Publications by authors named "Huijing Wang"

47 Publications

Yohimbine Directly Induces Cardiotoxicity on Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Cardiovasc Toxicol 2021 Nov 24. Epub 2021 Nov 24.

Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai, 200127, China.

Yohimbine is a highly selective and potent α-adrenoceptor antagonist, which is usually treated as an adjunction for impotence, as well for weight loss and natural bodybuilding aids. However, it was recently reported that Yohimbine causes myocardial injury and controversial results were reported in the setting of cardiac diseases. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to explore electrophysiologic characterization after exposure to Yohimbine. HiPSC-CMs were differentiated by employment of inhibitory Wnt compounds. For analysis of electrophysiological properties, conventional whole-cell patch-clamp recording was used. Specifically, spontaneous action potentials, pacemaker currents (I), sodium (Na) channel (I), and calcium (Ca) channel currents (I) were assessed in hiPSC-CMs after exposure to Yohimbine. HiPSC-CMs expressed sarcomeric-α-actinin and MLC2V proteins, as well as exhibited ventricular-like spontaneous action potential waveform. Yohimbine inhibited frequency of hiPSC-CMs spontaneous action potentials and significantly prolonged action potential duration in a dose-dependent manner. In addition, rest potential, threshold potential, amplitude, and maximal diastolic potential were decreased, whereas APD/APD was prolonged. Yohimbine inhibited the amplitude of I in low doses (IC = 14.2 μM, n = 5) and inhibited I in high doses (IC = 139.7 μM, n = 5). Whereas Yohimbine did not affect the activation curves, treatment resulted in left shifts in inactivation curves of both Na and Ca channels. Here, we show that Yohimbine induces direct cardiotoxic effects on spontaneous action potentials of I and I in hiPSC-CMs. Importantly, these effects were not mediated by α-adrenoceptor signaling. Our results strongly suggest that Yohimbine directly and negatively affects electrophysiological properties of human cardiomyocytes. These findings are highly relevant for potential application of Yohimbine in patients with atrioventricular conduction disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12012-021-09709-3DOI Listing
November 2021

One-year renal outcome in lupus nephritis patients with acute kidney injury: a nomogram model.

Rheumatology (Oxford) 2021 Nov 2. Epub 2021 Nov 2.

Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Objective: To develop a short-term renal outcome prediction model for acute kidney injury (AKI) in patients with lupus nephritis.

Methods: Two lupus AKI cohorts from 2 independent centers during 2013-2019 were included, i.e., a derivation cohort from a rheumatology center and a validation cohort from a nephrology center. Clinical characteristics and renal histologic features were obtained. The outcome measurement was the recovery of kidney function within 12-month. Lasso regression was used for feature selection. Prediction models with or without pathology were built and nomogram was plotted. Model evaluation including calibration curve and decision curve analysis was performed.

Results: 130 patients and 96 patients were included in the derivation and validation cohorts, of which 82 and 73 patients received renal biopsy, respectively. The prognostic nomogram model without pathology included determinants of SLE duration, days from AKI onset to treatment and baseline creatinine level (C-index 0.85 (95%CI 0.78∼0.91) and 0.79 (95%CI 0.70∼0.88) for the 2 cohorts). Combination of histologic interstitial tubular fibrosis in the nomogram gave an incremental predictive performance (C-index 0.93 vs 0.85, p = 0.039) in the derivation cohort, but failed to improve the performance in the validation cohort (C-index 0.81 vs 0.79, p = 0.78). Decision curve analysis suggested clinical benefit of the prediction models.

Conclusion: The predictive nomogram models might facilitate more accurate management for lupus patients with AKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab818DOI Listing
November 2021

Stereoselective total synthesis of (±)-vindeburnol and (±)-16--vindeburnol.

Chem Commun (Camb) 2021 Nov 4;57(88):11669-11672. Epub 2021 Nov 4.

Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

A concise stereoselective total synthesis of (±)-vindeburnol and its epimer (±)-16--vindeburnol is presented. This synthetic work features the utilization of Baeyer-Villiger oxidation to install different types of lactone substrate, and a sequence of aminolysis, aldimine condensation and acyl-Pictet-Spengler to deliver the crucial -fused indoloquinolizidine scaffold with high-level diastereocontrol.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d1cc04980aDOI Listing
November 2021

and Properties of an Injectable Hydrogel Derived From Acellular Ear Cartilage Extracellular Matrix.

Front Bioeng Biotechnol 2021 13;9:740635. Epub 2021 Sep 13.

Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Extracellular matrix (ECM) hydrogels provide advantages such as injectability, the ability to fill an irregularly shaped space, and the adequate bioactivity of native matrix. In this study, we developed decellularized cartilage ECM (dcECM) hydrogels from porcine ears innovatively via the main method of enzymatic digestion and verified good biocompatible properties of dcECM hydrogels to deliver chondrocytes and form subcutaneous cartilage . The scanning electron microscopy and turbidimetric gelation kinetics were used to characterize the material properties and gelation kinetics of the dcECM hydrogels. Then we evaluated the biocompatibility of hydrogels via the culture of chondrocytes . To further explore the dcECM hydrogels , grafts made from the mixture of dcECM hydrogels and chondrocytes were injected subcutaneously in nude mice for the gross and histological analysis. The structural and gelation kinetics of the dcECM hydrogels altered according to the variation in the ECM concentrations. The 10 mg/ml dcECM hydrogels could support the adhesion and proliferation of chondrocytes . , at 4 weeks after transplantation, cartilage-like tissues were detected in all groups with positive staining of toluidine blue, Safranin O, and collagen II, indicating the good gelation of dcECM hydrogels. While with the increasing concentration, the tissue engineering cartilages formed by 10 mg/ml dcECM hydrogel grafts were superior in weights, volumes, collagen, and glycosaminoglycan (GAG) content compared to the dcECM hydrogels of 1 mg/ml and 5 mg/ml. At 8 weeks after grafting, dcECM hydrogel grafts at 10 mg/ml showed very similar qualities to the control, collagen I grafts. After 12 weeks of culture, the histological analysis indicated that 10 mg/ml dcECM hydrogel grafts were similar to the normal cartilage from pig ears, which was the source tissue. In conclusion, dcECM hydrogel showed the promising potential as a tissue engineering biomaterial to improve the regeneration and heal injuries of ear cartilage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fbioe.2021.740635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474061PMC
September 2021

tRNA derived fragment (tRF)-3009 participates in modulation of IFN-α-induced CD4 T cell oxidative phosphorylation in lupus patients.

