Publications by authors named "Zhengyu Jiang"

66 Publications

Discovery of as a Potent and Orally Bioavailable Inhibitor of the WDR5-Mixed Lineage Leukemia 1 Protein-Protein Interaction for the Treatment of MLL Fusion Leukemia.

J Med Chem 2021 Jun 9. Epub 2021 Jun 9.

Jiangsu Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.

WD repeat-containing protein 5 (WDR5) is essential for the stability and methyltransferase activity of the mixed lineage leukemia 1 (MLL1) complex. Dysregulation of the gene is associated with human acute leukemias, and the direct disruption of the WDR5-MLL1 protein-protein interaction (PPI) is emerging as an alternative strategy for MLL-rearranged cancers. Here, we represent a new aniline pyrimidine scaffold for WDR5-MLL1 inhibitors. A comprehensive structure-activity analysis identified a potent inhibitor (), with an IC of 29 nM in a competitive fluorescence polarization assay and a value of 72.9 nM for the WDR5 protein. Compound selectively inhibited MLL histone methyltransferase activity and the proliferation of MLL translocation-harboring cells. Furthermore, displayed good pharmacokinetic properties and suppressed the growth of MV4-11 xenograft tumors in mice after oral administration, first verifying the efficacy of targeting the WDR5-MLL1 PPI by small molecules.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00091DOI Listing
June 2021

Preoperative Serum Metabolites and Potential Biomarkers for Perioperative Cognitive Decline in Elderly Patients.

Front Psychiatry 2021 20;12:665097. Epub 2021 May 20.

Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China.

Perioperative cognitive decline is one of the perioperative neurocognitive disorders common to see in elderly patients. Although POCD increases patient mortality and hospitalization time, the exact inflammatory and related mechanisms are still unknown. Besides, the diagnosis of POCD lacks a unified and straightforward evaluation neuropsychological scale. Metabolites could reveal chemical fingerprints left behind by the cellular process, which provides a new aspect to understand the biological process behind. According to the post-operative MMSE score, 56 patients who received elective orthopedics surgery were included and divided into POCD and Non-POCD groups. Preoperative serum metabolites in both groups and post-operative serum metabolites were analyzed. We then performed an SVM model using 10 differential metabolites in preoperative samples as features to evaluate the patients' risk of POCD, which appeared to be positively associated with POCD and could be a potential biomarker. We also analyzed differential serum metabolites from preoperative and post-operative samples of POCD patients. By analyzing their overlap differential metabolites with between POCD and Non-POCD patients, we further inferred seven metabolites positively related to the POCD mechanism. Our results provide a more convenient method to aid POCD diagnosis and prevention using biomarkers and explore the possible mechanism behind.
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http://dx.doi.org/10.3389/fpsyt.2021.665097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174563PMC
May 2021

Inhibitors of BCL2A1/Bfl-1 protein: Potential stock in cancer therapy.

Eur J Med Chem 2021 Aug 14;220:113539. Epub 2021 May 14.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

The Bcl-2 family members rigorously regulate cell endogenous apoptosis, and targeting anti-apoptotic members is a hot topic in design of anti-cancer drugs. At present, FDA and EMA have approved Bcl-2 inhibitor Venetoclax (ABT-199) for treating chronic lymphocytic leukemia (CLL). However, inhibitors of anti-apoptotic protein BCL2A1/Bfl-1 have not been vigorously developed, and no molecule with ideal activity and selectivity has been found yet. Here we review the biological function and protein structure of Bfl-1, discuss the therapeutic potential and list the currently reported inhibitory peptides and small molecules. This will provide a reference for Bfl-1 targeting drug discovery in the future.
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http://dx.doi.org/10.1016/j.ejmech.2021.113539DOI Listing
August 2021

Discovery of a covalent inhibitor of heat shock protein 90 with antitumor activity that blocks the co-chaperone binding via C-terminal modification.

Cell Chem Biol 2021 Apr 26. Epub 2021 Apr 26.

State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Heat shock protein (Hsp90), a critical molecular chaperone that regulates the maturation of a large number of oncogenic client proteins, plays an essential role in the growth of neoplastic cells. Herein, DDO-6600 is identified to covalent modification of Cys598 on Hsp90 from in silico study and is verified by a series of biological assays. We demonstrated that DDO-6600 covalently bound to Cys598 on the Hsp90 C terminus and exhibited antiproliferative activities against multiple tumor cells without inhibiting ATPase activity. Further studies showed that DDO-6600 disrupted the interaction between Hsp90 and Cdc37, which induced the degradation of kinase client proteins in multiple tumor cell lines, promoted apoptosis, and inhibited cell motility. Our findings offer mechanic insights into the covalent modification of Hsp90 and provide an alternative strategy for the development of Hsp90 covalent regulators or chemical probes to explore the therapeutical potential of Hsp90.
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http://dx.doi.org/10.1016/j.chembiol.2021.03.016DOI Listing
April 2021

Retrospective analysis of shoulder debridement and partial and complete repair in the treatment of shoulder cuff tear.

