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1.
J Infect Dis ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227123

RESUMO

BACKGROUND: Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China. We aimed to clarify the characteristics and clinical significance of peripheral lymphocyte subset alteration in COVID-19. METHODS: The levels of peripheral lymphocyte subsets were measured by flow cytometry in 60 hospitalized COVID-19 patients before and after treatment, and their association with clinical characteristics and treatment efficacy was analyzed. RESULTS: Total lymphocytes, CD4+ T cells, CD8+ T cells, B cells and natural killer (NK) cells decreased in COVID-19 patients, and severe cases had a lower level than mild cases. The subsets showed a significant association with the inflammatory status in COVID-19, especially CD8+ T cells and CD4+/CD8+ ratio. After treatment, 37 patients (67%) reached clinical response, with an increase of CD8+ T cells and B cells. No significant change of any subset was detected in non-response cases. In multivariate analysis, post-treatment decrease of CD8+ T cells and B cells and increase of CD4+/CD8+ ratio were indicated as independent predictors for poor efficacy. CONCLUSIONS: Peripheral lymphocyte subset alteration was associated with the clinical characteristics and treatment efficacy of COVID-19. CD8+ T cells tended to be an independent predictor for COVID-19 severity and treatment efficacy.

2.
Liver Int ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32239796

RESUMO

BACKGROUND: The SARS-CoV-2 pandemic is an ongoing global health emergency. The aim of our study was to investigate the changes of liver function and its clinical significance in COVID-19 patients. METHOD: This retrospective, single-center study was conducted on 115 confirmed cases of COVID-19 in Zhongnan hospital of Wuhan University from Jan 18 to Feb 22, 2020. Liver function and related indexes were analyzed to evaluate its relationship with disease progression in COVID-19 patients. RESULTS: Part of the COVID-19 patients presented with varying degrees of abnormality in liver function indexes. However, the levels of ALT, AST, TBIL, GGT and LDH in COVID-19 patients were not significantly different in compared with hospitalized community-acquired pneumonia patients, and the levels of albumin is even significantly higher. Levels of ALT, AST, TBIL, LDH and INR showed statistically significant elevation in severe COVID-19 cases compared with that in mild cases. However, the clinical significance of the elevation is unremarkable. Majority of severe COVID-19 patients showed significantly decreasing in albumin level and continuously decreasing in the progress of illness. Most of the liver function indexes in COVID-19 patients were correlated with CRP and NLR, the markers of inflammation. Logistic regression analysis further identified NLR as the independent risk factor for severe COVID-19, as well as age. CONCLUSIONS: Although abnormalities of liver function indexes are common in COVID-19 patients, the impairment of liver function is not a prominent feature of COVID-19, and also may not have serious clinical consequences.

3.
Dig Dis Sci ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32215815

RESUMO

BACKGROUND AND AIMS: Hypoxia represents one of the most pervasive microenvironmental stresses in HCC due to the overwhelming growth and inadequate blood supply. HIF1α as an important transcription factor participates in the regulation of various biological behaviors of HCC cells under hypoxia. Our previous study indicated that miR-375 is a hypoxia-associated miRNA. However, the interaction between miR-375 and HIF1α remains unclear. METHODS: Bioinformatic analysis was performed for miRNA screening. qRT-PCR, western blotting, and immunohistochemical staining were used to detect the expression of related molecules. Bioinformatic analysis and dual luciferase assay were used to predict and further confirm the target association. Transwell chamber assay and flow cytometry were, respectively, used to detect migration, invasion and apoptosis of hepatoma cells. RESULTS: MiR-375 presented an obviously differential expression in human HCCs versus background livers (BLs) and HCCs versus normal liver tissues (NLTs). In rat models, miR-375 was gradually declined during hepatocarcinogenesis. HIF1α was remarkably upregulated at protein level rather than at mRNA level in human HCCs versus BLs, HCCs versus NLTs, BLs versus NLTs, and in rat fibrotic livers versus NLTs. HIF1α was determined to be a target of miR-375. MiR-375 inhibitor induced the migration and invasive capabilities and attenuated apoptosis of hepatoma cells under hypoxia. Depriving HIF1α by siRNA could partially reverse the function of miR-375 inhibitor under hypoxia. CONCLUSIONS: MiR-375 impairs the invasive capabilities of HCC cells by targeting HIF1α under hypoxia.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32205349

RESUMO

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lies behind the ongoing outbreak of coronavirus disease 2019 (COVID-19). There is a growing understanding of SARS-CoV-2 in the virology, epidemiology and clinical management strategies. However, no anti-SARS-CoV-2 drug or vaccine has been officially approved due to the absence of adequate evidence. Scientists are racing towards the development of treatment for COVID-19. Recent studies have revealed many attractive threptic options, even if some of them remain to be further confirmed in rigorous preclinical models and clinical trials. In this minireview, we aim to summarize the updated potential approaches against SARS-CoV-2. We emphasize that further efforts are warranted to develop the safest and most effective approach.