J Transl Med 2021 07 13;19(1):305. Epub 2021 Jul 13.

Department of Rheumatology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.

Background: Accumulating evidence suggests tRNA-derived fragments (tRFs) play important roles in cellular homeostasis. Here we aimed to explore aberrant expression of tRFs in CD4 T cells from patients with systemic lupus erythematosus (SLE) and their potential function in the SLE pathogenesis.

Methods: First, small RNA sequencing was performed on CD4 T cells from four SLE patients and three healthy controls (HCs). Candidate tRFs were then validated in CD4 T cells from 97 SLE patients and their relevant disease controls using qRT-PCR. Then sequencing was used to investigate the profiles of HC-derived CD4 T cells transfected with tRF-3009. Lastly, tRF-3009 siRNA or tRF-3009 mimics were transfected into CD4 T cells with/without IFN-α. Changes in oxygen consumption rate (OCR), ATP, and ROS production were analyzed.

Results: We identified 482 differentially expressed tRFs from SLE CD4 T cells and chose tRF-3009 for further analysis due to its upregulation and the positive correlations between its expression and SLEDAI, active lupus nephritis and serum IFN-α levels. In vitro, tRF-3009 over-expressing CD4 T cell profiling and putative analysis linked this product to the type I IFN and oxidative phosphorylation (OXPHOS) pathways. Interestingly, IFN-α is capable of inducing ROS and ATP production in CD4 T cells, while knockdown of tRF-3009 reversed this process. Overexpression of tRF-3009 in CD4 T cells alone was sufficient to upregulate OCR, ROS, and ATP production.

Conclusions: Our study is the first to link aberrant tRF expression and SLE. tRF-3009 may participate in metabolic modulation of IFN-α-induced CD4 T cell OXPHOS in lupus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-021-02967-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8278670PMC
July 2021

Distribution Patterns (7B Rule) and Characteristics of Large Congenital Melanocytic Nevi: A Retrospective Cohort Study in China.

Front Med (Lausanne) 2021 19;8:637857. Epub 2021 Feb 19.

Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Large congenital melanocytic nevus has a high risk of malignancy. However, few studies have summarized its characteristics, treatments, outcomes and malignancy incidence in Chinese patients. This paper reviews a retrospective cohort study evaluating 1,171 patients from Shanghai Ninth People's Hospital between 1 January 1989 and 31 August 2019 using electronic medical records and phone calls to collect clinical and pathological data in which 133 patients were diagnosed with a large congenital melanocytic nevus. Three patients relapsed, and none developed melanoma among the qualified patients. Besides, a new "7B" rule for distribution patterns of large congenital melanocytic nevi was proposed, including bonce, bolero, back, bathing trunk, breast/belly, body extremity, and body. The most common distribution pattern of large congenital melanocytic nevi was bonce, and all blue nevi distributed as bonce. Statistical analysis showed a significant difference ( = 0.0249) in the "7B" patterns between the melanocytic nevus and the neuronevus. In conclusion, the malignancy rate of large congenital melanocytic nevi is much lower in China than in other regions and people of other races. The pathology of large congenital melanocytic nevus may decide its "7B" distribution pattern.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmed.2021.637857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933508PMC
February 2021

Chemically Modified SDF-1α mRNA Promotes Random Flap Survival by Activating the SDF-1α/CXCR4 Axis in Rats.

Front Cell Dev Biol 2021 4;9:623959. Epub 2021 Feb 4.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Random skin flaps are frequently applied in plastic and reconstructive surgery for patients suffering from soft tissue defects caused by congenital deformities, trauma and tumor resection. However, ischemia and necrosis in distal parts of random skin flaps remains a common challenge that limits the clinical application of this procedure. Recently, chemically modified mRNA (modRNA) was found to have great therapeutic potential. Here, we explored the potential of fibroblasts engineered to express modified mRNAs encoding the stromal cell-derived factor-1α (SDF-1α) to improve vascularization and survival of therapeutic random skin flaps. Our study showed that fibroblasts pre-treated with SDF-1α modRNA have the potential to salvage ischemic skin flaps. Through a detailed analysis, we revealed that a fibroblast SDF-1α modRNA combinatorial treatment dramatically reduced tissue necrosis and significantly promoted neovascularization in random skin flaps compared to that in the control and vehicle groups. Moreover, SDF-1α modRNA transcription in fibroblasts promoted activation of the SDF-1α/CXCR4 pathway, with concomitant inactivation of the MEK/ERK, PI3K/AKT, and JAK2/STAT3 signaling pathways, indicating a possible correlation with cell proliferation and migration. Therefore, fibroblast-mediated SDF-1α modRNA expression represents a promising strategy for random skin flap regeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2021.623959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890013PMC
February 2021

Performance of the 2019 EULAR/ACR systemic lupus erythematosus classification criteria in a cohort of patients with biopsy-confirmed lupus nephritis.

Lupus Sci Med 2021 02;8(1)

Kidney Disease Center, Zhejiang University School of Medicine First Affiliated Hospital; Institute of Nephrology, Zhejiang University; Key Laboratory of Kidney Disease Prevention and Control Technology, Hangzhou, Zhejiang, China

Objective: To evaluate the performance of the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) SLE classification criteria in a cohort of patients with biopsy-confirmed lupus nephritis (LN) and their renal prognosis.

Methods: Patients with newly diagnosed SLE attending and followed up for >12 months were included. A retrospective review of all patients with renal biopsy fulfilling a consensus expert opinion during 2014 and 2018. Clinical, serological and pathological data were collected and each patient was assigned a high/low criteria scores (HS/LS) group. Survival curves for flare adjusted for multiplicity on renal flares, was applied to the two groups.

