Publications by authors named "Xiaokun Li"

461 Publications

Large-Scale Preparation of Highly Stable Recombinant Human Acidic Fibroblast Growth Factor in BL21(DE3) plysS Strain.

Front Bioeng Biotechnol 2021 13;9:641505. Epub 2021 Apr 13.

Wenzhou Medical University, Chashan University Park, Wenzhou, China.

In this study, the optimum human gene encoding haFGF was cloned in pET3c and transferred to BL21(DE3) plysS. To enhance the yield of fermentation and the expression level of the target protein, the fermentation parameters, including temperature, pH, dissolved oxygen, glucose concentration, ammonium chloride concentration, induction time, and inducer (IPTG) concentration, were optimized. The optimized fermentation parameters were used in large-scale fermentation (30 L). Ion-exchange and heparin-affinity column chromatography techniques were used for separation and purification of rhaFGF protein. HPLC, isoelectric focusing electrophoresis, and mass spectrometry were used to detect the purity, isoelectric point, and molecular weight and peptide map of rhaFGF protein, respectively. Mitogenic activity of rhaFGF protein was detected in NIH-3T3 cells and a full-thickness injury wound diabetic rat model. The production and expression level of rhaFGF in the 30-L scale fermentation reached 80.4 ± 2.7 g/L culture and 37.8% ± 1.8%, respectively. The RP-HPLC and SDS-PAGE purity of the final rhaFGF product almost reached 100%, and the final pure protein yield was 158.6 ± 6.8 mg/L culture. Finally, the cell and animal experiments showed that rhaFGF retained a potent mitogenic activity. The large-scale process of rhaFGF production reported herein is relatively stable and time-saving, and thus, it can be used as an efficient and economic strategy for the synthesis of rhaFGF at the industrial level.
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http://dx.doi.org/10.3389/fbioe.2021.641505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072344PMC
April 2021

Potassium modulates central carbon metabolism to participate in regulating CO transport and assimilation in Brassica napus leaves.

Plant Sci 2021 Jun 24;307:110891. Epub 2021 Mar 24.

College of Resources and Environment, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River) Ministry of Agriculture and Rural Affairs, Wuhan 430070, China. Electronic address:

Potassium (K) regulates plant metabolism and enhances plant's ability to adapt to adversity. However, under different K deficiency stress, the net photosynthetic rate (A) was reduced, influenced by CO conductance or biochemical capacities. The interplay between metabolome and photosynthetic characteristics under K deficiency stress was analyzed to explore the mechanisms by which K regulates photosynthetic capacity. With increasing K deficiency stress, dominations limiting A varied from CO conductance to biochemical limitations. Multivariate analyses indicated that organic acids, amino acids and sedoheptulose-7-bisphosphate were significantly related to A, CO conductance and carboxylation rate. Under moderate K deficiency, organic acids were up-regulated. Acidification of subcellular compartments reduced sedoheptulose-1,7-bisphosphatase activity, inducing downregulation of sedoheptulose-7-bisphosphate and hindrance of ribulose bisphosphate regeneration. Moreover, increased CO shortage with increasing K deficiency induced a shift of increased citric acid to amino acid synthesis, causing excessive accumulation of amino acids. In addition, the reduced serine level indicated impaired photorespiration. These two changes triggered more serious reduction in photosynthetic capacity. The intimate, changes in photosynthetic capacities were tightly coupled with shifts in central C metabolism, which provides insights into the methods used to enhance A and plant's adaptability to abiotic stresses, through the regulation of C metabolites using molecular technology.
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http://dx.doi.org/10.1016/j.plantsci.2021.110891DOI Listing
June 2021

Metabolomics reveals sex-specific metabolic shifts and predicts the duration from positive to negative in non-severe COVID-19 patients during recovery process.

Comput Struct Biotechnol J 2021 6;19:1863-1873. Epub 2021 Apr 6.

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China.

Metabolic profiling in COVID-19 patients has been associated with disease severity, but there is no report on sex-specific metabolic changes in discharged survivors. Herein we used an integrated approach of LC-MS-and GC-MS-based untargeted metabolomics to analyze plasma metabolic characteristics in men and women with non-severe COVID-19 at both acute period and 30 days after discharge. The results demonstrate that metabolic alterations in plasma of COVID-19 patients during the recovery and rehabilitation process were presented in a sex specific manner. Overall, the levels of most metabolites were increased in COVID-19 patients after the cure relative to acute period. The major plasma metabolic changes were identified including fatty acids in men and glycerophosphocholines and carbohydrates in women. In addition, we found that women had shorter length of hospitalization than men and metabolic characteristics may contribute to predict the duration from positive to negative in non-severe COVID-19 patients. Collectively, this study shed light on sex-specific metabolic shifts in non-severe COVID-19 patients during the recovery process, suggesting a sex bias in prognostic and therapeutic evaluations based on metabolic profiling.
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http://dx.doi.org/10.1016/j.csbj.2021.03.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021501PMC
April 2021

Next-Generation Sequencing Reveals the Progression of COVID-19.

Front Cell Infect Microbiol 2021 11;11:632490. Epub 2021 Mar 11.