5.
Hepatology ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32221968

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death that develops as a consequence of obesity, cirrhosis and chronic hepatitis. However, the pathways along which these changes occur remain incompletely understood. In this study, we show that the deubiquitinase USP30 is abundant in HCCs that arise in mice maintained on high fat diets (HFDs). IKKß phosphorylated and stabilized USP30, which promoted USP30 to deubiquitinate ATP citrate lyase (ACLY) and fatty acid synthase (FASN). IKKß also directly phosphorylated ACLY and facilitated the interaction between USP30 and ACLY and the latter's deubiquitination. In HCCs arising in DEN/CCl4 -treated mice, USP30 deletion attenuated lipogenesis, inflammation and tumorigenesis irrespective of diet. The combination of ACLY inhibitor and PD-L1 antibody largely suppressed chemical-induced hepatocarcinogenesis. The IKKß-USP30-ACLY axis was also found to be upregulated in human HCCs. Conclusion: This study identifies a new IKKß-USP30-ACLY axis that plays an essential and wide-spread role in tumor metabolism and may be a potential therapeutic target in HCC.

6.
Clin Infect Dis ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32173725

RESUMO

BACKGROUND: Since December 2019, novel coronavirus (SARS-CoV-2)-infected pneumonia (COVID-19) occurred in Wuhan, and rapidly spread throughout China. This study aimed to clarify the characteristics of patients with refractory COVID-19. METHODS: In this retrospective single-center study, we included 155 consecutive patients with confirmed COVID-19 in Zhongnan Hospital of Wuhan University from January 1st to February 5th. The cases were divided into general and refractory COVID-19 groups according to the clinical efficacy after hospitalization, and the difference between groups were compared. RESULTS: Compared with general COVID-19 patients (45.2%), refractory patients had an older age, male sex, more underlying comorbidities, lower incidence of fever, higher levels of maximum temperature among fever cases, higher incidence of breath shortness and anorexia, severer disease assessment on admission, high levels of neutrophil, aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and C-reactive protein, lower levels of platelets and albumin, and higher incidence of bilateral pneumonia and pleural effusion (P<0.05). Refractory COVID-19 patients were more likely to receive oxygen, mechanical ventilation, expectorant, and adjunctive treatment including corticosteroid, antiviral drugs and immune enhancer (P<0.05). After adjustment, those with refractory COVID-19 were also more likely to have a male sex and manifestations of anorexia and fever on admission, and receive oxygen, expectorant and adjunctive agents (P<0.05) when considering the factors of disease severity on admission, mechanical ventilation, and ICU transfer. CONCLUSION: Nearly 50% COVID-19 patients could not reach obvious clinical and radiological remission within 10 days after hospitalization. The patients with male sex, anorexia and no fever on admission predicted poor efficacy.

7.
Int Immunol ; 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32154559

RESUMO

Intestinal macrophages participate in the pathogenesis of inflammatory bowel diseases (IBDs) through secreting pro-inflammatory and tissue-damaging factors as well as inducing the differentiation of T helper 1 (Th1) and T helper 17 (Th17) cells. Elucidating the regulatory mechanisms of intestinal macrophage activity in IBDs is important for developing new therapeutic approaches. In the current study, the expression of Sestrins in myeloid cells and lymphocytes in colonic lamina propria (LP) was evaluated in a murine acute colitis model. We found that Sestrin3 was significantly up-regulated in LP macrophages by the colonic LP microenvironment. In the in vitro experiments, lentivirus-mediated Sestrin3 knockdown significantly reduced the production of IL-12 and IL-23 in activated macrophages, in addition to decreasing the expression of classical pro-inflammatory cytokines such as IL-1ß, IL-6 and TNF-α. Additionally, Sestrin3 knockdown impaired macrophage-mediated generation of Th1 cells and Th17 cells generation from CD4+ T cells, probably through up-regulating the phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) in macrophages. In the in vivo experiments, adoptive transfer of Sestrin3-deficient macrophages alleviated the generation of Th1 and Th17 cells in the colonic LP and mesenteric lymph nodes. Furthermore, the adoptive transfer mitigated the severity of colitis, as demonstrated by less pro-inflammatory cytokines and less tissue lesion in the colon. Our study suggests that Sestrin3 might be crucial for macrophage-mediated generation of pathogenic Th1 and Th17 cells in IBDs.