Results: Applying EULAR/ACR criteria in our cohort of 126 patients, 6 (4.76%) did not meet the criterion, resulting in a sensitivity of 95.24%. The EULAR/ACR criteria scores was positively correlated with SLE disease activity index scores. Additionally, we noticed that a significant difference in clinical and immunological manifestations between HS and LS group. We observed a higher proportions of class Ⅲ or Ⅳ LN and lower proportions of class Ⅱ or V LN (p=0.034) and pathological higher activity index in HS group (p=0.007). Compared with LS groups, patients involved more severe renal damage and achieved higher rate of complete remission in the HS group. The Kaplan-Meier exploratory analyses, adjusted for LN classification, estimated glomerular filtration rate, activity index and chronicity index and induction and maintenance treatments, showed that patients in the HS group had a tendency of higher renal flare risk than that in the LS group (HR=0.21, p=0.04).

Conclusions: The EULAR/ACR criteria performed high sensitivity in identifying SLE in this cohort of biopsy-confirmed LN. Patients with LN with high criteria scores had more extrarenal manifestations, and worse renal prognosis in the short and long terms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/lupus-2020-000458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871694PMC
February 2021

BMP-2 and VEGF-A modRNAs in collagen scaffold synergistically drive bone repair through osteogenic and angiogenic pathways.

Commun Biol 2021 01 19;4(1):82. Epub 2021 Jan 19.

Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, 200127, Shanghai, China.

Bone has a remarkable potential for self-healing and repair, yet several injury types are non-healing even after surgical or non-surgical treatment. Regenerative therapies that induce bone repair or improve the rate of recovery are being intensely investigated. Here, we probed the potential of bone marrow stem cells (BMSCs) engineered with chemically modified mRNAs (modRNA) encoding the hBMP-2 and VEGF-A gene to therapeutically heal bone. Induction of osteogenesis from modRNA-treated BMSCs was confirmed by expression profiles of osteogenic related markers and the presence of mineralization deposits. To test for therapeutic efficacy, a collagen scaffold inoculated with modRNA-treated BMSCs was explored in an in vivo skull defect model. We show that hBMP-2 and VEGF-A modRNAs synergistically drive osteogenic and angiogenic programs resulting in superior healing properties. This study exploits chemically modified mRNAs, together with biomaterials, as a potential approach for the clinical treatment of bone injury and defects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-01606-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815925PMC
January 2021

Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model.

Stem Cell Res Ther 2020 11 19;11(1):490. Epub 2020 Nov 19.

Department of Ophthalmology, Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200011, China.

Background: Fat grafting, as a standard treatment for numerous soft tissue defects, remains unpredictable and technique-dependent. Human adipose-derived stem cells (hADSCs) are promising candidates for cell-assisted therapy to improve graft survival. As free-living fat requires nutritional and respiratory sources to thrive, insufficient and unstable vascularization still impedes hADSC-assisted therapy. Recently, cytotherapy combined with modified mRNA (modRNA) encoding vascular endothelial growth factor (VEGF) has been applied for the treatment of ischemia-related diseases. Herein, we hypothesized that VEGF modRNA (modVEGF)-engineered hADSCs could robustly enhance fat survival in a fat graft transplantation model.

Methods: hADSCs were acquired from lipoaspiration and transfected with modRNAs. Transfection efficiency and expression kinetics of modRNAs in hADSCs were first evaluated in vitro. Next, we applied an in vivo Matrigel plug assay to assess the viability and angiogenic potential of modVEGF-engineered hADSCs at 1 week post-implantation. Finally, modVEGF-engineered hADSCs were co-transplanted with human fat in a murine model to analyze the survival rate, re-vascularization, proliferation, fibrosis, apoptosis, and necrosis of fat grafts over long-term follow-up.

Results: Transfections of modVEGF in hADSCs were highly tolerable as the modVEGF-engineered hADSCs facilitated burst-like protein production of VEGF in both our in vitro and in vivo models. modVEGF-engineered hADSCs induced increased levels of cellular proliferation and proangiogenesis when compared to untreated hADSCs in both ex vivo and in vivo assays. In a fat graft transplantation model, we provided evidence that modVEGF-engineered hADSCs promote the optimal potency to preserve adipocytes, especially in the long-term post-transplantation phase. Detailed histological analysis of fat grafts harvested at 15, 30, and 90 days following in vivo grafting suggested the release of VEGF protein from modVEGF-engineered hADSCs significantly improved neo-angiogenesis, vascular maturity, and cell proliferation. The modVEGF-engineered hADSCs also significantly mitigated the presence of fibrosis, apoptosis, and necrosis of grafts when compared to the control groups. Moreover, modVEGF-engineered hADSCs promoted graft survival and cell differentiation abilities, which also induced an increase in vessel formation and the number of surviving adipocytes after transplantation.

Conclusion: This current study demonstrates the employment of modVEGF-engineered hADSCs as an advanced alternative to the clinical treatment involving soft-tissue reconstruction and rejuvenation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13287-020-02008-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678328PMC
November 2020

Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials.

Lupus Sci Med 2020 10;7(1)

Rheumatology, Renji Hospital South Campus, Shanghai Jiaotong University School of Medicine, Shanghai, China

Objective: To confirm that metformin prevents flares in patients with SLE with low disease activity, we performed a post hoc analysis combining our previous two randomised trials.

Methods: Post hoc analyses were performed on data from the open-labelled proof-of-concept trial (n=113, ChiCTR-TRC-12002419) and placebo-controlled 'Met Lupus' trial (n=140, NCT02741960) comparing the efficacy of metformin versus placebo/nil add-on to standard therapy in patients with SLE with low disease activity (SELENA-SLEDAI ≤4). The primary endpoint was defined by the SELENA-SLEDAI Flare Index at 12-month follow-up. A subgroup analysis was performed.

Results: Overall, 201 eligible patients were included, with 99 allocated to metformin group and 102 allocated to the placebo/nil group. By 12 months of follow-up, 21 patients (21.2%) flared in the metformin group, as compared with 36 (35.3%) in the placebo/nil group (p=0.027, risk ratio=0.68, 95% CI 0.46 to 0.96). Subgroup analysis showed that patients with negative anti-dsDNA antibody and normal complement at baseline, and a disease duration <5 years with concomitant use of hydroxychloroquine had a better response to metformin.