Department of Anesthesia and Critical Care, Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

The novel coronavirus SARS-CoV-2 (causing the disease COVID-19) has caused a highly transmissible and ongoing pandemic worldwide. Due to its rapid development, next-generation sequencing plays vital roles in many aspects. Here, we summarize the current knowledge on the origin and human transmission of SARS-CoV-2 based on NGS analysis. The ACE2 expression levels in various human tissues and relevant cells were compared to provide insights into the mechanism of SAS-CoV-2 infection. Gut microbiota dysbiosis observed by metagenome sequencing and the immunogenetics of COVID-19 patients according to single-cell sequencing analysis were also highlighted. Overall, the application of these sequencing techniques could be meaningful for finding novel intermediate SARS-CoV-2 hosts to block interspecies transmission. This information will further benefit SARS-CoV-2 diagnostic development and new therapeutic target discovery. The extensive application of NGS will provide powerful support for our fight against future public health emergencies.
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http://dx.doi.org/10.3389/fcimb.2021.632490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991797PMC
April 2021

Sex- and age-specific clinical and immunological features of coronavirus disease 2019.

PLoS Pathog 2021 03 26;17(3):e1009420. Epub 2021 Mar 26.

School of Basic Medical Science, Wenzhou Medical University, Wenzhou, China.

To simultaneously determine clinical and immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in young and old females and males, 681 coronavirus disease 2019 (COVID-19) patients and 369 normal controls (NCs) were analyzed based on age and sex classifications using multiple linear regression analysis. Compared to the age-matched NCs, both young and old male and female non-comorbid COVID-19 patients had lower lymphocyte counts and alanine aminotransferase (ALT) concentration, and only young male and female patients had lower neutrophil counts. Compared to young patients, both old males and females had significantly higher plasma ALT and AST concentrations. Compared to young and old females, age-matched males had higher plasma ALT and AST concentrations, but only young males had higher C-reactive protein (CRP) concentration. Compared to females, old males, but not young males, showed higher incidence of critical illness. Compared to young patients, old females had more leukocyte and neutrophil counts above the normal upper limit and B cell count below the normal lower limit (NLL), while old males had more lymphocyte and natural killer (NK) cell counts below the NLL. No sex or age associations with B cell and NK cell counts were observed. However, there were age-dependent decreases in CD8+ T-cell counts in both male and female COVID-19 patients. Age was negatively associated with CD8+ T cell counts but positively associated with neutrophil count, CRP, ALT, and AST concentrations, and sex (females) was negatively associated with neutrophil count, CRP, ALT, and AST concentrations. The present study suggests that SARS-CoV-2 infection mainly induced 1) beneficial sex (female)-related differences regarding reduced COVID-19 disease severity and negative associations with inflammatory responses and liver damage, and 2) harmful age-related differences relating to negative associations with CD8+ T cell count and positive associations with inflammatory responses and liver damage. Thus, sex and age are biological variables that should be considered in the prevention and treatment of COVID-19.
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http://dx.doi.org/10.1371/journal.ppat.1009420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026060PMC
March 2021

FGF1 prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression.

Signal Transduct Target Ther 2021 Mar 24;6(1):133. Epub 2021 Mar 24.

School of Pharmaceutical Sciences and Center for Structural Biology, Wenzhou Medical University, Wenzhou, Zhejiang, China.

As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1 treatment. Both in vivo and in vitro studies indicate that FGF1 exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5' AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1 testify to its promising potential for use in the treatment of DCM and other metabolic disorders.
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http://dx.doi.org/10.1038/s41392-021-00542-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991671PMC
March 2021

FAM83A and FAM83A-AS1 both play oncogenic roles in lung adenocarcinoma.

Oncol Lett 2021 Apr 17;21(4):297. Epub 2021 Feb 17.

Department of Cardiothoracic Surgery, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu 210000, P.R. China.

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Nevertheless, the detailed molecular mechanisms of the progression of LUAD remain largely unknown. The present bioinformatics analysis reported that FAM83A and FAM83A-AS1 were upregulated in LUAD tissues and associated with prognosis in patients with LUAD. The purpose of the current study was to investigate the role of FAM83A and its antisense long non-coding (lnc)RNA FAM83A-AS1 in LUAD. Gene Expression Profiling Interactive Analysis was used to screen for potential oncogenes in LUAD and to analyze the clinical significance of FAM83A and FAM83A-AS1. Small interfering RNAs were constructed and transfected into LUAD cells to knock down the expression of FAM83A and FAM83A-AS1. EdU, Cell Counting Kit-8, Transwell and Matrigel assays were performed to detect the proliferation, migration and invasion of LUAD cells. The interaction between FAM83A-AS1, microRNA (miR)-495-3p and FAM83A was explored using a luciferase reporter assay. FAM83A and FAM83A-AS1 were both overexpressed in LUAD tissues compared with adjacent normal tissues. High expression of FAM83A and FAM83A-AS1 predicted worse survival and more advanced clinical stage. Knockdown of FAM83A or FAM83A-AS1 could inhibit the proliferation, migration and invasion of LUAD cells. Moreover, lncRNA FAM83A-AS1 regulated the expression of FAM83A by functioning as competing endogenous RNA for miR-495-3p. These results implicated that FAM83A and FAM83A-AS1 both played oncogenic roles in LUAD and FAM83A-AS1 could regulate the expression of FAM83A by sponging miR-495-3p. The study revealed a novel regulatory mechanism of tumor development in LUAD and FAM83A and FAM83A-AS1 may be novel biomarkers and therapeutic targets for LUAD.
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http://dx.doi.org/10.3892/ol.2021.12558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905536PMC
April 2021

Corrigendum: The Reciprocal Causation of the ASK1-JNK1/2 Pathway and Endoplasmic Reticulum Stress in Diabetes-Induced Cognitive Decline.

