated. The intracellular molecular alteration MSI is a result of F.n infection and the microbiology-molecular pathological epidemiology (MPE) has become a new trend to analysis F.n and tumorigenesis. Chemoresistance of tumor cells is also affected by F.n induced microenvironment, or F.n achieves it directly. Finally, F.n could be a biomarker of CRC. All in all, our review will lay a foundation for the therapy of CRC through the interference of F.n and perspective to follow-up studies.
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http://dx.doi.org/10.1016/j.biopha.2019.108988DOI Listing
August 2019

Porous Hydrogel-Encapsulated Photonic Barcodes for Multiplex Detection of Cardiovascular Biomarkers.

ACS Sens 2019 05 19;4(5):1384-1390. Epub 2019 Apr 19.

Department of Cardiology , Zhongda Hospital Affiliated with Southeast University , Nanjing , Jiangsu 210009 , China.

Early detection of cardiac troponin I (cTnI), B-type natriuretic peptide (BNP), and myoglobin (Myo) is essential for the diagnosis of acute myocardial infarction (AMI) and heart failure (HF). We designed a porous hydrogel-encapsulated photonic crystal (PhC) barcode-based suspension array for multiple cardiovascular marker detection. The hybrid hydrogel was composed of polyethylene glycol diacrylate (PEGDA) and gelatin, resulting in a porous and hydrophilic scaffold which ensured stability of the PhC in aqueous solutions. The encapsulated PhC barcodes had stable diffraction peaks for the corresponding markers. Using a sandwich format, the proposed suspension array was used for simultaneous multiplex detection of cardiovascular biomarkers in a single tube. The immunoassay results we tested on cTnI, BNP, and Myo could be assayed in the ranges of 0.01 to 1000 ng/mL, 0.1 to 10 000 pg/mL, and 1 to 10 000 ng/mL with limits of detection of 0.009 ng/mL, 0.084 pg/mL, and 0.68 ng/mL at 3σ, respectively. This method also showed acceptable accuracy and repeated detection, and the results were consistent with the results of conventional clinical methods for detecting actual clinical samples. Therefore, suspension arrays based on hydrogel-encapsulated PhC barcodes are highly promising for AMI diagnosis.
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http://dx.doi.org/10.1021/acssensors.9b00352DOI Listing
May 2019

Inverse opal substrate-loaded mesenchymal stem cells contribute to decreased myocardial remodeling after transplantation into acute myocardial infarction mice.

Int J Nanomedicine 2018 2;13:7033-7046. Epub 2018 Nov 2.

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China,

Background: The two-dimensional incubation method is now the most commonly method for mesenchymal stem cell (MSC) production. however, gene expression and secretion of growth factors are relatively low; thus, the transplanted cells cannot be effectively utilized for potential clinical applications after acute myocardial infarction (AMI).

Objectives: We aimed to investigate whether our newly made substrates of inverse opal with specific surface microstructures for MSC culturing can increase the viability of the cells and can contributes to decreased myocardial remodeling after transplanted to AMI mice.

Methods: The inverse opal structure is fabricated by the convenient bottom-up approach of the self-assembly of colloidal nanoparticles. Mouse-derived MSCs were then cultured on the substrates when expanded at different times to investigate the cell growth status including morphology. Then the inverse opal substrates loaded MSCs were transplanted to AMI mice, cardiomyocyte apoptosis and LV remodeling were further compared. To explore the possible mechanisms of curation, the secretions and viability of MSCs on substrates were determined using mice ELISA kits and JC-1 mitochondrial membrane potential assay kits respectively at normal and hypoxic conditions.

Results: 6 times expanded inverse opals allowed greatly the orderly growth of MSCs as compared to four (34% ± 10.6%) and two (20%±7.2%) times expanded as well as unexpanded (13%±4.1%) (<0.001). Nearly 90% of MSCs showed orientation angle intervals of less than 30° when at the 6X expanded (89.6%±25%) compared to the percent of cells with 30°-60° (8.7%±2.6%) or ≥60° (1.7%±1.0%) orientation angle (<0.001). After inverse opal loaded MSCs transplanted to AMI mice, greatly decreased apoptosis of cardiomyocytes (20.45%±8.64% vs.39.63%±11.71%, <0.001) and infarction area (5.87±2.18 mm vs 9.31±3.11 mm, <0.001) were identified. In the end, the viability of inverse opal loaded MSCs determined by membrane potential (<0.001) and the secretion of growth factors including VEGF-α, SDF-1 and Ang-1 (<0.001) were both confirmed significantly higher than that of the conventional culture in petri dish.