8.
Dig Dis Sci ; 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32144602

RESUMO

BACKGROUND: The transformation of hepatic stellate cells (HSCs) into collagen-producing myofibroblasts is a key event in hepatic fibrogenesis. Recent studies have shown that microRNAs (miRNAs) play a critical role in the transformation of HSCs. However, the function of miR-489-3p in liver fibrosis remains unclear. METHODS: Here, we detected the levels of miR-489-3p and jagged canonical Notch ligand 1 (JAG1) in liver fibrosis by using CCl4-treated rats as an in vivo model and transforming growth factor-beta 1 (TGF-ß1)-treated HSC cell lines LX-2 and HSC-T6 as in vitro models. The expression of profibrotic markers was affected by transfecting LX-2 cells with either miR-489-3p mimic or si-JAG1. A dual-luciferase reporter assay was carried out to study the interaction of JAG1 with miR-489-3p. RESULTS: We found that miR-489-3p was remarkably decreased while JAG1 was increased in liver fibrosis models both in vivo and in vitro. Overexpression of miR-489-3p reduced the expression of profibrotic markers and the activation of LX-2 cells induced by TGF-ß1. Moreover, miR-489-3p decreased the expression of jagged canonical Notch ligand 1 (JAG1) in LX-2 cells by interacting with its 3'-UTR. As JAG1 is a Notch ligand, decreased JAG1 by miR-489-3p inhibited the Notch signaling pathway. Moreover, the downregulation of JAG1 inhibited the expression of fibrotic markers. CONCLUSION: Our results indicate that miR-489-3p can inhibit HSC activation by inhibiting the JAG1/Notch3 signaling pathway.

10.
J Clin Invest ; 130(3): 1252-1270, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32039918

RESUMO

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-ß signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32108873

RESUMO

OBJECTIVES: To clarify the transmission mechanism of the blaCTX-M-64 gene between Escherichia coli and Salmonella isolates from food animals. METHODS: A total of 329 E. coli and 60 Salmonella isolates collected from food animals in 2016 were screened for the presence of blaCTX-M-64 genes. The blaCTX-M-64-positive isolates were typed and plasmid and chromosome DNA was sequenced to determine the genetic context of blaCTX-M-64 and the plasmid types present. RESULTS: The blaCTX-M-64 gene was identified in only three E. coli isolates but was the predominant gene in the Salmonella isolates (n = 9). These 12 CTX-M-64-positive isolates were all resistant to ampicillin, cefotaxime, ceftiofur, ceftriaxone, ceftazidime and florfenicol and 9 were resistant to ciprofloxacin. The blaCTX-M-64 gene was located on transferable IncI2 plasmids and an IncHI2 plasmid in three E. coli and one Salmonella isolate, respectively. The remaining eight Salmonella isolates contained blaCTX-M-64 integrated into the chromosome. Different genetic contexts of blaCTX-M-64 genes were found among the 12 isolates: ISEcp1-blaCTX-M-64-orf477-A/C on IncI2 plasmids of 3 E. coli isolates; ΔISEcp1-blaCTX-M-64-orf477-A/C in the chromosome of 1 Salmonella isolate; and ISEcp1-blaCTX-M-64-orf477 on the IncHI2 plasmid and chromosome of 8 Salmonella isolates. CONCLUSIONS: To the best of our knowledge, this is the first report of chromosomally encoded CTX-M-64 in Salmonella isolates. ISEcp1-mediated transposition is likely to be responsible for the spread of blaCTX-M-64 between different plasmids and chromosomes in Enterobacteriaceae especially E. coli and Salmonella.