Front Cell Dev Biol 2021 24;9:639486. Epub 2021 Feb 24.

Research Units of Clinical Translation of Cell Growth Factors and Diseases Research of Chinese Academy of Medical Science, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.

[This corrects the article DOI: 10.3389/fcell.2020.00602.].
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http://dx.doi.org/10.3389/fcell.2021.639486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945694PMC
February 2021

Age cohorts stratified according to age-distributions of COVID-19 morbidity statistics identify uniquely age-dependent CD3CD8 T-cell lymphocytopenia in COVID-19 patients without comorbidities on admission.

Aging (Albany NY) 2021 03 10;13(6):7713-7722. Epub 2021 Mar 10.

School of Basic Medical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China.

If age boundaries are arbitrarily or roughly defined, age-related analyses can result in questionable findings. Here, we aimed to delineate the uniquely age-dependent immune features of coronavirus disease 2019 (COVID-19) in a retrospective study of 447 patients, stratified according to age distributions of COVID-19 morbidity statistics into well-defined age-cohorts (2-25y, 26-38y, 39-57y, 58-68y, and 69-79y). Age-dependent susceptibilities and severities of the disease were observed in COVID-19 patients. A comparison of the lymphocyte counts among the five age-groups indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection led to age-dependent lymphopenia. Among the lymphocyte subsets, the CD8 T cell count alone was significantly and age-dependently decreased (520, 385, 320, 172, and 139 n/μl in the five age-groups, respectively). In contrast, the CD4 T cell, B cell, and natural killer cell counts did not differ among age-cohorts. Age and CD8 T cell counts (r=‒0.435, p<0.0001) were negatively correlated in COVID-19 patients. Moreover, SARS-CoV-2 infection age-dependently increased the plasma C-reactive protein concentrations (2.0, 5.0, 9.0, 11.6, and 36.1 mg/L in the five age-groups, respectively). These findings can be used to elucidate the role of CD8 T cells in age-related pathogenesis and to help develop therapeutic strategies for COVID-19.
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http://dx.doi.org/10.18632/aging.202691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034949PMC
March 2021

bFGF alleviates diabetes-associated endothelial impairment by downregulating inflammation via S-nitrosylation pathway.

Redox Biol 2021 May 20;41:101904. Epub 2021 Feb 20.

School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, PR China. Electronic address:

Protein S-nitrosylation is a reversible protein modification implicated in both physiological and pathophysiological regulation of protein function. However, the relationship between dysregulated S-nitrosylation homeostasis and diabetic vascular complications remains incompletely understood. Here, we demonstrate that basic fibroblast growth factor (bFGF) is a key regulatory link between S-nitrosylation homeostasis and inflammation, and alleviated endothelial dysfunction and angiogenic defects in diabetes. Subjecting human umbilical vein endothelial cells (HUVECs) to hyperglycemia and hyperlipidemia significantly decreased endogenous S-nitrosylated proteins, including S-nitrosylation of inhibitor kappa B kinase β (IKKβ) and transcription factor p65 (p65), which was alleviated by bFGF co-treatment. Pretreatment with carboxy-PTIO (c-PTIO), a nitric oxide scavenger, abolished bFGF-mediated S-nitrosylation increase and endothelial protection. Meanwhile, nitrosylation-resistant IKKβ and p65 mutants exacerbated endothelial dysfunction in db/db mice, and in cultured HUVECs subjected to hyperglycemia and hyperlipidemia. Mechanistically, bFGF-mediated increase of S-nitrosylated IKKβ and p65 was attributed to synergistic effects of increased endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx) activity. Taken together, the endothelial protective effect of bFGF under hyperglycemia and hyperlipidemia can be partially attributed to its role in suppressing inflammation via the S-nitrosylation pathway.
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http://dx.doi.org/10.1016/j.redox.2021.101904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7972985PMC
May 2021

Long Noncoding RNA Nuclear Paraspeckle Assembly Transcript 1 Promotes Progression and Angiogenesis of Esophageal Squamous Cell Carcinoma Through miR-590-3p/MDM2 Axis.

Front Oncol 2020 19;10:618930. Epub 2021 Feb 19.

Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.

Angiogenesis has been identified as one of the hallmarks of cancer and aggravates cancer development and progression. Accumulating evidence indicated that long noncoding RNAs (lncRNAs) are powerful factors in regulating various cancer behaviors. The aim of this study is to verify the function and potential mechanisms of lncRNA NEAT1 in progression and angiogenesis of esophageal squamous cell carcinoma (ESCC). We found that NEAT1 was overexpressed in ESCC tissues and correlated with clinical characteristics of patients. Silence of NEAT1 inhibited proliferation, migration, invasion and angiogenesis of ESCC cells. High throughput sequencing and western blotting revealed that NEAT1 regulated MDM2/p53 pathway. Rescue of MDM2 restored the effect of NEAT1 on progression and angiogenesis of ESCC cells. Nude mice xenograft models further validated the role of NEAT1 . Importantly, NEAT1 functioned as a competing endogenous RNA for miR-590-3p to regulate MDM2 expression and miR-590-3p acted as a tumor suppressor in ESCC progression and angiogenesis. These findings suggested that NEAT1/miR-590-3p/MDM2 axis might serve as potential therapeutic targets for ESCC patients.
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http://dx.doi.org/10.3389/fonc.2020.618930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933463PMC
February 2021

Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity.