Minerva Surg 2021 Apr 14. Epub 2021 Apr 14.

Department of Orthopedics, Liyang People's Hospital, Liyang, China -

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http://dx.doi.org/10.23736/S2724-5691.21.08871-7DOI Listing
April 2021

An explainable machine learning algorithm for risk factor analysis of in-hospital mortality in sepsis survivors with ICU readmission.

Comput Methods Programs Biomed 2021 Jun 7;204:106040. Epub 2021 Mar 7.

Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China. Electronic address:

Background And Objective: Patients who survive sepsis in the intensive care unit (ICU) (sepsis survivors) have an increased risk of long-term mortality and ICU readmission. We aim to identify the risk factors for in-hospital mortality in sepsis survivors with later ICU readmission and visualize the quantitative relationship between the individual risk factors and mortality by applying machine learning (ML) algorithm.

Methods: Data were obtained from the Medical Information Mart for Intensive Care III (MIMIC-III) database for sepsis and non-sepsis ICU survivors who were later readmitted to the ICU. The data on the first day of ICU readmission and the in-hospital mortality was combined for the ML algorithm modeling and the SHapley Additive exPlanations (SHAP) value of the correlation between the risk factors and the outcome.

Results: Among the 2970 enrolled patients, in-hospital mortality during ICU readmission was significantly higher in sepsis survivors (n = 2228) than nonsepsis survivors (n = 742) (50.4% versus 30.7%, P<0.001). The ML algorithm identified 18 features that were associated with a risk of mortality in these groups; among these, BUN, age, weight, and minimum heart rate were shared by both groups, and the remaining mean systolic pressure, urine output, albumin, platelets, lactate, activated partial thromboplastin time (APTT), potassium, pCO2, pO2, respiration rate, Glasgow Coma Scale (GCS) score for eye-opening, anion gap, sex and temperature were specific to previous sepsis survivors. The ML algorithm also calculated the quantitative contribution and noteworthy threshold of each factor to the risk of mortality in sepsis survivors.

Conclusion: 14 specific parameters with corresponding thresholds were found to be associated with the in-hospital mortality of sepsis survivors during the ICU readmission. The construction of advanced ML techniques could support the analysis and development of predictive models that can be used to support the decisions and treatment strategies made in a clinical setting in critical care patients.
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http://dx.doi.org/10.1016/j.cmpb.2021.106040DOI Listing
June 2021

Blood metabolomic profiling predicts postoperative gastrointestinal function of colorectal surgical patients under the guidance of goal-directed fluid therapy.

Aging (Albany NY) 2021 03 10;13(6):8929-8943. Epub 2021 Mar 10.

Faculty of Anesthesiology, Changhai Hospital, Naval Medical University/ Second Military Medical University, PLA, Shanghai 200433, China.

Postoperative gastrointestinal function influences postoperative recovery and length of hospital stay for patients undergoing colorectal surgery. Goal-directed fluid therapy (GDFT) restricts fluid administration to an amount required to prevent dehydration. Although the fluid management of GDFT could decrease the incidence of postoperative complications in patients who undergo high-risk surgery, certain patients may not respond to GDFT. Thus, to achieve optimal treatment, identification of patients suitable for GDFT is necessary. Metabolomic profiling of 48 patients undergoing surgery for colorectal cancer was performed. Patients were divided into delayed- and enhanced-recovered groups based on gastrointestinal function within 72 hours, and the results of omics analysis showed differential serum metabolites between the two groups of patients in the post anesthesia care unit 24 hours after surgery. A support vector machine model was applied to evaluate the curative effects of GDFT in different patients. Four metabolites, oleamide, ubiquinone-1, acetylcholine, and oleic acid, were found to be highly associated with postoperative gastrointestinal function and could be used as potential biomarkers. Moreover, four pathways were found to be highly related to postoperative gastrointestinal recovery. Among them, the vitamin B6 metabolism pathway may be a common pathway for improving postoperative recovery in various diseases. Our findings proposed a novel method to predict postoperative recovery of gastrointestinal function based on metabolomic profiling and suggested the potential mechanisms contributing to gastrointestinal function after surgical resection of colorectal cancer under the fluid management of GDFT.
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http://dx.doi.org/10.18632/aging.202711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034902PMC
March 2021

Acute Intestinal Inflammation Depletes/Recruits Histamine-Expressing Myeloid Cells From the Bone Marrow Leading to Exhaustion of MB-HSCs.

Cell Mol Gastroenterol Hepatol 2021 26;11(4):1119-1138. Epub 2020 Nov 26.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. Electronic address:

Background & Aims: Histidine decarboxylase (HDC), the histamine-synthesizing enzyme, is expressed in a subset of myeloid cells but also marks quiescent myeloid-biased hematopoietic stem cells (MB-HSCs) that are activated upon myeloid demand injury. However, the role of MB-HSCs in dextran sulfate sodium (DSS)-induced acute colitis has not been addressed.

