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1.
Mol Carcinog ; 60(2): 151-163, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33428809

RESUMO

Regorafenib is approved for patients with unresectable hepatocellular carcinoma (HCC) following sorafenib. However, the effect of regorafenib on HCC metastasis and its mechanism are poorly understood. Here, our data showed that regorafenib significantly restrained the migration, invasion and vasculogenic mimicry (VM) of HCC cells, and downregulated the expression of epithelial-to-mesenchymal transition (EMT)/VM-related molecules. Using RNA-seq and cellular thermal shift assays, we found that inhibitor of differentiation 1 (ID1) was a key target of regorafenib. In HCC tissues, the protein expression of ID1 was positively correlated with EMT and VM formation (CD34- /PAS+ ). Functionally, ID1 knockdown inhibited HCC cell migration, invasion, metastasis, and VM formation in vitro and in vivo, with upregulation of E-cadherin and downregulation of Snail and VE-cadherin. Moreover, Snail overexpression promoted the migration, invasion, and VM formation of ID1 knockdown cells. Snail knockdown reduced the migration, invasion, and VM formation of ID1 overexpression cells. Finally, regorafenib suppressed VM formation and decreased the expression of ID1, VE-cadherin and Snail in HCC PDX model. In conclusion, we manifested that regorafenib distinctly inhibited EMT in HCC cells via targeting ID1, leading to the suppression of cell migration, invasion and VM formation. These findings suggest that regorafenib may be developed as a suitable therapeutic agent for HCC metastasis.

2.
J Investig Med ; 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33441480

RESUMO

In this study, 60 patients with septic shock were selected over the course of 1 year, and the effects of dopamine and norepinephrine combined with dobutamine on hepatic and intestinal circulation and intestinal barrier in patients with septic shock were studied by comparison between the control group and the experimental group. All patients received mechanical ventilation to maintain breathing at 14 to 20 times/min. The experimental group was treated with vascular active drugs after adequate rehydration, and the control group only received adequate rehydration. There were extremely significant differences (p<0.01) in the total effective rate of each group. There were significant differences in the hemodynamic indexes in each group (p<0.05). There was a significant difference in total 24-hour bile output (p<0.01). There were significant differences in liver function and blood lipid values in patients (p<0.01). There were significant differences in the repair of epithelial injury at 0 hour, 48 hours and 96 hours (p<0.01). There were significant differences in the transmembrane resistance of monolayer cells (p<0.01). The expression differences of three proteins ZO-1, occludin and ß-actin were also significant, among which the three proteins in the control group were weak, while those in groups A and B were strong. The expression of tight junction protein in monolayer cells was weakly positive in expression and strong in other proteins. In conclusion, vasoactive drugs had significant effects on hepatic and intestinal circulation and intestinal barrier in patients with septic shock.

3.
JAMA Oncol ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33443541

RESUMO

Importance: There is no current consensus on the role of chemotherapy in addition to radiation for postoperative adjuvant treatment of patients with early-stage cervical cancer with adverse pathological factors. Objective: To evaluate the clinical benefits of sequential chemoradiation (SCRT) and concurrent chemoradiation (CCRT) compared with radiation alone (RT) as a postoperative adjuvant treatment in early-stage cervical cancer. Design, Setting, and Participants: After radical hysterectomy at 1 of 8 participating hospitals in China, patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IIA cervical cancer with adverse pathological factors were randomized 1:1:1 to receive adjuvant RT, CCRT, or SCRT. Data were collected from February 2008 to December 2018. Interventions: Patients received adjuvant RT (total dose, 45-50 Gy), CCRT (weekly cisplatin, 30-40 mg/m2), or SCRT (cisplatin, 60-75 mg/m2, plus paclitaxel, 135-175 mg/m2) in a 21-day cycle, given 2 cycles before and 2 cycles after radiotherapy, respectively. Main Outcomes and Measures: The primary end point was the rate of disease-free survival (DFS) at 3 years. Results: A total of 1048 women (median [range] age, 48 [23-65] years) were included in the analysis (350 in the RT group, 345 in the CCRT group, and 353 in the SCRT group). Baseline demographic and disease characteristics were balanced among the treatment groups except that the rate of lymph node involvement was lowest in the RT group (18.3%). In the intention-to-treat population, SCRT was associated with a higher rate of DFS than RT (3-year rate, 90.0% vs 82.0%; hazard ratio [HR], 0.52; 95% CI, 0.35-0.76) and CCRT (90.0% vs 85.0%; HR, 0.65; 95% CI, 0.44-0.96). Treatment with SCRT also decreased cancer death risk compared with RT (5-year rate, 92.0% vs 88.0%; HR, 0.58; 95% CI, 0.35-0.95) after adjustment for lymph node involvement. However, neither DFS nor cancer death risk was different among patients treated with CCRT or RT. Conclusions and Relevance: In this randomized clinical trial, conducted in a postoperative adjuvant treatment setting, SCRT, rather than CCRT, resulted in a higher DFS and lower risk of cancer death than RT among women with early-stage cervical cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT00806117.