Cancers (Basel) 2021 Feb 13;13(4). Epub 2021 Feb 13.

Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and (Kirsten rat sarcoma 2 viral oncogene homolog) mutations have been considered a critical driver of PDAC initiation and progression. However, the effects of mutant KRAS alone do not recapitulate the full spectrum of pancreatic pathologies associated with PDAC development in adults. Historically, mutant KRAS was regarded as constitutively active; however, recent studies have shown that endogenous levels of mutant KRAS are not constitutively fully active and its activity is still subject to up-regulation by upstream stimuli. Obesity is a metabolic disease that induces a chronic, low-grade inflammation called meta-inflammation and has long been recognized clinically as a major modifiable risk factor for pancreatic cancer. It has been shown in different animal models that obesogenic high-fat diet (HFD) and pancreatic inflammation promote the rapid development of mutant KRAS-mediated PDAC with high penetrance. However, it is not clear why the pancreas with endogenous levels of mutant KRAS is vulnerable to chronic HFD and inflammatory challenges. Recently, the discovery of fibroblast growth factor 21 (FGF21) as a novel anti-obesity and anti-inflammatory factor and as a downstream target of mutant KRAS has shed new light on this problem. This review is intended to provide an update on our knowledge of the vulnerability of the pancreas to KRAS-mediated invasive PDAC in the context of challenges engendered by obesity and associated inflammation.
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http://dx.doi.org/10.3390/cancers13040778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918840PMC
February 2021

The Property-Based Practical Applications and Solutions of Genetically Encoded Acetylcholine and Monoamine Sensors.

J Neurosci 2021 Mar 24;41(11):2318-2328. Epub 2021 Feb 24.

Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, Virginia 22908.

Neuromodulatory communication among various neurons and non-neuronal cells mediates myriad physiological and pathologic processes, yet defining regulatory and functional features of neuromodulatory transmission remains challenging because of limitations of available monitoring tools. Recently developed genetically encoded neuromodulatory transmitter sensors, when combined with superresolution and/or deconvolution microscopy, allow the first visualization of neuromodulatory transmission with nanoscale or microscale spatiotemporal resolution. and experiments have validated several high-performing sensors to have the qualities necessary for demarcating fundamental synaptic properties of neuromodulatory transmission, and initial analysis has unveiled unexpected fine control and precision of neuromodulation. These new findings underscore the importance of synaptic dynamics in synapse-, subcellular-, and circuit-specific neuromodulation, as well as the prospect of genetically encoded transmitter sensors in expanding our knowledge of various behaviors and diseases, including Alzheimer's disease, sleeping disorders, tumorigenesis, and many others.
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http://dx.doi.org/10.1523/JNEUROSCI.1062-19.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984589PMC
March 2021

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Cell Death Dis 2021 Feb 16;12(2):189. Epub 2021 Feb 16.

Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University, Stony Brook, NY, USA.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RAS and RAS, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRAS-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.
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http://dx.doi.org/10.1038/s41419-021-03473-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887267PMC
February 2021

FGF20 Protected Against BBB Disruption After Traumatic Brain Injury by Upregulating Junction Protein Expression and Inhibiting the Inflammatory Response.

Front Pharmacol 2020 25;11:590669. Epub 2021 Jan 25.

School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and , rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response.
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http://dx.doi.org/10.3389/fphar.2020.590669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868342PMC
January 2021

Hypoxia response element-directed expression of bFGF in dental pulp stem cells improve the hypoxic environment by targeting pericytes in SCI rats.

Bioact Mater 2021 Aug 30;6(8):2452-2466. Epub 2021 Jan 30.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.

Cell-based transplantation strategies possess great potential for spinal cord injury (SCI) repair. Basic fibroblast growth factor (bFGF) has been reported to have multiple neuro-promoting effects on developing and adult nervous system of mammals and considered a promising therapy for nerve injury following SCI. Human dental pulp stem cells (DPSCs) are abundant stem cells with low immune rejection, which can be considered for cell replacement therapy. The purpose of this study was to investigate the roles of DPSCs which express bFGF under the regulation of five hypoxia-responsive elements (5HRE) using an adeno-associated virus (AAV-5HRE-bFGF-DPSCs) in SCI repairing model. In this study, DPSCs were revealed to differentiate into CD13 pericytes and up-regulate N-cadherin expression to promote the re-attachment of CD13 pericytes to vascular endothelial cells. The re-attachment of CD13 pericytes to vascular endothelial cells subsequently increased the flow rate of blood in microvessels via the contraction of protuberance. As a result, increased numbers of red blood cells carried more oxygen to the damaged area and the local hypoxia microenvironment in SCI was improved. Thus, this study represents a step forward towards the potential use of AAV-5HRE-bFGF-DPSCs in SCI treatment in clinic.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850944PMC
August 2021

Camelina lipid droplets as skin delivery system promotes wound repair by enhancing the absorption of hFGF2.

Int J Pharm 2021 Apr 2;598:120327. Epub 2021 Feb 2.