Conclusion: Post hoc pooled analyses suggested that metformin reduced subsequent disease flares in patients with SLE with low disease activity, especially for serologically quiescent patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/lupus-2020-000429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583791PMC
October 2020

Investigation of the presence of Ochrobactrum spp. and Brucella spp. in Haemaphysalis longicornis.

Ticks Tick Borne Dis 2021 01 5;12(1):101588. Epub 2020 Oct 5.

College of Medicine, Pingdingshan University, Pingdingshan City, 467000, Henan Province, China.

Ticks are common vectors of human and animal diseases. Ochrobactrum spp. belong to the Brucellaceae family and have recently been recognized as emerging human pathogens. The ability of Haemaphysalis longicornis ticks to carry Ochrobactrum spp. remains uncertain. During June and July 2018, 686 ticks were collected from 11 sites in Pingdingshan Henan province in central China. We extracted 169 DNA samples for Brucellaceae 16S rRNA nested PCR and sequenced them in order to identify Ochrobactrum spp. The data sequences were aligned with NCBI BLAST program and phylogenetic tree was constructed using Mega 5.0. Twenty samples were sequenced successfully out of a total forty-one positive for Brucellaceae. Thirteen DNA samples were identical to O. intermedium (99.85 %-100.00 %) and 3 were identical to O. cicer (99.85 %-100.00 %) (15 collected from host and one from vegetation). Four DNA samples (3 collected from host and one from vegetation) had 99.83-100 % B. melitensis identity. This study adds to the growing body of evidence that shows Ochrobactrum spp. are present in H. longicornis. Ochrobactrum spp. and Brucella spp. are phenotypically and genetically closely related pathogens. Our finding highlights the importance of gene sequencing and phylogenetic analysis to differentiate between Ochrobactrum spp. and Brucella spp. in the research and potentially clinical setting. Future work is required to investigate the transmission potential of Ochrobactrum spp. by H. longicornis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ttbdis.2020.101588DOI Listing
January 2021

Effectiveness and safety of light vegetarian diet and Qingjiang Tiaochang Recipe for functional constipation: An exploratory study protocol for randomized controlled trial.

Medicine (Baltimore) 2020 Sep;99(39):e21363

Department of Gastroenterology of Traditional Chinese Medicine, China-Japan Friendship Hospital.

Introduction: Functional constipation is a chronic disease that is common in children and adults around the world. The treatments for functional constipation include diet and lifestyle interventions, medications, and surgery. The diet pattern plays an important role in the occurrence of constipation. We found in clinical practice that simple application of drugs cannot achieve long-term relief of constipation, and a large number of patients are not satisfied with the existing treatment. We have concluded that Qingjiang Tiaochang Recipe (QJTCR) and light vegetarian diet (LVD) can effectively improve constipation. However, there is no enough evidence for the description of the effect. This protocol aims at exploratorily investigating effectiveness and safety of LVD and QJTCR following a rigorous clinical trial.

Methods And Analysis: We will recruit 90 patients to participate in this prospective, placebo-controlled, randomized trial, and exploratory study at the China-Japan Friendship Hospital, including traditional Chinese medicine group, placebo + diet group, traditional Chinese medicine + diet group. Patients in the diet intervention group must strictly abide by LVD, and the study will continue for 28 days. During the intervention period, we need to record a designed diary to assess diet quality and defecation. The primary outcomes for this clinical study were weekly complete spontaneous bowel movements. The secondary outcomes were constipation-related symptom rating scale, traditional Chinese medicine syndrome scale, and 48-hour gastrointestinal transit time, high-resolution anorectal manometry, Bristol stool score, constipation quality of life assessment scale, constipation symptoms self-assessment scale, short-chain fatty acids in feces. In addition, the study will determine the safety of the intervention.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000021363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523849PMC
September 2020

Epitranscriptomic N4-Acetylcytidine Profiling in CD4 T Cells of Systemic Lupus Erythematosus.

Front Cell Dev Biol 2020 28;8:842. Epub 2020 Aug 28.

Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.

The emerging epitranscriptome plays an essential role in autoimmune disease. As a novel mRNA modification, N4-acetylcytidine (acC) could promote mRNA stability and translational efficiency. However, whether epigenetic mechanisms of RNA acC modification are involved in systemic lupus erythematosus (SLE) remains unclear. Herein, we detected eleven modifications in CD4 T cells of SLE patients using mass spectrometry (LC-MS/MS). Furthermore, using samples from four CD4 T cell pools, we identified lower modification of acC mRNA in SLE patients as compared to that in healthy controls (HCs). Meanwhile, significantly lower mRNA acetyltransferase NAT10 expression was detected in lupus CD4 T cells by RT-qPCR. We then illustrated the transcriptome-wide acC profile in CD4 T cells of SLE patients by acC-RIP-Seq and found acC distribution in mRNA transcripts to be highly conserved and enriched in mRNA coding sequence regions. Using bioinformatics analysis, the 3879 and 4073 acC hyper-acetylated and hypoacetylated peaks found in SLE samples, respectively, were found to be significantly involved in SLE-related function enrichments, including multiple metabolic and transcription-related processes, ROS-induced cellular signaling, apoptosis signaling, and NF-κB signaling. Moreover, we demonstrated the acC-modified regulatory network of gene biological functions in lupus CD4 T cells. Notably, we determined that the 26 upregulated genes with hyperacetylation played essential roles in autoimmune diseases and disease-related processes. Additionally, the unique acC-related transcripts, including , , and , regulate mRNA catabolic processes and translational initiation. Our study identified novel dysregulated acC mRNAs associated with critical immune and inflammatory responses, that have translational potential in lupus CD4 T cells. Hence, our findings reveal transcriptional significance and potential therapeutic targets of mRNA acC modifications in SLE pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.00842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483482PMC
August 2020

TCONS_00483150 as a novel diagnostic biomarker of systemic lupus erythematosus.

Epigenomics 2020 06 17;12(11):973-988. Epub 2020 Jul 17.

Department of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, PR China.