Methods: We investigated HDC+ MB-HSCs and myeloid cells by flow cytometry in acute intestinal inflammation by treating HDC-green fluorescent protein (GFP) male mice with 5% DSS at various time points. HDC+ myeloid cells in the colon also were analyzed by flow cytometry and immunofluorescence staining. Knockout of the HDC gene by using HDC-/-; HDC-GFP and ablation of HDC+ myeloid cells by using HDC-GFP; HDC-tamoxifen-inducible recombinase Cre system; diphtheria toxin receptor (DTR) mice was performed. The role of H2-receptor signaling in acute colitis was addressed by treatment of DSS-treated mice with the H2 agonist dimaprit dihydrochloride. Kaplan-Meier survival analysis was performed to assess the effect on survival.

Results: In acute colitis, rapid activation and expansion of MB-HSC from bone marrow was evident early on, followed by a gradual depletion, resulting in profound HSC exhaustion, accompanied by infiltration of the colon by increased HDC+ myeloid cells. Knockout of the HDC gene and ablation of HDC+ myeloid cells enhance the early depletion of HDC+ MB-HSC, and treatment with H2-receptor agonist ameliorates the depletion of MB-HSCs and resulted in significantly increased survival of HDC-GFP mice with acute colitis.

Conclusions: Exhaustion of bone marrow MB-HSCs contributes to the progression of DSS-induced acute colitis, and preservation of quiescence of MB-HSCs by the H2-receptor agonist significantly enhances survival, suggesting the potential for therapeutic utility.
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http://dx.doi.org/10.1016/j.jcmgh.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903065PMC
November 2020

Hydrogen Peroxide Inducible JAK3 Covalent Inhibitor: Prodrug for the Treatment of RA with Enhanced Safety Profile.

ACS Med Chem Lett 2020 Nov 5;11(11):2182-2189. Epub 2020 Oct 5.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Selective inhibition of Janus kinases (JAKs) is an arising strategy in drug discovery. Covalent inhibitors targeting a unique cysteine in JAK3 exhibit ultraselectivity among JAK family members. However, safety and tissue specific concerns still remain. A prodrug of a known JAK3 covalent inhibitor sensitive to HO was designed and synthesized and its therapeutic effect was evaluated in the CIA (collagen-induced arthritis) mice model of RA (rheumatoid arthritis). The prodrug strategy relied on the introduction of a hydrogen peroxide-sensitive borate trigger group to avoid random covalent binding to thiol functionalities in biomacromolecules. The results show that the prodrug can be activated and released under pathophysiological concentration of HO. In addition, the prodrug demonstrated stability to the physiological environment. In comparison to the parent compound, the prodrug showed a similar therapeutic effect in the CIA model but notably exhibited lower toxicity and a larger therapeutic window.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667863PMC
November 2020

Modulation of protein fate decision by small molecules: targeting molecular chaperone machinery.

Acta Pharm Sin B 2020 Oct 7;10(10):1904-1925. Epub 2020 Feb 7.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Modulation of protein fate decision and protein homeostasis plays a significant role in altering the protein level, which acts as an orientation to develop drugs with new mechanisms. The molecular chaperones exert significant biological functions on modulation of protein fate decision and protein homeostasis under constantly changing environmental conditions through extensive protein-protein interactions (PPIs) with their client proteins. With the help of molecular chaperone machinery, the processes of protein folding, trafficking, quality control and degradation of client proteins could be arranged properly. The core members of molecular chaperones, including heat shock proteins (HSPs) family and their co-chaperones, are emerging as potential drug targets since they are involved in numerous disease conditions. Development of small molecule modulators targeting not only chaperones themselves but also the PPIs among chaperones, co-chaperones and clients is attracting more and more attention. These modulators are widely used as chemical tools to study chaperone networks as well as potential drug candidates for a broader set of diseases. Here, we reviewed the key checkpoints of molecular chaperone machinery HSPs as well as their co-chaperones to discuss the small molecules targeting on them for modulation of protein fate decision.
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http://dx.doi.org/10.1016/j.apsb.2020.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606112PMC
October 2020

PD-1 Signaling Promotes Tumor-Infiltrating Myeloid-Derived Suppressor Cells and Gastric Tumorigenesis in Mice.

Gastroenterology 2021 Feb 29;160(3):781-796. Epub 2020 Oct 29.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York. Electronic address:

Background & Aims: Immune checkpoint inhibitors have limited efficacy in many tumors. We investigated mechanisms of tumor resistance to inhibitors of programmed cell death-1 (PDCD1, also called PD-1) in mice with gastric cancer, and the role of its ligand, PD-L1.