Conclusion: The structure of inverse opal can not only adjust the arrangement of MSCs but also contribute to its orientated growth. Inverse opal loaded MSCs transplantation extremely curbed myocardial remodeling, the underlying mechanisms might be the high viability and extremely higher secretions of growth factors of MSCs as devoted by this method.
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http://dx.doi.org/10.2147/IJN.S178270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220438PMC
December 2018

Proteomic identification of hippocalcin and its protective role in heatstroke-induced hypothalamic injury in mice.

J Cell Physiol 2019 04 7;234(4):3775-3789. Epub 2018 Sep 7.

Department of Critical Care Medicine, General Hospital of Guangzhou Military Command, Guangzhou, China.

Heatstroke is a devastating condition that is characterized by severe hyperthermia and central nervous system dysfunction. However, the mechanism of thermoregulatory center dysfunction of the hypothalamus in heatstroke is unclear. In this study, we established a heatstroke mouse model and a heat-stressed neuronal cellular model on the pheochromocytoma-12 (PC12) cell line. These models revealed that HS promoted obvious neuronal injury in the hypothalamus, with high pathological scores. In addition, PC12 cell apoptosis was evident by decreased cell viability, increased caspase-3 activity, and high apoptosis rates. Furthermore, 14 differentially expressed proteins in the hypothalamus were analyzed by fluorescence two-dimensional difference gel electrophoresis and identified by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Expression changes in hippocalcin (HPAC), a downregulated neuron-specific calcium-binding protein, were confirmed in the hypothalamus of the heatstroke mice and heat-stressed PC12 cells by immunochemistry and western blot. Moreover, HPAC overexpression and HPAC-targeted small interfering RNA experiments revealed that HPAC functioned as an antiapoptotic protein in heat-stressed PC12 cells and hypothalamic injury. Lastly, ulinastatin (UTI), a cell-protective drug that is clinically used to treat patients with heatstroke, was used in vitro and in vivo to confirm the role of HPAC; UTI inhibited heat stress (HS)-induced downregulation of HPAC expression, protected hypothalamic neurons and PC12 cells from HS-induced apoptosis and increased heat tolerance in the heatstroke animals. In summary, our study has uncovered and demonstrated the protective role of HPAC in heatstroke-induced hypothalamic injury in mice.
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http://dx.doi.org/10.1002/jcp.27143DOI Listing
April 2019

Coupled Fluorometer-Potentiostat System and Metal-Free Monochromatic Luminophores for High-Resolution Wavelength-Resolved Electrochemiluminescent Multiplex Bioassay.

ACS Sens 2018 07 21;3(7):1362-1367. Epub 2018 Jun 21.

Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, School of Chemistry and Chemical Engineering, Medical School , Southeast University , Nanjing 211189 , China.

The sensitive simultaneous detection of multiple biomarkers is critical for the early diagnosis of diseases. Electrochemiluminescence (ECL) offers outstanding advantages, e.g., low background, over other optical sensing techniques. However, multiplexed ECL bioassay is hindered not only by the lack of generally available ECL spectrometers but also by the limited number of biocompatible monochromatic ECL luminophores for decades. Herein, we report addressing these issues by re-examination of the recent tabletop spectrofluorometer coupled potentiostat as a high-resolution ECL spectrum acquisition system and using carbon nitrides as monochromatic luminophores. A wavelength-resolved multiplexing ECL biosensor is demonstrated to simultaneously detect CA19-9 and mesothelin, two pancreatic cancer biomarkers, at a single-electrode interface. This work could initiate new opportunities for more general multiplex ECL biosensors with competitive performances.
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http://dx.doi.org/10.1021/acssensors.8b00292DOI Listing
July 2018

Competitive Multiple-Mechanism-Driven Electrochemiluminescent Detection of 8-Hydroxy-2'-deoxyguanosine.

J Am Chem Soc 2018 02 19;140(8):2801-2804. Epub 2018 Feb 19.

Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, School of Chemistry and Chemical Engineering, Medical School, Southeast University , Nanjing 211189, China.