We aimed to identify differentially expressed Long noncoding RNAs (lncRNAs) and explore their functional roles in systemic lupus erythematosus (SLE). We identified dysregulated lncRNAs and investigated their prognostic values and potential functions using MiRTarget2, catRAPID omics and Bedtools/blast/Pearson analyses. Among the 143 differentially expressed lncRNAs, TCONS_00483150 could be used to distinguish patients with SLE from healthy controls and those with rheumatoid arthritis and patients with active/stable SLE from healthy controls. TCONS_00483150 was significantly correlated with anti-Rib-P antibody positivity and low C3 levels; TCONS_00483150 dysregulation might contribute to the metabolism of RNA and proteins in SLE patients. Overall, our findings offer a transcriptome-wide overview of aberrantly expressed lncRNAs in patients with SLE and highlight TCONS_00483150 as a potential novel diagnostic biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/epi-2019-0265DOI Listing
June 2020

Intrinsic Color Sensing System Allows for Real-Time Observable Functional Changes on Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

ACS Nano 2020 07 8;14(7):8232-8246. Epub 2020 Jul 8.

Department of Pediatric Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China.

Stem-cell based differentiation for disease modeling offers great value to explore the molecular and functional underpinnings driving many types of cardiomyopathy and congenital heart diseases. Nevertheless, one major caveat in the application of differentiation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) involves the immature phenotype of the CMs. Most of the existing methods need complex apparatus and require laborious procedures in order to monitor the cardiac differentiation/maturation process and often result in cell death. Here we developed an intrinsic color sensing system utilizing a microgroove structural color methacrylated gelatin film, which allows us to monitor the cardiac differentiation process of hiPSC-derived cardiac progenitor cells in real time. Subsequently this system can be employed as an assay system to live monitor induced functional changes on hiPSC-CMs stemming from drug treatment, the effects of which are simply revealed through color diversity. Our research shows that early intervention of cardiac differentiation through simple physical cues can enhance cardiac differentiation and maturation to some extent. Our system also simplifies the previous complex experimental processes for evaluating the physiological effects of successful differentiation and drug treatment and lays a solid foundation for future transformational applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsnano.0c01745DOI Listing
July 2020

Disease Activity-Associated Alteration of mRNA m C Methylation in CD4 T Cells of Systemic Lupus Erythematosus.

Front Cell Dev Biol 2020 5;8:430. Epub 2020 Jun 5.

Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, Institute of Tropical Medicine, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.

Epigenetic processes including RNA methylation, post-translational modifications, and non-coding RNA expression have been associated with the heritable risks of systemic lupus erythematosus (SLE). In this study, we aimed to explore the dysregulated expression of 5-methylcytosine (mC) in CD4 T cells from patients with SLE and the potential function of affected mRNAs in SLE pathogenesis. mRNA methylation profiles were ascertained through chromatography-coupled triple quadrupole mass spectrometry in CD4 T cells from two pools of patients with SLE exhibiting stable activity, two pools with moderate-to-major activity, and two pools of healthy controls (HCs). Simultaneously, mRNA methylation profiles and expression profiling were performed using RNA-Bis-Seq and RNA-Seq, respectively. Integrated mRNA methylation and mRNA expression bioinformatics analysis was comprehensively performed. mRNA methyltransferase NSUN2 expression was validated in CD4 T cells from 27 patients with SLE and 28 HCs using real-time polymerase chain reaction and western blot analyses. Hypomethylated-mRNA profiles of NSUN2-knockdown HeLa cells and of CD4 T cells of patients with SLE were jointly analyzed using bioinformatics. Eleven methylation modifications (including elevated Am, 3'OMeA, mA, and mA and decreased Ψ, mC, mG, mU, and tA levels) were detected in CD4 T cells of patients with SLE. Additionally, decreased mC levels, albeit increased number of mC-containing mRNAs, were observed in CD4 T cells of patients with SLE compared with that in CD4 T cells of HCs. mC site distribution in mRNA transcripts was highly conserved and enriched in mRNA translation initiation sites. In particular, hypermethylated mC or/and significantly up-regulated genes in SLE were significantly involved in immune-related and inflammatory pathways, including immune system, cytokine signaling pathway, and interferon signaling. Compared to that in HCs, NSUN2 expression was significantly lower in SLE CD4 T cells. Notably, hypomethylated mC genes in SLE and in NSUN2-knockdown HeLa cells revealed linkage between eukaryotic translation elongation and termination, and mRNA metabolism. Our study identified novel aberrant mC mRNAs relevant to critical immune pathways in CD4 T cells from patients with SLE. These data provide valuable perspectives for future studies of the multifunctionality and post-transcriptional significance of mRNA mC modification in SLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcell.2020.00430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291606PMC
June 2020

DNA-based artificial molecular signaling system that mimics basic elements of reception and response.

Nat Commun 2020 02 20;11(1):978. Epub 2020 Feb 20.

Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, College of Biology, and Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, Hunan, 410082, People's Republic of China.

In order to maintain tissue homeostasis, cells communicate with the outside environment by receiving molecular signals, transmitting them, and responding accordingly with signaling pathways. Thus, one key challenge in engineering molecular signaling systems involves the design and construction of different modules into a rationally integrated system that mimics the cascade of molecular events. Herein, we rationally design a DNA-based artificial molecular signaling system that uses the confined microenvironment of a giant vesicle, derived from a living cell. This system consists of two main components. First, we build an adenosine triphosphate (ATP)-driven DNA nanogatekeeper. Second, we encapsulate a signaling network in the biomimetic vesicle, consisting of distinct modules, able to sequentially initiate a series of downstream reactions playing the roles of reception, transduction and response. Operationally, in the presence of ATP, nanogatekeeper switches from the closed to open state. The open state then triggers the sequential activation of confined downstream signaling modules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-14739-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033183PMC
February 2020

Release of Porcine Sperm from Oviduct Cells is Stimulated by Progesterone and Requires CatSper.

Sci Rep 2019 12 20;9(1):19546. Epub 2019 Dec 20.

Department of Animal Sciences and Institute of Genomic Biology, University of Illinois at Urbana-Champaign, 1207 West Gregory Drive, Urbana, IL, 61801, USA.