Methods: Gastrin-deficient mice were given N-methyl-N-nitrosourea (MNU) in drinking water along with Helicobacter felis to induce gastric tumor formation; we also performed studies with H/K-ATPase-hIL1B mice, which develop spontaneous gastric tumors at the antral-corpus junction and have parietal cells that constitutively secrete interleukin 1B. Mice were given injections of an antibody against PD-1 or an isotype control before tumors developed, or anti-PD-1 and 5-fluorouracil and oxaliplatin, or an antibody against lymphocyte antigen 6 complex locus G (also called Gr-1), which depletes myeloid-derived suppressor cells [MDSCs]), after tumors developed. We generated knock-in mice that express PD-L1 specifically in the gastric epithelium or myeloid lineage.

Results: When given to gastrin-deficient mice before tumors grew, anti-PD-1 significantly reduced tumor size and increased tumor infiltration by T cells. However, anti-PD-1 alone did not have significant effects on established tumors in these mice. Neither early nor late anti-PD-1 administration reduced tumor growth in the presence of MDSCs in H/K-ATPase-hIL-1β mice. The combination of 5-fluorouracil and oxaliplatin reduced MDSCs, increased numbers of intra-tumor CD8 T cells, and increased the response of tumors to anti-PD-1; however, this resulted in increased tumor expression of PD-L1. Expression of PD-L1 by tumor or immune cells increased gastric tumorigenesis in mice given MNU. Mice with gastric epithelial cells that expressed PD-L1 did not develop spontaneous tumors, but they developed more and larger tumors after administration of MNU and H felis, with accumulation of MDSCs.

Conclusions: In mouse models of gastric cancer, 5-fluorouracil and oxaliplatin reduce numbers of MDSCs to increase the effects of anti-PD-1, which promotes tumor infiltration by CD8 T cells. However, these chemotherapeutic agents also induce expression of PD-L1 by tumor cells. Expression of PD-L1 by gastric epithelial cells increases tumorigenesis in response to MNU and H felis, and accumulation of MDSCs, which promote tumor progression. The timing and site of PD-L1 expression is therefore important in gastric tumorigenesis and should be considered in design of therapeutic regimens.
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http://dx.doi.org/10.1053/j.gastro.2020.10.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878361PMC
February 2021

Dexmedetomidine inhibits LPS-induced proinflammatory responses via suppressing HIF1α-dependent glycolysis in macrophages.

Aging (Albany NY) 2020 05 20;12(10):9534-9548. Epub 2020 May 20.

Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.

Dexmedetomidine, a highly selective α2-adrenoceptor agonist, has been reported to exert an anti-inflammatory effect in several animal models, but the mechanism remains unclear. Previous studies have shown that hypoxia inducible factor 1α-induced glycolysis is essential for the activation of inflammatory macrophages. However, whether dexmedetomidine influences hypoxia inducible factor 1α-induced glycolysis and thus exerts an anti-inflammatory effect has been poorly investigated. This study aims to elucidate the anti-inflammatory mechanism of dexmedetomidine involving the hypoxia inducible factor 1α-dependent glycolytic pathway. We showed that dexmedetomidine could suppress lipopolysaccharide-induced inflammatory cytokine production; inhibit the extracellular acidification rate, glucose consumption and lactate production; and decrease the expression of glycolytic genes in macrophages. The enhancement of glycolysis by the granulocyte-macrophage colony-stimulating factor or higher concentration of glucose could reverse the anti-inflammatory effect of dexmedetomidine on lipopolysaccharide-treated macrophages. Moreover, dexmedetomidine significantly inhibited the upregulation of hypoxia inducible factor 1α at the mRNA and protein levels. Genetic inhibition of hypoxia inducible factor 1α expression could reverse the anti-inflammatory effect of dexmedetomidine. Taken together, our results indicate that dexmedetomidine attenuates lipopolysaccharide-induced proinflammatory responses partially by suppressing hypoxia inducible factor 1α-dependent glycolysis in macrophages.
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http://dx.doi.org/10.18632/aging.103226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288940PMC
May 2020

A hydrogen peroxide responsive prodrug of Keap1-Nrf2 inhibitor for improving oral absorption and selective activation in inflammatory conditions.

Redox Biol 2020 07 11;34:101565. Epub 2020 May 11.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

Transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) and its negative regulator, the E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1), control the redox and metabolic homeostasis and oxidative stress. Inhibitors of Keap1-Nrf2 interaction are promising in oxidative stress related inflammatory diseases but now hit hurdles. By utilizing thiazolidinone moiety to shield the key carboxyl pharmacophore in Keap1-Nrf2 inhibitor, a hydrogen peroxide (HO)-responsive prodrug pro2 was developed. The prodrug modification improved the physicochemical properties and cell membrane permeability of the parent drug. Pro2 was stable and stayed inactive under various physiological conditions, while became active by stimulation of HO or inflammation derived reactive oxygen species. Moreover, pro2 exhibited proper pharmacokinetic profile suitable for oral administration and enhanced anti-inflammatory efficiency in vivo. Thus, this novel prodrug approach may not only provide an important advance in the therapy of chronic inflammatory diseases with high level of HO, but also offer a fresh solution to improve the drug-like and selectivity issues of Keap1-Nrf2 inhibitors.
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http://dx.doi.org/10.1016/j.redox.2020.101565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231841PMC
July 2020

Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression.