College of Life Science, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun 130118, China; College of Tropical Crops, Hainan University, Haikou, China. Electronic address:

Human basic fibroblast growth factor (hFGF2) is widely recognized for accelerating skin wound healing in both animal models and randomized clinical trials. However, the low skin permeation and bioavailability of hFGF2 remain the most limiting factors in the pharmacological application. For the first time, Camelina Lipid Droplets (CLD) delivery system was displayed important virtue, by promoting the skin absorption of hFGF2, which is a key factor that accelerates the skin wound repair, and provide a new alternative for skin therapy. In this study, we used the CLD as a safer material to prepare the nanoparticles, which were characterized by size and morphology. Our data revealed that particle sizes of Camelina Lipid Droplets linked to hFGF2 (CLD-hFGF2) were around 133.5 nm; it also displayed that the complex of CLD-hFGF2 penetrates the skin barrier in deeper than an individual hFGF2. This suggests that once the hFGF2 is fixed onto the surface of CLD, it can cross the stratum corneum and play a therapeutic role into the dermis. Furthermore, we demonstrated that CLD-hFGF2 enhances fibroblast migration, and significantly improves skin regeneration for accelerating wound healing without any significant toxicity. This paper highlights the importance of CLD as an emerging delivery system; it is also providing a new and applicable therapeutic research direction through enhancing the skin permeation of hFGF2 to accelerate wound healing.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120327DOI Listing
April 2021

Cinobufagin suppresses colorectal cancer growth via STAT3 pathway inhibition.

Am J Cancer Res 2021 1;11(1):200-214. Epub 2021 Jan 1.

Institute of Life Sciences, Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University Wenzhou 325035, Zhejiang, China.

Colorectal cancer (CRC) has become one of the most common types of cancer with the highest morbidity and mortality rates globally. Cinobufagin, a natural product extracted from toad venom and a major active ingredient in cinobufotalin, exhibits high antitumor activity. Here, we investigated the and antitumor activities of cinobufagin and explored the underlying mechanisms in CRC. Cinobufagin could inhibit proliferation, migration, invasion and promote apoptosis of HCT116, RKO, and SW480 cells . Mechanistically, cinobufagin simultaneously suppressed the phosphorylation of signal transducer and activator of transcription 3 (STAT3) and blocked the interleukin-6 (IL6)-induced nuclear translocation of STAT3. IL6 activated the STAT3 pathway, subsequently inducing epithelial-mesenchymal transition (EMT). Furthermore, cinobufagin suppressed EMT in CRC by inhibiting the STAT3 pathway. Animal experiments clearly showed that cinobufagin could reduce tumor growth. Cinobufagin may be used clinically as a novel STAT3 inhibitor for CRC adjuvant therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840714PMC
January 2021

Acidic fibroblast growth factor attenuates type 2 diabetes-induced demyelination via suppressing oxidative stress damage.

Cell Death Dis 2021 Jan 21;12(1):107. Epub 2021 Jan 21.

Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, 325000, Wenzhou, Zhejiang, China.

Prolonged type 2 diabetes mellitus (T2DM) produces a common complication, peripheral neuropathy, which is accompanied by nerve fiber disorder, axon atrophy, and demyelination. Growing evidence has characterized the beneficial effects of acidic fibroblast growth factor (aFGF) and shown that it relieves hyperglycemia, increases insulin sensitivity, and ameliorates neuropathic impairment. However, there is scarce evidence on the role of aFGF on remodeling of aberrant myelin under hyperglycemia condition. Presently, we observed that the expression of aFGF was rapidly decreased in a db/db T2DM mouse model. Administration of exogenous aFGF was sufficient to block acute demyelination and nerve fiber disorganization. Furthermore, this strong anti-demyelinating effect was most likely dominated by an aFGF-mediated increase of Schwann cell (SC) proliferation and migration as well as suppression of its apoptosis. Mechanistically, the beneficial biological effects of aFGF on SC behavior and abnormal myelin morphology were likely due to the inhibition of hyperglycemia-induced oxidative stress activation, which was most likely activated by kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid-derived-like 2 (Nrf2) signaling. Thus, this evidence indicates that aFGF is a promising protective agent for relieving myelin pathology through countering oxidative stress signaling cascades under diabetic conditions.
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http://dx.doi.org/10.1038/s41419-021-03407-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819983PMC
January 2021

Association Between Systemic Immune-Inflammation Index and Diabetic Depression.

Clin Interv Aging 2021 11;16:97-105. Epub 2021 Jan 11.

Department of Endocrinology, Yanbian University Hospital, Yanji, Jilin, People's Republic of China.

Background: Depression is highly prevalent in patients with diabetes mellitus (DM). Diabetic depression has been shown to be associated with low-grade systemic inflammation. In recent years, the systemic immune-inflammation (SII) index has been developed as an integrated and novel inflammatory indicator. The aims of this study were to investigate the relationship between diabetic depression and SII levels, adjusting for a wide range of potential confounding factors, to examine the potential of SII in predicting diabetic depression.

Methods: The present cross-sectional study was conducted among adults with DM in the National Health and Nutrition Examination Survey between 2009 and 2016, the SII level was calculated as the platelet counts × neutrophil counts/lymphocyte counts. Patient Health Questionnaire-9 was used to measure depression in patients with DM. Multivariable logistic regression and propensity score-matched analysis were used to analyze the association between SII levels and depression.