Sperm storage in the female reproductive tract after mating and before ovulation is a reproductive strategy used by many species. When insemination and ovulation are poorly synchronized, the formation and maintenance of a functional sperm reservoir improves the possibility of fertilization. In mammals, the oviduct regulates sperm functions, such as Ca influx and processes associated with sperm maturation, collectively known as capacitation. A fraction of the stored sperm is released by unknown mechanisms and moves to the site of fertilization. There is an empirical association between the hormonal milieu in the oviduct and sperm detachment; therefore, we tested directly the ability of progesterone to induce sperm release from oviduct cell aggregates. Sperm were allowed to bind to oviduct cells or an immobilized oviduct glycan and then challenged with progesterone, which stimulated the release of 48% of sperm from oviduct cells or 68% of sperm from an immobilized oviduct glycan. The effect of progesterone on sperm release was specific; pregnenolone and 17α-OH-progesterone did not affect sperm release. Ca influx into sperm is associated with capacitation and development of hyperactivated motility. Progesterone increased sperm intracellular Ca, which was abrogated by blocking the sperm-specific Ca channel CatSper with NNC 055-0396. NNC 055-0396 also blocked the progesterone-induced sperm release from oviduct cells or immobilized glycan. An inhibitor of the non-genomic progesterone receptor that activates CatSper similarly blocked sperm release. This is the first report indicating that release of sperm from the sperm reservoir is induced by progesterone action through CatSper channels.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-55834-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925244PMC
December 2019

Effectiveness and safety of light vegetarian diet on functional constipation with gastrointestinal damp-heat pattern: An exploratory study protocol for randomized controlled trial.

Medicine (Baltimore) 2019 Dec;98(50):e18325

Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, China.

Introduction: Functional constipation (FC) is one of the common gastrointestinal disorders that affects people of almost every age. Persistent FC significantly affects quality of life and well-being along with economic burden on patients as well as health care system. Therapeutic efficacy of currently used treatment strategies becomes limited shortly after their discontinuation as constipation occurs again as a result of inappropriate dietary habits. Previous studies have revealed that light vegetarian diet (LVD) can significantly improve both typical and atypical subtypes of major traditional Chinese medicine (TCM) FC syndrome such as gastrointestinal damp-heat syndrome. This protocol aims at exploratorily investigating effectiveness and safety of LVD following a rigorous clinical trial.

Methods And Design: Total 92 patients in each of the 2 subtypes will be recruited in China-Japan Friendship Hospital for participating in this prospective, placebo-controlled, randomized trial and exploratory study. The patients in each subtype will be randomly divided into 4 groups according to 1:1:1:1 ratio with allocation concealment, which are drug + diet group, drug group, placebo + diet group and placebo group. Patients in the group with diet intervention will be required to strictly follow the LVD. The study will continue for a period of 28 days, including a drug or placebo supervised intervention and a 14th-day telephone follow-up. During the intervention, patients will be required to record a designed diary for controlling the diet quality (DQ) and analyzing the defecation. The study will focus investigation of complete spontaneous bowel movements (CSBM) per week as its primary outcome and constipation-related symptom rating scale (CSS), TCM syndrome scale (TCMSS), 48-hour gastrointestinal transit time (48-hour GITT), high resolution anorectal manometry (HRAM) and fecal flora detection (FFD) will be included in secondary outcomes. Furthermore, the study will also determine safety, DQ and compliance indicators.

Ethics And Dissemination: This study has been approved by China-Japan Friendship Hospital clinical research ethics committee (No. 2017-46-1). A SPIRIT checklist is available for this protocol.

Trial Registration Number: ChiCTR1800019686 in Chinese Clinical Trial Registry (WHO ICTRP member).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MD.0000000000018325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922355PMC
December 2019

Hsa_circ_0000479 as a Novel Diagnostic Biomarker of Systemic Lupus Erythematosus.

Front Immunol 2019 24;10:2281. Epub 2019 Sep 24.

Department of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.

Accumulating evidence suggests that differentially expressed non-coding circular RNAs (circRNAs) play critical roles in the progress of autoimmune diseases. However, the role of circRNAs in systemic lupus erythematosus (SLE) remains unclear. We initially used next-generation sequencing (NGS) to comprehensively analyze circRNA expression profiles in peripheral blood mononuclear cells (PBMCs) from 10 SLE patients, stratified by their disease activity characteristics (stable or active SLE), and 10 healthy controls (HCs). Candidate circRNAs identified were first validated by quantitative reverse-transcription (qRT)-PCR in PBMC samples from a training-phase cohort of five SLE patients and five HCs. The significantly dysregulated circRNAs were then confirmed by qRT-PCR in a validation cohort of 23 SLE patients and 21 HCs, and in an external validation cohort with 64 SLE patients, 58 HCs, and 50 patients with rheumatoid arthritis (RA). In addition, we conducted bioinformatics analysis and western blotting investigating the relationships between the candidate circRNAs and SLE progression. Multilayer integrative analysis of circRNA regulation showed that 84 circRNAs were upregulated and 30 were downregulated in patients with SLE compared with HCs. We then analyzed the intersection of these differentially expressed circRNAs in an SLE-stable cohort, an SLE-active cohort, and HCs. This enabled us to narrow down dysregulated circRNAs to 15 upregulated circRNAs. Only hsa_circ_0000479 was significantly upregulated in PBMCs of patients with SLE compared with HCs ( < 0.05). Furthermore, the diagnostic potential of hsa_circ_0000479 expression to distinguish SLE patients from HCs and RA patients was also significantly increased in the validation-phase and external-validation-phase cohorts ( < 0.05). When distinguishing SLE patients from HCs, the diagnostic specificities of hsa_circ_0000479 were 0.619 and 1.0 in two validation cohorts, respectively (AUCs = 0.731 and 0.730, respectively). It was also significantly increased in either stable SLE patients or active SLE patients compared with HCs in these two cohorts ( < 0.05). We also used bioinformatics analysis to show that hsa_circ_0000479 regulates SLE progression by modulating metabolic pathways and the Wnt signaling pathway. Western blotting revealed that the expression of Wnt-16 protein was significantly decreased in SLE. Our results suggest that hsa_circ_0000479 has potential as a novel biomarker for the diagnosis of SLE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.02281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771011PMC
November 2020

Generating Giant Membrane Vesicles from Live Cells with Preserved Cellular Properties.