Gut 2021 Feb 10;70(2):330-341. Epub 2020 May 10.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA

Objective: Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression.

Design: We crossed LSL-;-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples.

Results: KC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8 T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1 B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival.

Conclusion: We show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.
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http://dx.doi.org/10.1136/gutjnl-2019-319912DOI Listing
February 2021

Adult Pancreatic Acinar Progenitor-like Populations in Regeneration and Cancer.

Trends Mol Med 2020 08 30;26(8):758-767. Epub 2020 Apr 30.

Division of Digestive and Liver Disease, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address:

The bulk of the pancreas primarily comprises long-lived acinar cells that are not considered a bona fide source for stem cells. However, certain acinar subpopulations have a repopulating capacity during regeneration, raising the hypothesis as to the presence of regenerative progenitor-like populations in the adult pancreas. Here, we describe recent discoveries based on fate-mapping techniques that support the existence of progenitor-like acinar subpopulations, including active progenitor-like cells that maintain tissue homeostasis and facultative progenitor-like cells that drive tissue regeneration. A possible link between progenitor-like acinar cells and cancer initiators is proposed. Further analysis of these cellular components is needed, because it would help uncover possible cellular sources for regeneration and cancer, as well as potential targets for therapy.
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http://dx.doi.org/10.1016/j.molmed.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395864PMC
August 2020

Angiotensin II contributes to intratumoral immunosuppressionvia induction of PD-L1 expression in non-small cell lung carcinoma.

Int Immunopharmacol 2020 Jul 24;84:106507. Epub 2020 Apr 24.

State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China. Electronic address:

The formation of an immunosuppressive microenvironment and up-regulation of PD-L1 protein are the main causes of tumor immune escape. Previous reports suggest that Angiotensin II (Ang II) can modulate the immune status of tumor microenvironment in non-small cell lung cancer (NSCLC), but the underlying mechanism remains not fully understood. Here we demonstrated that AngII treatment causes the reduction of intratumoral infiltrating CD4 T lymphocytes in tumor-bearing mice, increases the accumulation of immunosuppressive granulocytes and TAMs in tumor tissue, and upregulates the expression levels of immunosuppressive marker genes. In addition, AngII/AGTR1 axis triggers cell PD-L1 expression through a mechanism involving increases in PD-L1 mRNA stability by human antigen R (HuR), an AU-rich element (ARE)-binding protein. Collectively, AngII/AGTR1 signaling promotes the tumor immunosuppressive microenvironment by upregulating PD-L1 in NSCLC, the mechanism of which is largely accounted by HuR-mediated PD-L1 mRNA stabilization.
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http://dx.doi.org/10.1016/j.intimp.2020.106507DOI Listing
July 2020

Contribution of neutrophils in the pathogenesis of rheumatoid arthritis.

J Biomed Res 2019 Oct;34(2):86-93

Division of Arthritis and Rheumatic Diseases, Oregon Health & Science University, Portland, OR 97239, USA;Rheumatology Section, VA Portland Healthcare System, Portland, OR 97239, USA.

Neutrophils are major innate immune effector cells for host defense and have been a topic of active research for their participation in the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis (RA) due to recently discovered neutrophil extracellular trap (NET) formation. NET formation and other mechanisms leading to the release of neutrophil nuclear and cytoplasmic contents are implicated as a source of citrullinated antigens in RA. Further investigations are required to delineate what factors diverge neutrophils from host defense to autoimmune response in RA.
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http://dx.doi.org/10.7555/JBR.33.20190075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183296PMC
October 2019

p62 as a therapeutic target for tumor.

Eur J Med Chem 2020 May 17;193:112231. Epub 2020 Mar 17.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Electronic address:

p62/SQSTM1 (hereafter as p62) is a stress-inducible cellular protein, which interacts with various signaling proteins to regulate a variety of cellular functions. Growing lines of evidence supported a critical role of p62 in tumorigenesis, and p62 may become a therapeutic target for tumor. In this review, we summarize biological functions of structural domains of p62, reported bioactive molecules targeting p62, and the relationship between p62 and tumorigenesis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112231DOI Listing
May 2020

Identification of Sca-1Abcg1 bronchioalveolar epithelial cells as the origin of lung adenocarcinoma in Gprc5a-knockout mouse model through the interaction between lung progenitor AT2 and Lgr5 cells.

Oncogene 2020 04 10;39(18):3754-3773. Epub 2020 Mar 10.