12.
Org Lett ; 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32105089

RESUMO

We report that phosphorane can activate (salen)TiCl2 complex to achieve unprecedented excellent enantioselectivity and a broad substrate scope in the cyanation of nitroolefins. Our cyanating reagent Me2(CH2Cl)SiCN proves to be more active than TMSCN in this reaction, allowing 11 ß-aliphatic nitrolefins and 12 ß-CF3 nitroolefins (either ß-aryl or aliphatic) to work well to give the corresponding tertiary or quaternary ß-nitronitriles with high to excellent enantioselectivity.

13.
Cancer Sci ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32073706

RESUMO

Resistance to chemotherapy is a major challenge for the treatment of patients with colorectal cancer (CRC). Previous studies have found that microRNAs (miRNAs) play key roles in drug resistance; however, the role of miRNA-373-3p (miR-375-3p) in CRC remains unclear. The current study aimed to explore the potential function of miR-375-3p in 5-fluorouracil (5-FU) resistance. MicroRNA-375-3p was found to be widely downregulated in human CRC cell lines and tissues and to promote the sensitivity of CRC cells to 5-FU by inducing colon cancer cell apoptosis and cycle arrest and by inhibiting cell growth, migration, and invasion in vitro. Thymidylate synthase (TYMS) was found to be a direct target of miR-375-3p, and TYMS knockdown exerted similar effects as miR-375-3p overexpression on the CRC cellular response to 5-FU. Lipid-coated calcium carbonate nanoparticles (NPs) were designed to cotransport 5-FU and miR-375-3p into cells efficiently and rapidly and to release the drugs in a weakly acidic tumor microenvironment. The therapeutic effect of combined miR-375 + 5-FU/NPs was significantly higher than that of the individual treatments in mouse s.c. xenografts derived from HCT116 cells. Our results suggest that restoring miR-375-3p levels could be a future novel therapeutic strategy to enhance chemosensitivity to 5-FU.

15.
J Neuroinflammation ; 17(1): 17, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31926564

RESUMO

BACKGROUND: Dendritic cell-associated C-type lectin-1 (Dectin-1) receptor has been reported to be involved in neuroinflammation in Alzheimer's disease and traumatic brain injury. The present study was designed to investigate the role of Dectin-1 and its downstream target spleen tyrosine kinase (Syk) in early brain injury after ischemic stroke using a focal cortex ischemic stroke model. METHODS: Adult male C57BL/6 J mice were subjected to a cerebral focal ischemia model of ischemic stroke. The neurological score, adhesive removal test, and foot-fault test were evaluated on days 1, 3, 5, and 7 after ischemic stroke. Dectin-1, Syk, phosphorylated (p)-Syk, tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) expression was analyzed via western blotting in ischemic brain tissue after ischemic stroke and in BV2 microglial cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury in vitro. The brain infarct volume and Iba1-positive cells were evaluated using Nissl's and immunofluorescence staining, respectively. The Dectin-1 antagonist laminarin (LAM) and a selective inhibitor of Syk phosphorylation (piceatannol; PIC) were used for the intervention. RESULTS: Dectin-1, Syk, and p-Syk expression was significantly enhanced on days 3, 5, and 7 and peaked on day 3 after ischemic stroke. The Dectin-1 antagonist LAM or Syk inhibitor PIC decreased the number of Iba1-positive cells and TNF-α and iNOS expression, decreased the brain infarct volume, and improved neurological functions on day 3 after ischemic stroke. In addition, the in vitro data revealed that Dectin-1, Syk, and p-Syk expression was increased following the 3-h OGD and 0, 3, and 6 h of reperfusion in BV2 microglial cells. LAM and PIC also decreased TNF-α and iNOS expression 3 h after OGD/R induction. CONCLUSION: Dectin-1/Syk signaling plays a crucial role in inflammatory activation after ischemic stroke, and further investigation of Dectin-1/Syk signaling in stroke is warranted.

16.
Nat Commun ; 11(1): 460, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974363

RESUMO

Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation.

17.
FASEB J ; 34(1): 648-662, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31914678

RESUMO

Histone deacetylases 3 (HDAC3) modulates the acetylation state of histone and non-histone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia. Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild-type littermates. RGFP966 failed to exhibit extra protective effects in AIM2-/- stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome.