Results: A total of 2566 patients with DM were included in the study, of which 370 (13.3%) were diagnosed with depression. Multivariable logistic regression showed that high SII level was an independent risk factor for diabetic depression (OR = 1.347, 95% CI: 1.031-1.760, = 0.02882) after adjusting for covariates. The relationship between SII and diabetic depression was further verified by propensity score-matched analysis.

Conclusion: Our data suggest that SII is a risk factor for depression in patients with DM. The SII may be an easily accessible and cost-effective strategy for identifying depression in patients with DM. More studies are warranted to further analyze the role of SII in depression in diabetic patients.
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http://dx.doi.org/10.2147/CIA.S285000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810592PMC
May 2021

The protective effects of fibroblast growth factor 10 against hepatic ischemia-reperfusion injury in mice.

Redox Biol 2021 04 7;40:101859. Epub 2021 Jan 7.

School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China. Electronic address:

Hepatic ischemia-reperfusion injury (IRI) is a major complication of liver surgery and transplantation. IRI leads to hepatic parenchymal cell death, resulting in liver failure, and lacks effective therapeutic approaches. Fibroblast growth factor 10 (FGF10) is a paracrine factor which is well-characterized with respect to its pro-proliferative effects during embryonic liver development and liver regeneration, but its role in hepatic IRI remains unknown. In this study, we investigated the role of FGF10 in liver IRI and identified signaling pathways regulated by FGF10. In a mouse model of warm liver IRI, FGF10 was highly expressed during the reperfusion phase. In vitro experiments demonstrated that FGF10 was primarily secreted by hepatic stellate cells and acted on hepatocytes. The role of FGF10 in liver IRI was further examined using adeno-associated virus-mediated gene silencing and overexpression. Overexpression of FGF10 alleviated liver dysfunction, reduced necrosis and inflammation, and protected hepatocytes from apoptosis in the early acute injury phase of IRI. Furthermore, in the late phase of IRI, FGF10 overexpression also promoted hepatocyte proliferation. Meanwhile, gene silencing of FGF10 had the opposite effect. Further studies revealed that overexpression of FGF10 activated nuclear factor-erythroid 2-related factor 2 (NRF2) and decreased oxidative stress, mainly through activation of the phosphatidylinositol-3-kinase/AKT pathway, and the protective effects of FGF10 overexpression were largely abrogated in NRF2 knockout mice. These results demonstrate the protective effects of FGF10 in liver IRI, and reveal the important role of NRF2 in FGF10-mediated hepatic protection during IRI.
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http://dx.doi.org/10.1016/j.redox.2021.101859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806526PMC
April 2021

Dermal toxicity, dermal irritation, and delayed contact sensitization evaluation of oil body linked oleosin-hEGF microgel emulsion transdermal drug delivery for wound healing.

Cutan Ocul Toxicol 2021 Mar 25;40(1):45-53. Epub 2021 Jan 25.

College of Life Science, Engineering Research Center of the Chinese Ministry of Education for Bioreactor and Pharmaceutical Development, Jilin Agricultural University, Changchun, PR China.

The expression of therapeutic proteins in plant oil body bioreactors has attracted much attention. But its safety is not yet clear. This article determines the risk of safety after using the drug. The oil body-linked oleosin-hEGF microgel emulsion (OBEME) was prepared by mixing the xanthan gum with suitable concentrations in an appropriate proportion. Skin irritation and sensitization reaction were investigated in rats and guinea pigs using OBEME as test article. The OBEME did not produce dermal erythema/eschar or oedema responses. The dermal subacute and subchronic toxicity of OBEME were evaluated in accordance with OECD guidelines. Compared with the control group, the basic physical signs, such as weight, feed, drinking, excretion, and behaviour of experimental animals, were not abnormal. In addition, no abnormality was found in haematological parameters, biochemical indexes, relative organ weight, and histopathological observation of organs, and there was no significant difference compared with normal saline treatment group. Therefore, we conclude that OBEME has no toxic effects and is safe and reliable to be used for topical application.
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http://dx.doi.org/10.1080/15569527.2021.1874008DOI Listing
March 2021

Calcineurin controls proximodistal blastema polarity in zebrafish fin regeneration.

Proc Natl Acad Sci U S A 2021 01;118(2)

Jiangxi Engineering Laboratory of Zebrafish Modeling and Drug Screening for Human Diseases, Jiangxi Key Laboratory of Developmental Biology of Organs, Affiliated Hospital of Jinggangshan University, College of Life Sciences, Jinggangshan University, Ji'an, 343009 Jiangxi, China;

Planarian flatworms regenerate their heads and tails from anterior or posterior wounds and this regenerative blastema polarity is controlled by Wnt/β-catenin signaling. It is well known that a regeneration blastema of appendages of vertebrates such as fish and amphibians grows distally. However, it remains unclear whether a regeneration blastema in vertebrate appendages can grow proximally. Here, we show that a regeneration blastema in zebrafish fins can grow proximally along the proximodistal axis by calcineurin inhibition. We used fin excavation in adult zebrafish to observe unidirectional regeneration from the anterior cut edge (ACE) to the posterior cut edge (PCE) of the cavity and this unidirectional regeneration polarity occurs as the PCE fails to build blastemas. Furthermore, we found that calcineurin activities in the ACE were greater than in the PCE. Calcineurin inhibition induced PCE blastemas, and calcineurin hyperactivation suppressed fin regeneration. Collectively, these findings identify calcineurin as a molecular switch to specify the PCE blastema of the proximodistal axis and regeneration polarity in zebrafish fin.
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http://dx.doi.org/10.1073/pnas.2009539118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812827PMC
January 2021

aFGF alleviates diabetic endothelial dysfunction by decreasing oxidative stress via Wnt/β-catenin-mediated upregulation of HXK2.