Department of Immunology and Microbiology, Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

The reason for the reduced efficacy of lung cancer therapy is the existence of lung cancer stem cells (CSCs). Targeting CSCs results in evolved phenotypes with increased malignancy, leading to therapy failure. Here, we propose a new therapeutic strategy: investigating the "transitional" cells that represent the stage between normal lung stem cells and lung CSCs. Identifying and targeting the key molecule that drives carcinogenesis to inhibit or reverse this process would thus provide new perspectives for early diagnosis and intervention in lung cancer. We used Gprc5a-knockout (KO) mice, the first animal model of spontaneous lung adenocarcinoma established by the deletion of a single lung tumor suppressor gene. We investigated the interaction of lung progenitor cells AT2 with Lgr5 cells in the generation of CSCs and related signaling mechanism. In the present study, using Gprc5a-KO mice, we found the initiator Sca-1Abcg1 subset with a CSC-like phenotype within the lung progenitor AT2 cell population in mice that had not yet developed tumors. We confirmed the self-renewal and tumor initiation capacities of this subset in vitro, in vivo, and clinical samples. Mechanistically, we found that the generation of Sca-1Abcg1 cells was associated with an interaction between AT2 and Lgr5 cells and the subsequent activation of the ECM1-α6β4-ABCG1 axis. Importantly, Sca-1Abcg1 and SPAABCG1 cells specifically existed in the small bronchioles of Gprc5a-KO mice and patients with pneumonia, respectively. Thus, the present study unveiled a new kind of lung cancer-initiating cells (LCICs) and provided potential markers for the early diagnosis of lung cancer.
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http://dx.doi.org/10.1038/s41388-020-1251-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190569PMC
April 2020

Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis.

Cell Stem Cell 2020 05 5;26(5):739-754.e8. Epub 2020 Mar 5.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address:

Cancer is believed to arise from stem cells, but mechanisms that limit the acquisition of mutations and tumor development have not been well defined. We show that a +4 stem cell (SC) in the gastric antrum, marked by expression of Cck2r (a GPCR) and Delta-like ligand 1 (DLL1), is a label-retaining cell that undergoes predominant asymmetric cell division. This +4 antral SC is Notch1/ Numb and repressed by signaling from gastrin-expressing endocrine (G) cells. Chemical carcinogenesis of the stomach is associated with loss of G cells, increased symmetric stem cell division, glandular fission, and more rapid stem cell lineage tracing, a process that can be suppressed by exogenous gastrin treatment. This hormonal suppression is associated with a marked reduction in gastric cancer mutational load, as revealed by exomic sequencing. Taken together, our results show that gastric tumorigenesis is associated with increased symmetric cell division that facilitates mutation and is suppressed by GPCR signaling.
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http://dx.doi.org/10.1016/j.stem.2020.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214188PMC
May 2020

Lidocaine attenuates lipopolysaccharide-induced inflammatory responses and protects against endotoxemia in mice by suppressing HIF1α-induced glycolysis.

Int Immunopharmacol 2020 Mar 17;80:106150. Epub 2020 Jan 17.

Faculty of Anesthesiology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai 200433, China. Electronic address:

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infections. Previous studies have indicated that lidocaine, an amide local anesthetic, has anti-inflammatory properties; however, the underlying mechanism remains unclear. In this study, we have shown that lidocaine dose-dependently inhibits lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in macrophages and that lidocaine protects mice from LPS-induced inflammation. Moreover, we have demonstrated that lidocaine reduces the release of TNF-α and IL-6 through the reduction of the expression of GLUT1 and HK2 to further suppress HIF1α-induced aggravation of inflammatory cascades. Lidocaine can inhibit the enhanced glycolysis and glycolytic capacity induced by LPS in the macrophages. As an inhibitor of PHDs (prolyl hydroxylases), Dimethyloxalylglycine (DMOG) can reduce the anti-inflammatory effects of lidocaine. In conclusion, the present study indicates that lidocaine can be used as a potential therapeutic agent for sepsis.
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http://dx.doi.org/10.1016/j.intimp.2019.106150DOI Listing
March 2020

Recent progress in the development of small molecule Nrf2 activators: a patent review (2017-present).

Expert Opin Ther Pat 2020 Mar 6;30(3):209-225. Epub 2020 Feb 6.

State Key Laboratory of Natural Medicines, and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.

: The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is the first line of defense against a plethora of environmental or endogenous deviations in redox metabolism, proteostasis, inflammation, etc. Therefore, pharmacological activation of Nrf2 is a potential therapeutic approach for several diseases related to oxidative stress and inflammation, such as cancer, cardiovascular, and neurodegenerative diseases.: The authors first describe the biological function of Nrf2 and the molecular regulatory mechanism of Keap1-Nrf2-ARE ((Kelch-like ECH-Associating protein 1)-Nrf2-(antioxidant response element)). Then, they review recent progress of covalent activators and non-covalent Keap1-Nrf2 protein-protein interaction (PPI) inhibitors from patents and publications in 2017-present, consisting of new chemical molecules, structure optimization of reported activators and progress in preclinical or clinical trials.: Despite significant achievements in the development of Nrf2 activators, the selectivity is the primary consideration. Due to reacting with redox-sensitive cysteines in proteins except for Keap1, electrophilic activators often exhibit off-target effects. For Keap1-Nrf2 PPI inhibitors, how to enhance efficacy and/or penetrate blood-brain barrier (BBB) to reach central nervous system (CNS) is also challenging. Fragment-based drug discovery (FBDD), carboxylic acid bioisosteric replacement and prodrug approach might be used to circumvent this challenge. Moreover, the possibility of cancer risk caused by Nrf2 activation needs to be considered carefully.
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http://dx.doi.org/10.1080/13543776.2020.1715365DOI Listing
March 2020

Prox1-positive cells monitor and sustain the murine intestinal epithelial cholinergic niche.