4.
Environ Sci Technol ; 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33444018

RESUMO

Oxidation of ammonium to nitrite rather than nitrate, i.e., nitritation, is critical for autotrophic nitrogen removal. This study demonstrates a robust nitritation process in treating low-strength wastewater, obtained from a mixture of real mainstream sewage with sidestream anaerobic digestion liquor. This is achieved through cultivating acid-tolerant ammonia-oxidizing bacteria (AOB) in a laboratory nitrifying bioreactor at pH 4.5-5.0. It was shown that nitrite accumulation with a high NO2-/(NO2- + NO3-) ratio of 95 ± 5% was stably maintained for more than 300 days, and the obtained volumetric NH4+ removal rate (i.e., 188 ± 14 mg N L-1 d-1) was practically useful. 16S rRNA gene sequencing analyses indicated the dominance of new AOB, "Candidatus Nitrosoglobus," in the nitrifying guild (i.e., 1.90 ± 0.08% in the total community), with the disappearance of typical activated sludge nitrifying microorganisms, including Nitrosomonas, Nitrospira, and Nitrobacter. This is the first identification of Ca. Nitrosoglobus as key ammonia oxidizers in a wastewater treatment system. It was found that Ca. Nitrosoglobus can tolerate low pH (<5.0), and free nitrous acid (FNA) at levels that inhibit AOB and nitrite-oxidizing bacteria (NOB) commonly found in wastewater treatment processes. The in situ inhibition of NOB leads to accumulation of nitrite (NO2-), which along with protons (H+) also produced in ammonium oxidation generates and sustains FNA at 3.0 ± 1.4 mg HNO2-N L-1. As such, robust PN was achieved under acidic conditions, with a complete absence of NOB. Compared to previous nitritation systems, this acidic nitritation process is featured by a higher nitric oxide (NO) but a lower nitrous oxide (N2O) emission level, with the emission factors estimated at 1.57 ± 0.08 and 0.57 ± 0.03%, respectively, of influent ammonium nitrogen load.

5.
Pediatr Surg Int ; 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-33423101

RESUMO

PURPOSE: To assess the long-term results after Rex bypass (RB) shunt and Rex transposition (RT) shunt and determine the optimal approach. METHODS: Between 2010 and 2019, traditional RB shunt was performed in 24 patients, and modified RT shunt was performed in 23 children with extrahepatic portal hypertension (pHTN). A retrospective study was conducted based on comparative symptoms, platelet counts, color Doppler ultrasonography and computed tomographic portography of the portal system, and gastroscopic gastroesophageal varices postoperatively. The portal venous pressure was evaluated intraoperatively. RESULTS: The operation in the RB group was notably more time-consuming than that in the RT group (P < 0.05). Compared to RT shunt, the reduction in gastroesophageal varix grading, the increases in platelets, and the caliber of the bypass were greater in the RB group (P < 0.05). Although not statistically significant, higher morbidity of surgical complications was found after RT shunt (17.4%) compared with RB shunt (8.3%) with patency rates of 82.6 and 91.7%, respectively. Additionally, patients exhibited a lower rate of rebleeding under the RB procedure (12.5%) than under the RT procedure (21.7%). CONCLUSIONS: The RT procedure is an alternative option for the treatment of pediatric extrahepatic pHTN, and RB shunt is the preferred procedure in our center.