Redox Biol 2021 02 19;39:101811. Epub 2020 Dec 19.

School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, PR China. Electronic address:

Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis.
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http://dx.doi.org/10.1016/j.redox.2020.101811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772795PMC
February 2021

Myocardial protection by heparin-based coacervate of FGF10.

Bioact Mater 2021 Jul 10;6(7):1867-1877. Epub 2020 Dec 10.

School of Pharmacy, Key Laboratory of Biotechnology and Pharmaceutical Engineering, Wenzhou Medical University, Wenzhou, 325035, China.

Heart disease is still the leading killer all around the world, and its incidence is expected to increase over the next decade. Previous reports have already shown the role of fibroblast growth factor10 (FGF10) in alleviating heart diseases. However, FGF10 has not been used to treat heart diseases because the free protein has short half-life and low bioactivity. Here, an injectable coacervate was designed to protect growth factor from degradation during delivery and the effects of the FGF10 coacervate were studied using a mice acute myocardial infarction (MI) model. As shown in our echocardiographic results, a single injection of FGF10 coacervate effectively inhibited preserved cardiac contractibility and ventricular dilation when compared with free FGF10 and the saline treatment 6 weeks after MI. It is revealed in histological results that the MI induced myocardial inflammation and fibrosis was reduced after FGF10 coacervate treatment. Furthermore, FGF10 coacervate treatment could improve arterioles and capillaries stabilization through increasing the proliferation of endothelial and mural cells. However, with the same dosage, no statistically significant difference was shown between free FGF10, heparin+FGF10 and saline treatment, especially in long term. On another hand, FGF10 coacervate also increased the expression of cardiac-associated the mRNA (cTnT, Cx43 and α-SMA), angiogenic factors (Ang-1 and VEGFA) and decreased the level of inflammatory factor (tumor necrosis factor-α). The downstream signaling of the FGF10 was also investigated, with the western blot results showing that FGF10 coacervate activated the -FGFR, PI3K/Akt and ERK1/2 pathways to a more proper level than free FGF10 or heparin+FGF10. In general, it is revealed in this research that one-time injection of FGF10 coacervate sufficiently attenuated MI induced injury when compared with an equal dose of free FGF10 or heparin+FGF10 injection.
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http://dx.doi.org/10.1016/j.bioactmat.2020.12.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732874PMC
July 2021

Thalidomide combined with short-term low-dose glucocorticoid therapy for the treatment of severe COVID-19: A case-series study.

Int J Infect Dis 2021 Feb 14;103:507-513. Epub 2020 Dec 14.

The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. Electronic address:

Objectives: The aim was to evaluate the safety and effectiveness of thalidomide, an immunomodulatory agent, in combination with glucocorticoid, for the treatment of COVID-19 patients with life-threatening symptoms.

Methods: A nonrandomized comparative case series study was performed. Six patients received thalidomide 100 mg per day (with therapy lasting for ≥7 days) plus low-dose short-term dexamethasone, and 6 control patients matched with patients in the thalidomide group, received low-dose short-term treatment with dexamethasone alone. The main outcomes were: the duration of SARS-CoV-2 negative conversion from admission; length of hospital stay; and changes in inflammatory cytokine concentrations and lymphocyte subsets.

Results: The median thalidomide treatment time was 12.0 days. The median duration of SARS-CoV-2 negative conversion from admission and hospital stay length were briefer in the thalidomide group compared to the control group (respectively, 11.0 vs 23.0 days, P = 0.043; 18.5 vs 30.0 days, P = 0.043). The mean reduction rates at 7-10 days after treatment for serum interleukin-6 and interferon-γ concentrations were greater in the thalidomide group compared to the control group. Alterations in lymphocyte numbers in the subsets between the 2 groups were similar.

Conclusions: Thalidomide plus short-term glucocorticoid therapy is an effective and safe regimen for the treatment of severely ill COVID-19 patients. The mechanism of action is most likely inhibition of inflammatory cytokine production.
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http://dx.doi.org/10.1016/j.ijid.2020.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834521PMC
February 2021

Dynamic folding modulation generates FGF21 variant against diabetes.

EMBO Rep 2021 Jan 9;22(1):e51352. Epub 2020 Dec 9.

High Magnetic Field Laboratory, CAS Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China.

Fibroblast growth factor 21 (FGF21) is a regulator of glucose and lipid metabolism. It has been widely considered as a promising candidate for the treatment of type 2 diabetes mellitus (T2DM) and other related metabolic disorders. However, lack of structural and dynamic information has limited FGF21-based drug development. Here, using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of FGF21 and find that its non-canonical flexible β-trefoil conformation affects the folding of β2-β3 hairpin and further overall protein stability. To modulate folding dynamics, we designed an FGF21-FGF19 chimera, FGF21 . As expected, FGF21 shows better thermostability without inducing hepatocyte proliferation. Functional characterization of FGF21 shows its better insulin sensitivity, reduced inflammation in 3T3-L1 adipocytes, and lower blood glucose and insulin levels in ob/ob mice compared with wild type. Our dynamics-based rational design provides a promising approach for FGF21-based therapeutic development against T2DM.
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http://dx.doi.org/10.15252/embr.202051352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788455PMC
January 2021

FGF21 in obesity and cancer: New insights.