Nat Commun 2020 01 8;11(1):111. Epub 2020 Jan 8.

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA.

The enteric neurotransmitter acetylcholine governs important intestinal epithelial secretory and immune functions through its actions on epithelial muscarinic Gq-coupled receptors such as M3R. Its role in the regulation of intestinal stem cell function and differentiation, however, has not been clarified. Here, we find that nonselective muscarinic receptor antagonism in mice as well as epithelial-specific ablation of M3R induces a selective expansion of DCLK1-positive tuft cells, suggesting a model of feedback inhibition. Cholinergic blockade reduces Lgr5-positive intestinal stem cell tracing and cell number. In contrast, Prox1-positive endocrine cells appear as primary sensors of cholinergic blockade inducing the expansion of tuft cells, which adopt an enteroendocrine phenotype and contribute to increased mucosal levels of acetylcholine. This compensatory mechanism is lost with acute irradiation injury, resulting in a paucity of tuft cells and acetylcholine production. Thus, enteroendocrine tuft cells appear essential to maintain epithelial homeostasis following modifications of the cholinergic intestinal niche.
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http://dx.doi.org/10.1038/s41467-019-13850-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949263PMC
January 2020

Plasma metabolomics of early parenteral nutrition followed with enteral nutrition in pancreatic surgery patients.

Sci Rep 2019 12 11;9(1):18846. Epub 2019 Dec 11.

Faculty of Anesthesiology, Changhai Hospital, Second Military Medical University/Naval Medical University, 200433, Shanghai, China.

Nutrition support is essential for surgical patients. Patients undergoing pancreaticoduodenectomy (PD) require tremendous nutrient support but also faced with risks of infection and gastrointestinal complications. Early parenteral nutrition has recently shown benefits while limited information provided about the influence on metabolism. This prospective single-center cohort study used plasma metabolomics to clarify metabolic alteration after early parenteral nutrition followed with enteral nutrition. Patients undergoing pancreaticoduodenectomy (n = 52) were enrolled. 36 patients received parenteral nutrition within 3 days postoperatively followed with EN (TPN group), 16 patients received standard fluids followed with EN (GIK group). We found that the weight loss is reduced in TPN group while the other clinical outcomes and inflammatory cytokines showed no statistical significance. The TPN group showed significance in amino acids, lipid, and phospholipids metabolism compared with the GIK group. Moreover, integration analysis indicated that early TPN could promote the metabolism of long-chain fatty acids, phospholipids, ketone bodies, and branched-chain amino acids. We conclude that early TPN support followed with EN for patients undergoing PD reduced the perioperative weight loss and promoted the metabolic transition to anabolic metabolism with the recovery of lipid metabolism, suggesting its benefits for the recovery of patients.
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http://dx.doi.org/10.1038/s41598-019-55440-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906312PMC
December 2019

Ets2 suppresses inflammatory cytokines through MAPK/NF-κB signaling and directly binds to the IL-6 promoter in macrophages.

Aging (Albany NY) 2019 11 27;11(22):10610-10625. Epub 2019 Nov 27.

Faculty of Anesthesiology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai 200433, China.

Proper activation of Toll-like receptor (TLR)-mediated signaling and production of proinflammatory cytokines are critical for the initiation of innate immunity, while the specific mechanism maintaining inflammatory homeostasis remains mostly unknown. Here, we show that Ets2 is upregulated following LPS and VSV stimulation. Ets2 knockdown or knockout leads to increased IL-6, TNF-α, and IFN-β production in macrophages. Consistently, Ets2-deficient mice show exacerbated inflammatory cytokine production and are more susceptible to CLP-induced sepsis. Mechanistically, Ets2 inhibits the LPS- and VSV-induced activation of ERK1/2, JNK, p38, and p65. Ets2 also binds to the promoter of IL-6 to inhibit transcription. Collectively, the results of the present study show the negative regulatory role of Ets2 in LPS- and VSV-induced inflammation through the suppression of MAPK/NF-κB signaling, direct binding to the IL-6 promoter and inhibition of transcription.
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http://dx.doi.org/10.18632/aging.102480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914388PMC
November 2019

Actinomycin D-Activated RNase L Promotes H2A.X/H2B-Mediated DNA Damage and Apoptosis in Lung Cancer Cells.

Front Oncol 2019 25;9:1086. Epub 2019 Oct 25.

Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, China.