18.
Drug Dev Ind Pharm ; 46(1): 42-49, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31794271

RESUMO

The number of Parkinson's disease (PD) patients with the advanced phase and motor fluctuations is increasing. The objective of this study is developing levodopa/benzylhydrazine orally disintegrating tablets (L/B ODTs), which would provide greater convenience and ease of use than conventional tablets for these patients. In the present study, the L/B ODTs were developed successfully with an optimized formulation using response surface methodology (RSM). The direct compression technology was employed for the preparation of L/B ODTs. Considerably shorter disintegration time and faster dissolution profile were obtained under the optimum formulation with microcrystalline cellulose 25.7%, cross-polyvinylpyrrolidone 6.22% and Sodium carboxymethyl starch 5.36%. The content uniformity (%) of levodopa and benzylhydrazine was 50 ± 1.4% and 14.25 ± 0.6%, respectively. Thickness, friability, hardness and wetting time were 2.8 ± 0.05 mm, 0.46 ± 0.21%, 5.42 ± 1.1 kp and 31.2 ± 2.1 s, respectively, and all of data well comply with the General Principles of the Chinese Pharmacopeia. Mannitol of 22% in formulation could bring a pleasant taste: sweet, cool and refreshing. Almost all the volunteers felt that the ODTs had good taste, no roughness, and no gritty feeling, indicating that the ODTs prepared had good palatability, so patients will have good compliance when taking medicine.

19.
Mol Cell ; 77(1): 138-149.e5, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31735643

RESUMO

PGAM5 is a mitochondrial serine/threonine phosphatase that regulates multiple metabolic pathways and contributes to tumorigenesis in a poorly understood manner. We show here that PGAM5 inhibition attenuates lipid metabolism and colorectal tumorigenesis in mice. PGAM5-mediated dephosphorylation of malic enzyme 1 (ME1) at S336 allows increased ACAT1-mediated K337 acetylation, leading to ME1 dimerization and activation, both of which are reversed by NEK1 kinase-mediated S336 phosphorylation. SIRT6 deacetylase antagonizes ACAT1 function in a manner that involves mutually exclusive ME1 S336 phosphorylation and K337 acetylation. ME1 also promotes nicotinamide adenine dinucleotide phosphate (NADPH) production, lipogenesis, and colorectal cancers in which ME1 transcripts are upregulated and ME1 protein is hypophosphorylated at S336 and hyperacetylated at K337. PGAM5 and ME1 upregulation occur via direct transcriptional activation mediated by ß-catenin/TCF1. Thus, the balance between PGAM5-mediated dephosphorylation of ME1 S336 and ACAT1-mediated acetylation of K337 strongly influences NADPH generation, lipid metabolism, and the susceptibility to colorectal tumorigenesis.

20.
Cell Death Differ ; 27(1): 85-101, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31065105

RESUMO

Hepatocellular carcinoma (HCC) generally occurs in the presence of chronic liver injury, often as a sequela of liver fibrosis. Hepatic progenitor cells (HPCs) are known to be capable of forming both hepatocytes and cholangiocytes in chronic liver injury, which are also considered a source of myofibroblasts and tumor-initiating cells, under carcinogenic circumstances. However, the underlying mechanisms that activate HPCs to give rise to HCC are still unclear. In current study, the correlation between HPCs activation and liver fibrosis and carcinogenesis was investigated in rats and human specimens. We analyzed the role of HPCs in tumorigenesis, by transplanting exogenous HPCs in a diethylnitrosamine-induced rat HCC model. Our data indicated that HPC activation correlated with hepatic fibrosis and hepatocarcinogenesis. We further found that exogenous HPC infusion promoted liver fibrosis and hepatocarcinogenesis, while lipopolysaccharides (LPS) played an important role in this process. However, results of our study indicated that LPS did not induce HPCs to form tumor in nude mice directly. Rather, LPS induced myofibroblast-like morphology in HPCs, which enhanced the tumorigenic potential of HPCs. Further experiments showed that LPS/Toll-like receptor 4 (TLR4) signaling mediated the differentiation of HPCs into myofibroblasts and enhanced the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which led to the aberrant expression of Ras and p53 signaling pathways in HPCs, and finally, promoted the proliferation and malignant transformation of HPCs, by long non-coding RNA regulation. Besides, examination of HCC clinical samples demonstrated that IL-6 and TNF-α production correlated with HPC activation, hepatic fibrosis, and HCC recurrence. Our study indicates that both myofibroblasts and tumor cells are derived from HPCs. HPC-derived myofibroblasts create tumor microenvironment and contribute to the proliferation and malignant transformation of HPCs. Furthermore, LPS present in the chronic liver inflammation microenvironment might play an important role in hepatocarcinogenesis, by regulating the plastic potential of HPCs.

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