Cancer Lett 2021 Feb 29;499:5-13. Epub 2020 Nov 29.

Division of Gastroenterology and Hepatology, Department of Medicine, Stony Brook University, Stony Brook, NY, 11794, USA; School of Pharmaceutical Science, Wenzhou Medical University, China; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China; Centeer BioTherapeutics Ltd Co, Houston, TX, 77030, USA. Electronic address:

The endocrine FGF21 was discovered as a novel metabolic regulator in 2005 with new functions bifurcating from the canonic heparin-binding FGFs that directly promote cell proliferation and growth independent of a co-receptor. Early studies have demonstrated that FGF21 is a stress sensor in the liver and possibly, several other endocrine and metabolic tissues. Hepatic FGF21 signals via endocrine routes to quench episodes of metabolic derangements, promoting metabolic homeostasis. The convergence of mouse and human studies shows that FGF21 promotes lipid catabolism, including lipolysis, fatty acid oxidation, mitochondrial oxidative activity, and thermogenic energy dissipation, rather than directly regulating insulin and appetite. The white and brown adipose tissues and, to some extent, the hypothalamus, all of which host a transmembrane receptor binary complex of FGFR1 and co-receptor KLB, are considered the essential tissue and molecular targets of hepatic or pharmacological FGF21. On the other hand, a growing body of work has revealed that pancreatic acinar cells form a constitutive high-production site for FGF21, which then acts in an autocrine or paracrine mode. Beyond regulation of macronutrient metabolism and physiological energy expenditure, FGF21 appears to function in forestalling the development of fatty pancreas, steato-pancreatitis, fatty liver, and steato-hepatitis, thereby preventing the development of advanced pathologies such as pancreatic ductal adenocarcinoma or hepatocellular carcinoma. This review is intended to provide updates on these new discoveries that illuminate the protective roles of FGF21-FGFR1-KLB signal pathway in metabolic anomalies-associated severe tissue damage and malignancy, and to inform potential new preventive or therapeutic strategies for obesity-inflicted cancer patients via reducing metabolic risks and inflammation.
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http://dx.doi.org/10.1016/j.canlet.2020.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779663PMC
February 2021

Optimal potassium management strategy to enhance crop yield and soil potassium fertility under paddy-upland rotation.

J Sci Food Agric 2020 Nov 24. Epub 2020 Nov 24.

Key Laboratory of Arable Land Conservation (Middle and Lower Reaches of Yangtze River), Ministry of Agriculture and Rural Affairs, Wuhan, China.

Background: An unbalanced application of potassium (K) fertilizer usually destabilizes crop yield and affects soil K fertility. Developing a sustainable K management strategy requires improvements in crop yield without reducing soil K supply capacity over the long term. A combination of field experiments of K fertilization and straw return using rice (Oryza sativa L.)-oilseed rape (Brassica napus L.) rotation was designed to develop an optimal K management strategy.

Results: The results showed the best strategy to maintain yield was K +S (input equivalent K removed by seed treatment and straw return), K +K (input equivalent K removed by straw and seed) and K +S (conventional K fertilization and straw return) treatments, and the yield gap among different treatments expanded with the extension of planting years. There were significant differences present in rice and rape K uptake, although no differences in seed K uptake were observed under different K management strategies. The K balance was approximately maintained under K +S and K +K treatments, and negative K balances were present for K (no K application), K (conventional fertilization), +S (straw return) and K treatments (input equivalent K that removed by straw treatment). A positive balance was observed under K +S treatment. Slight changes in soil exchangeable and nonexchangeable K were observed under K +S and +S treatments. However, high inputs of K fertilizer prevented the improvement of agronomic efficiency and recovery efficiency of K.

Conclusions: In summary, the optimal K management strategy was K +S, which stabilizes the crop yield, maintains soil K fertility and maximizes K use efficiency. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10970DOI Listing
November 2020

Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability.

Proc Natl Acad Sci U S A 2020 11 3;117(46):29025-29034. Epub 2020 Nov 3.

School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035 Zhejiang, China;

As a physiological regulator of bile acid homeostasis, FGF19 is also a potent insulin sensitizer capable of normalizing plasma glucose concentration, improving lipid profile, ameliorating fatty liver disease, and causing weight loss in both diabetic and diet-induced obesity mice. There is therefore a major interest in developing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease. However, the known tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its clinical potential. Here, we show that nonmitogenic FGF19 variants that retain the full beneficial glucose-lowering and bile acid regulatory activities of WT FGF19 (FGF19) can be engineered by diminishing FGF19's ability to induce dimerization of its cognate FGF receptors (FGFR). As proof of principle, we generated three such variants, each with a partial defect in binding affinity to FGFR (FGF19) and its coreceptors, i.e., βklotho (FGF19) or heparan sulfate (FGF19). Pharmacological assays in WT and mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19 in eliciting glycemic control and regulating bile acid synthesis. This approach provides a robust framework for the development of safer and more efficacious FGF19 analogs.
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http://dx.doi.org/10.1073/pnas.2010984117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682408PMC
November 2020