Natural selection over billions of years has developed highly effective in vivo signal transduction that is often governed by a series of competitive multiple mechanisms. Several artificial signal transduction pathways have inspired numerous biosensing systems, but most of these are driven by a single mechanism. Herein we describe a multiple-mechanism-driven electrochemiluminescent (ECL) biosensor that utilizes competitive catalytic and steric hindrance effects by assembling hemin/G-quadruplex on carbon nitride nanosheets. Taking the detection of 8-hydroxy-2'-deoxyguanosine (8-OHdG) as example, the dynamic ranges of the detectable concentrations from the different mechanisms were integrated into a single sensor interface. Moreover, the detection sensitivity was more precisely controlled by the competition between the two mechanisms and inherently boosted compared with that of single-mechanism-driven detection. Going beyond the conventional single-mechanism-driven biosensing, the elaborate biomimetic coupling of multiple mechanisms in a single interface may open a new approach for future multiplexed biosensing.
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http://dx.doi.org/10.1021/jacs.8b00515DOI Listing
February 2018

Highly Sensitive and Quality Self-Testable Electrochemiluminescence Assay of DNA Methyltransferase Activity Using Multifunctional Sandwich-Assembled Carbon Nitride Nanosheets.

ACS Appl Mater Interfaces 2018 Feb 13;10(8):6887-6894. Epub 2018 Feb 13.

Jiangsu Engineering Laboratory of Smart Carbon-Rich Materials and Device, Jiangsu Province Hi-Tech Key Laboratory for Bio-Medical Research, School of Chemistry and Chemical Engineering, Southeast University , Nanjing 211189, China.

DNA methylation catalyzed by methylase plays a key role in many biological activities. However, developing a highly sensitive, simple, and reliable way for evaluation of DNA methyltransferase (MTase) activity is still a challenge. Here, we report a sandwich-assembled electrochemiluminescence (ECL) biosensor using multifunctional carbon nitride nanosheets (CNNS) to evaluate the Dam MTase activity. The CNNS could not only be used as an excellent substrate to conjugate a large amount of hairpin probe DNA to improve the sensitivity but also be utilized as an internal reliability checker and an analyte reporter in the bottom and top layers of the biosensor, respectively. Such a unique sandwich configuration of CNNS well coupled the advantages of ECL luminophor that were generally assembled in the bottom or top layer in a conventional manner. As a result, the biosensor exhibited an ultralow detection limit down to 0.043 U/mL and a linear range between 0.05 and 80 U/mL, superior to the MTase activity assay in most previous reports. We highlighted the great potential of emerging CNNS luminophor in developing highly sensitive and smart quality self-testable ECL sensing systems using a sandwiched configuration for early disease diagnosis, treatment, and management.
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http://dx.doi.org/10.1021/acsami.7b17813DOI Listing
February 2018

CD4+ and Perivascular Foxp3+ T Cells in Glioma Correlate with Angiogenesis and Tumor Progression.

Front Immunol 2017 7;8:1451. Epub 2017 Nov 7.

Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, United States.

Background: Angiogenesis and immune cell infiltration are key features of gliomas and their manipulation of the microenvironment, but their prognostic significance remains indeterminate. We evaluate the interconnection between tumor-infiltrating lymphocyte (TIL) and tumor blood-vasculatures in the context of glioma progression.

Methods: Paired tumor tissues of 44 patients from three tumor-recurrent groups: diffuse astrocytomas (DA) recurred as DA, DA recurred as glioblastomas (GBM), and GBM recurred as GBM were evaluated by genetic analysis, immunohistochemistry for tumor blood vessel density, TIL subsets, and clinical outcomes. These cells were geographically divided into perivascular and intratumoral TILs. Associations were examined between these TILs, CD34+ tumor blood vessels, and clinical outcomes. To determine key changes in TIL subsets, microarray data of 15-paired tumors from patients who failed antiangiogenic therapy- bevacizumab, and 16-paired tumors from chemo-naïve recurrent GBM were also evaluated and compared.

Results: Upon recurrence in primary gliomas, similar kinetic changes were found between tumor blood vessels and each TIL subset in all groups, but only CD4+ including Foxp3+ TILs, positively correlated with the density of tumor blood vessels. CD4 was the predominant T cell population based on the expression of gene-transcripts in primary GBMs, and increased activated CD4+ T cells were revealed in Bevacizumab-resistant recurrent tumors (not in chemo-naïve recurrent tumors). Among these TILs, 2/3 of them were found in the perivascular niche; Foxp3+ T cells in these niches not only correlated with the tumor vessels but were also an independent predictor of shortened recurrence-free survival (RFS) (HR = 4.199, 95% CI 1.522-11.584,  = 0.006).

Conclusion: The minimal intratumoral T cell infiltration and low detection of CD8 transcripts expression in primary GBMs can potentially limit antitumor response. CD4+ and perivascular Foxp3+ TILs associate with tumor angiogenesis and tumor progression in glioma patients. Our results suggest that combining antiangiogenic agents with immunotherapeutic approaches may help improve the antitumor efficacy for patients with malignant gliomas.
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http://dx.doi.org/10.3389/fimmu.2017.01451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673996PMC
November 2017