Research (Wash D C) 2019 17;2019:6523970. Epub 2019 Jun 17.

Molecular Science and Biomedicine Laboratory (MBL), State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Aptamer Engineering Center of Hunan Province, Hunan University, Changsha, China.

Biomimetic giant membrane vesicles, with size and lipid compositions comparable to cells, have been recognized as an attractive experimental alternative to living systems. Due to the similarity of their membrane structure to that of body cells, cell-derived giant plasma membrane vesicles have been used as a membrane model for studying lipid/protein behavior of plasma membranes. However, further application of biomimetic giant membrane vesicles has been hampered by the side-effects of chemical vesiculants and the utilization of osmotic buffer. We herein develop a facile strategy to derive giant membrane vesicles (GMVs) from mammalian cells in biofriendly medium with high yields. These GMVs preserve membrane properties and adaptability for surface modification and encapsulation of exogenous molecules, which would facilitate their potential biological applications. Moreover, by loading GMVs with therapeutic drugs, GMVs could be employed for drug transport to tumor cells, which represents another step forward in the biomedical application of giant membrane vesicles. This study highlights biocompatible GMVs with biomimicking membrane surface properties and adaptability as an ideal platform for drug delivery strategies with potential clinical applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.34133/2019/6523970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750080PMC
June 2019

Stereochemistry of Linoleic Acid Esters of Hydroxy Linoleic Acids.

Org Lett 2019 10 23;21(19):8080-8084. Epub 2019 Sep 23.

Skaggs School of Pharmacy and Pharmaceutical Sciences , UC San Diego , 9500 Gilman Drive , La Jolla , California 92093-0934 , United States.

The syntheses of linoleic acid esters of hydroxy linoleic acids (LAHLAs) present in oat oil and human serum have been achieved, providing access to material for testing and the determination of the stereochemistry of the natural compounds. While 9- and 13-LAHLAs were found to be a mixture of enantiomers 15-LAHLA is generated in a single optical form in oat oil. The stereochemistry of 15-LAHLA in oat oil was found to be opposite to that reported for digalactosyldiacylglycerol that possesses an embedded 15-LAHLA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.orglett.9b03054DOI Listing
October 2019

C-H alkenylation/cyclization and sulfamidation of 2-phenylisatogens using N-oxide as a directing group.

Chem Commun (Camb) 2019 Aug;55(71):10623-10626

Key Laboratory of Drug Targeting and Drug Delivery System of Education Ministry, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, No. 17, 3th Section, South Renmin Road, Chengdu, 610041, P. R. China.

The first example of transition-metal-catalyzed C-H activations of 2-phenylisatogens with alkynes and sulfonyl azides has been developed using N-oxide as the directing group. Ru(ii)-Catalyzed C-H alkenylation/cyclization and Ir(iii)-catalyzed direct C-H sulfamidation proceeded with good yields and excellent functional group tolerance. Importantly, these two transformations provided straightforward routes for the synthesis of indol-3-one derivatives and sulfamidated 2-phenylisatogens respectively, which might be of considerable bioactivities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c9cc05719fDOI Listing
August 2019

Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia.

J Control Release 2019 09 16;310:103-114. Epub 2019 Aug 16.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Synthetic chemically modified mRNAs (modRNA) encoding vascular endothelial growth factor (VEGF) represents an alternative to gene therapy for the treatment of ischemic cardiovascular injuries. However, novel delivery approaches of modRNA are needed to improve therapeutic efficacy in the diseased setting. We hypothesized that cell-mediated modRNA delivery may enhance the in vivo expression kinetics of VEGF protein thus promoting more potent angiogenic effects. Here, we employed skin fibroblasts as a "proof of concept" to probe the therapeutic potential of a cell-mediated mRNA delivery system in a murine model of critical limb ischemia (CLI). We show that fibroblasts pre-treated with VEGF modRNA have the potential to fully salvage ischemic limbs. Using detailed molecular analysis we reveal that a fibroblast-VEGF modRNA combinatorial treatment significantly reduced tissue necrosis and dramatically improved vascular densities in CLI-injured limbs when compared to control and vehicle groups. Furthermore, fibroblast-delivered VEGF modRNA treatment increased the presence of Pax7 satellite cells, indicating a possible correlation between VEGF and satellite cell activity. Our study is the first to demonstrate that a cell-mediated modRNA therapy could be an alternative advanced strategy for cardiovascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jconrel.2019.08.014DOI Listing
September 2019

microRNAs in Cardiovascular Disease: Small Molecules but Big Roles.

Curr Top Med Chem 2019 ;19(21):1918-1947

Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

microRNAs (miRNAs) are an evolutionarily conserved class of small single-stranded noncoding RNAs. The aberrant expression of specific miRNAs has been implicated in the development and progression of diverse cardiovascular diseases. For many decades, miRNA therapeutics has flourished, taking advantage of the fact that miRNAs can modulate gene expression and control cellular phenotypes at the posttranscriptional level. Genetic replacement or knockdown of target miRNAs by chemical molecules, referred to as miRNA mimics or inhibitors, has been used to reverse their abnormal expression as well as their adverse biological effects in vitro and in vivo in an effort to fully implement the therapeutic potential of miRNA-targeting treatment. However, the limitations of the chemical structure and delivery systems are hindering progress towards clinical translation. Here, we focus on the regulatory mechanisms and therapeutic trials of several representative miRNAs in the context of specific cardiovascular diseases; from this basic perspective, we evaluate chemical modifications and delivery vectors of miRNA-based chemical molecules and consider the underlying challenges of miRNA therapeutics as well as the clinical perspectives on their applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1568026619666190808160241DOI Listing
November 2019

Chronic hepatitis B virus infection is associated with a poorer prognosis in diffuse large B-cell lymphoma: a meta-analysis and systemic review.

J Cancer 2019 9;10(15):3450-3458. Epub 2019 Jun 9.

MOE/NHC/CAMS Key Lab of Medical Molecular Virology, School of Basic Medical Sciences & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, 200032, P.R. China.