6.
Cell ; 184(1): 149-168.e17, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33278357

RESUMO

COVID-19 is characterized by excessive production of pro-inflammatory cytokines and acute lung damage associated with patient mortality. While multiple inflammatory cytokines are produced by innate immune cells during SARS-CoV-2 infection, we found that only the combination of TNF-α and IFN-γ induced inflammatory cell death characterized by inflammatory cell death, PANoptosis. Mechanistically, TNF-α and IFN-γ co-treatment activated the JAK/STAT1/IRF1 axis, inducing nitric oxide production and driving caspase-8/FADD-mediated PANoptosis. TNF-α and IFN-γ caused a lethal cytokine shock in mice that mirrors the tissue damage and inflammation of COVID-19, and inhibiting PANoptosis protected mice from this pathology and death. Furthermore, treating with neutralizing antibodies against TNF-α and IFN-γ protected mice from mortality during SARS-CoV-2 infection, sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock. Collectively, our findings suggest that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.


Assuntos
/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Interferon gama/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Anticorpos Neutralizantes/administração & dosagem , Morte Celular , Modelos Animais de Doenças , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/imunologia , Inflamação/patologia , Linfo-Histiocitose Hemofagocítica/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Células THP-1
7.
Sci Total Environ ; 757: 143990, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33316522

RESUMO

Here we present multiproxy inorganic geochemical records from a peat core (ZK5) from the Dajiuhu Basin in central China to investigate peatland deposition processes and atmospheric metal pollution and to explore their relationships with East Asian monsoon change and human activities in the Middle Yangtze Valley since 20,000 cal yr BP. The peat physicochemical data including total organic carbon (TOC), trace elements, and grain-size show that the site has changed from a lake during the cold-wet Last Glacial Maximum (LGM; 20,000-18,000 cal yr BP), to a marshy wetland during the mild last deglaciation (18,000-11,500 cal yr BP) and a peatland during the mostly warm and dry Holocene (11,500 cal yr BP-present). This general sequence corresponds with changes in East Asian monsoon indicated by stalagmites δ18O records and boreal summer insolation. Marked decreases in trace element concentrations correspond to two periods of peatland expansion during the abrupt hydroclimatic transitions from the LGM to the last deglaciation and from the last deglaciation to the early Holocene. Warm-dry mid-Holocene might induce high organic matter decomposition in peat sediments. Increasing natural element concentrations since the late Holocene are correlated with the weakening of the summer monsoon and elevated atmospheric dust deposition. Increasing Cu and Pb concentrations in peat record indicate large-scale Cu smelting during the Bronze Age and excessive coal burning during the 10th century or so. The anthropogenic heavy metals were transported by prevailing East Asian summer monsoon and deposited in the Dajiuhu Basin during periods of heightened human activities. Our compilation of heavy metals records across China confirmed the noticeable impacts of the historical human activity on deposition environments during the late Holocene. Consequently, trace elements from the Dajiuhu Basin are reliable proxies for capturing monsoon climate-induced peatland deposition response and present important evidence for a historical atmospheric heavy metal pollution in the Middle Yangtze Valley. Our results offer useful references for peatland evolution and protection under the background of global change.

8.
Meat Sci ; 172: 108346, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33142155

RESUMO

Although high level of purine in foods is considered a risk factor for hyperuricemia and gout, purine-rich foods continue to be popular for their delicious taste. The main objective of this study was to investigate the effects of purine bases on the sensory quality of pork. A total of 406 longissimus thoracis et lumborum samples were collected from a heterogeneous F6 pig population to determine purine composition and its correlation to sensory quality of pork. The contents of total purine and two major uricogenic bases (adenine and hypoxanthine) were negatively correlated with tenderness, juiciness, oiliness and overall liking (r < -0.2, P < 0.05), but they were not significantly correlated with umami. In contrast, guanine content, which accounts for only about 10% of the total purine content, was positively correlated with umami (r = 0.15, P < 0.05), and had no significant relationships with other sensory indicators. These results imply that purine bases with different uricogenic effects also influence different sensory quality indices of pork.