Chemotherapy is an essential component for comprehensive cancer treatment, while drug resistance usually fails therapy. DNA repair mechanism of cancer cells restrains the efficacy of therapeutics targeting DNA damage. Investigating target-inducing irreversible cell death of cancer cells may be promising. The present study used lung cancer cell lines, transplanted tumor model of lung cancers derived from patients with lung adenocarcinoma, and molecular experiments to investigate the effects and mechanism of Actinomycin D (Act D)-activated RNase L in lung canceers. We report that RNase L, when activated by Act D, induces Caspase-3/PARP activation. The latter further enables ROCK-1 to initiate subsequent membrane blebbing and, meanwhile, result in DNA cleavage and cell cycle arrest mediated by H2A.X/H2B-p21 axis, leading to irreversible DNA damage, and apoptosis of lung cancer cells. The present study highlighted the crucial role of RNase L in triggering apoptosis mechanism through the Caspase-3/ROCK-1/PARP/H2A.X+H2B/p21 axis during Act D treatment. Moreover, activation of RNase L suppressed the tumor formation and the induction of lung cancer stem cells. This study unveiled the regulatory function and related mechanism of RNase L and implied the promising application of therapeutics targeting RNase L in lung cancer.
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http://dx.doi.org/10.3389/fonc.2019.01086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842983PMC
October 2019

Small-molecule inhibitor targeting the Hsp90-Cdc37 protein-protein interaction in colorectal cancer.

Sci Adv 2019 09 18;5(9):eaax2277. Epub 2019 Sep 18.

State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.
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http://dx.doi.org/10.1126/sciadv.aax2277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750927PMC
September 2019

IFN-γ restores the impaired function of RNase L and induces mitochondria-mediated apoptosis in lung cancer.

Cell Death Dis 2019 09 9;10(9):642. Epub 2019 Sep 9.

Cancer Institute, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.

RNase L is an essential component in interferon (IFN)-mediated antiviral signaling that showed antitumor effects in cancer. Cancer immunotherapy based on interferon has achieved encouraging results that indicate an applicable potential for cancer therapy. Here we showed that function of RNase L, though highly upregulated, was functionally impaired both in nuclear and cytoplasm in lung cancer cells. In normal lung epithelial cells, RNase L activation induced by 2-5A promoted nuclear condensation, DNA cleavage, and cell apoptosis, while in lung cancer cells, these processes were inhibited and RNase L-mediated downregulation of fibrillarin, Topo I and hnRNP A1 was also impaired in lung cancer cells. Moreover, the impairment of RNase L in lung cancer cells was due to the elevated expression of RLI. Application of IFN-γ to lung cancer cells led to enhanced expression of RNase L that compensated the RLI inhibition and restored the cytoplasmic and nuclear function of RNase L, leading to apoptosis of lung cancer cells. Thus, the present study discovered the impaired function and mechanism of RNase L in lung cancer cells and proved the efficacy of IFN-γ in restoring RNase L function and inducing apoptosis in the lung cancer cell. These results indicated the RNase L as a therapeutic target in lung cancer cells and immunotherapy of IFN-γ may serve as an adjuvant to enhance the efficacy.
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http://dx.doi.org/10.1038/s41419-019-1902-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733796PMC
September 2019

Publisher Correction: Acetate attenuates inflammasome activation through GPR43-mediated Ca-dependent NLRP3 ubiquitination.

Exp Mol Med 2019 Aug 14;51(8). Epub 2019 Aug 14.

Faculty of Anesthesiology, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s12276-019-0296-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802615PMC
August 2019

Acetate attenuates inflammasome activation through GPR43-mediated Ca-dependent NLRP3 ubiquitination.

Exp Mol Med 2019 07 23;51(7):1-13. Epub 2019 Jul 23.

Faculty of Anesthesiology, Changhai Hospital, Second Military Medical University, 200433, Shanghai, China.

Acetate has been indicated to be elevated and to regulate inflammation in inflammatory and metabolic diseases. The inflammasome serves as a key component of immune homeostasis, and its dysregulation can lead to various inflammatory disorders. However, little is known about the effects of acetate on inflammasome activation and the underlying mechanism. Here, we demonstrate that acetate attenuates inflammasome activation via GPR43 in a Ca-dependent manner. Through binding to GPR43, acetate activates the G subunit and subsequent phospholipase C-IP signaling to decrease Ca mobilization. In addition, acetate activates soluble adenylyl cyclase (sAC), promotes NLRP3 inflammasome ubiquitination by PKA, and ultimately induces NLRP3 degradation through autophagy. In vivo, acetate protects mice from NLRP3 inflammasome-dependent peritonitis and LPS-induced endotoxemia. Collectively, our research demonstrates that acetate regulates the NLRP3 inflammasome via GPR43 and Ca-dependent mechanisms, which reveals the mechanism of metabolite-mediated NLRP3 inflammasome attenuation and highlights acetate as a possible therapeutic strategy for NLRP3 inflammasome-related diseases.
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http://dx.doi.org/10.1038/s12276-019-0276-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802670PMC
July 2019