Accumulating evidence from clinical trials indicates chronic hepatitis B virus (HBV) infection is associated with the incidence of diffuse large B-cell lymphoma (DLBCL) and may be associated with the prognosis of DLBCL, though this suggestion remains controversial. We performed a meta-analysis to assess whether HBV infection is associated with prognosis and response to chemotherapy in DLBCL. After a strict literature search strategy, a total of 809 HBV surface antigen (HBsAg) seropositive patients with DLBCL and 2849 HBsAg seronegative patients with DLBCL from twelve trials were included. DLBCL patients with chronic HBV infection had significantly poorer 2- and 5-year overall survival (OS) (HR 1.54, 95% CI 1.23-1.92, <0.001 and 1.79, 1.48-2.17, <0.001) and 2- and 5-year progression-free survival (PFS) (HR 1.44, 95% CI 1.14-1.81, =0.002 and HR 1.34, 95% CI 1.02-1.75, =0.03). HBsAg-seronegative patients also had a lower complete response (CR) rate (OR 0.48, 95% CI 0.34-0.68, <0.001), higher progressive disease (PD) rate (OR 2.08, 95% CI 1.34-3.24, =0.001), and more advanced clinical features. This meta-analysis indicates HBV infection leads to a poorer prognosis and poorer response to standard chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.31033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603406PMC
June 2019

Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals.

J Biol Chem 2019 07 31;294(27):10698-10707. Epub 2019 May 31.

From the Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California 92037,

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids. Here we identify the linoleic acid ester of 13-hydroxy linoleic acid (13-LAHLA) as an anti-inflammatory lipid. An oat oil fraction and FAHFA-enriched extract from this fraction showed anti-inflammatory activity in a lipopolysaccharide-induced cytokine secretion assay. Structural studies identified three LAHLA isomers (15-, 13-, and 9-LAHLA) as being the most abundant FAHFAs in the oat oil fraction. Of these LAHLAs, 13-LAHLA is the most abundant LAHLA isomer in human serum after ingestion of liposomes made of fractionated oat oil, and it is also the most abundant endogenous LAHLA in mouse and human adipose tissue. As a result, we chemically synthesized 13-LAHLA for biological assays. 13-LAHLA suppresses lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1074/jbc.RA118.006956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615670PMC
July 2019

Synthesis of chemically edited derivatives of the endogenous regulator of inflammation 9-PAHSA.

J Antibiot (Tokyo) 2019 06 15;72(6):498-506. Epub 2019 Apr 15.

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0934, USA.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are a growing class of natural products found in organisms ranging from plants to humans. The roles these endogenous derivatives of fatty acids play in biology and their novel pathways for controlling inflammation have increased our understanding of basic human physiology. FAHFAs incorporate diverse fatty acids into their structures, however, given their recent discovery non-natural derivatives have not been a focus and as a result structure-activity relationships remain unknown. The importance of the long chain hydrocarbons extending from the ester linkage as they relate to anti-inflammatory activity is unknown. Herein the systematic removal of carbons from either the hydroxy fatty acid or fatty acid regions of the most studied FAHFA, palmitic acid ester of 9-hydroxystearic acid (9-PAHSA), was achieved and these synthetic, abridged analogs were tested for their ability to attenuate IL-6 production. Reduction of the carbon chain lengths of the 9-hydroxystearic acid portion or palmitic acid hydrocarbon chain resulted in lower molecular weight analogs that maintained anti-inflammatory activity or in one case enhanced activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41429-019-0180-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784544PMC
June 2019

NovelmiRNA-25 inhibits AMPD2 in peripheral blood mononuclear cells of patients with systemic lupus erythematosus and represents a promising novel biomarker.

J Transl Med 2018 12 22;16(1):370. Epub 2018 Dec 22.

Department of Nephrology, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325035, China.

Background: Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease with various clinical manifestations. MicroRNAs (miRNAs) and immunometabolism are recognized as key elements in SLE pathogenesis; however, the relationship between miRNAs in peripheral blood mononuclear cells (PBMCs) and metabolism in SLE remains unclear.

Methods: We detected PBMC miRNA and mRNA profiles from 3 pooled SLE patients and 3 healthy controls (HCs) using next-generation sequencing, predicted miRNA targets in dysregulated mRNAs, predicted functions and interactions of differentially expressed genes using bioinformatics analysis, validated candidate miRNAs using qRT-PCR, and investigated the association between the expression of candidate miRNAs and SLE clinical characteristics. Moreover, we validated the direct and transcriptional regulatory effect of NovelmiRNA-25 on adenosine monophosphate deaminase 2 (AMPD2) using a dual-luciferase reporter assay and western blot and confirmed AMPD2 mRNA and protein expression in PBMCs using qRT-PCR and western blot, respectively.

Results: Multilayer integrative analysis of microRNA and mRNA regulation showed that 10 miRNAs were down-regulated and 19 miRNAs were up-regulated in SLE patient PBMCs compared with HCs. Bioinformatics analysis of regulatory networks between miRNAs and mRNAs showed that 19 miRNAs were related to metabolic processes. Two candidate miRNAs, NovelmiRNA-25 and miR-1273h-5p, which were significantly increased in the PBMCs of SLE patients (P < 0.05), represented diagnostic biomarkers with sensitivities of 94.74% and 89.47%, respectively (area under the curve = 0.574 and 0.788, respectively). NovelmiRNA-25 expression in PBMCs was associated with disease activity in SLE patients, in both active and stable groups (P < 0.05). NovelmiRNA-25 overexpression downregulated AMPD2 expression in HEK293T cells through direct targeting of the AMPD2 3'UTR (P < 0.01), while inhibition of NovelmiRNA-25 activity led to increased AMPD2 expression (P < 0.01). NovelmiRNA-25 overexpression also downregulated AMPD2 protein expression in HEK293T cells; AMPD2 protein expression in SLE patient PBMCs was decreased. Our results show that differentially expressed miRNAs play an important role in SLE.

Conclusions: Our data demonstrate a novel mechanism in SLE development that involves the targeting of AMPD2 expression by NovelmiRNA-25. miRNAs may serve as novel biomarkers for the diagnosis and evaluation of disease activity of SLE and represent potential therapeutic targets for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12967-018-1739-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303892PMC
December 2018
-->