9.
Sci Total Environ ; 752: 141876, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32889285

RESUMO

Recent studies have shown that free nitrous acid (FNA, i.e., HNO2) is biocidal to many microorganisms, promoting the development of FNA-based technology in biological wastewater treatment. Suppression of nitrite-oxidizing bacteria (NOB) is a critical step for autotrophic nitrogen removal via anammox. In this study, the biocidal effect of FNA on NOB was determined by developing a model methodology combined with NOB incubation. Sixteen groups of FNA exposure tests were conducted at five different FNA concentrations from 0 to 4 mg HNO2-N/L, obtained from three pH values (5.0, 5.5 and 6.0) with nitrite ranged from 21 to 1680 mg NO2--N/L, with one as a control. Nitrate production curves were tracked during incubations of the FNA-exposed sludge, and then used to estimate active NOB concentrations by the kinetic model-based fitting. The results showed that with 24-hour exposure to FNA at a level of over 1 mg HNO2-N/L, the active NOB decreased around two orders of magnitude compared with that in the primordial sludge. The Weibull model can well describe the biocidal effect, which would be useful for the optimization of FNA conditions. The maximum NOB growth rate was increased after FNA exposure. This result suggests that long-term implementation of FNA-based technology can select fast-growing NOB in activated sludge, causing a 'NOB adaptation' issue.


Assuntos
Nitritos , Ácido Nitroso , Bactérias , Reatores Biológicos , Cinética , Oxirredução , Esgotos
11.
Cell Discov ; 6(1): 76, 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33298872

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally with more than 33 million patients diagnosed, taking more than a million lives. Abundant mutations were observed but the functional consequences of these mutations are largely unknown. We report the mutation spectrum, replication dynamics, and infectivity of 11 patient-derived viral isolates in diverse cell lines, including the human lung cancer cell line Calu-3. We observed 46 mutations, including 9 different mutations in the spike gene. Importantly, these viral isolates show significant and consistent variations in replication dynamics and infectivity in tested cell lines, up to a 1500-fold difference in viral titers at 24 h after infecting Calu-3 cells. Moreover, we show that the variations in viral titers among viral isolates are positively correlated with blood clotting function but inversely correlated with the amount of red blood cell and hemoglobin in patients. Therefore, we provide direct evidence that naturally occurring mutations in SARS-CoV-2 can substantially change its replication dynamics and infectivity in diverse human cell lines, with clinical implications in vivo.

12.
Aging (Albany NY) ; 12(23): 24318-24332, 2020 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-33260158

RESUMO

Hepatocellular carcinoma (HCC) is an aggressive malignancy with high rates of metastasis and relapse. Isoquercitrin (ISO), a natural flavonoid present in the Chinese bayberry and other plant species, reportedly exerts notable inhibitory effects on tumor cell proliferation, though the mechanism is unknown. In the present study, we exposed HepG2 and Huh7 human liver cancer cells to ISO and examined the roles of autophagy and apoptosis in ISO-mediated cell death. We found that ISO exposure inhibited cell viability and colony growth, activated apoptotic pathway, and triggered dysregulated autophagy by activating the AMPK/mTOR/p70S6K pathway. Autophagy inhibition using 3-methyladenine (3-MA) or Atg5-targeted siRNA decreased the Bax/Bcl-2 ratio, caspase-3 activation, and PARP cleavage and protected cells against ISO-induced apoptosis. Moreover, autophagy inhibition reversed the upregulation of AMPK phosphorylation and downregulation of mTOR and p70S6K phosphorylation elicited by ISO. By contrast, application of a broad-spectrum caspase inhibitor failed to inhibit autophagy in ISO-treated cells. These data indicate that ISO simultaneously induced apoptosis and autophagy, and abnormal induction of autophagic flux contributed to ISO-triggered caspase-3-dependent apoptosis.

13.
Life Sci ; 267: 118984, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33383049

RESUMO

An increase in oxidative stress is an important pathological mechanism of heart injury induced by doxorubicin (DOX). Tranilast is an anti-allergy drug that has been shown to possess good antioxidant activity in previous studies. The overexpression and secretion of chymase by mast cells (MCs) increase the pathological overexpression of angiotensin II (Ang II), which plays a crucial role in myocardial hypertrophy and the deterioration of heart disease. The MC stabilizer tranilast (N-(3,4-dimethoxycinnamoyl) anthranilic acid; tran) prevents mast cells from degranulating, which may reduce DOX-induced Ang II synthesis. Therefore, in the present study, we hypothesized that tranilast will protect rats from DOX-induced myocardial damage via its antioxidant activity, thereby inhibiting Ang II expression. Thirty male Wistar rats were divided into three groups (n = 10 in each group) that received DOX, a combination of DOX and tranilast or saline (the control group) to test this hypothesis. Tranilast suppressed chymase expression, reduced Ang II levels and prevented the myocardial hypertrophy and the deterioration of heart function induced by DOX. Based on the findings of the present study, the suppression of chymase-dependent Ang-II production and the direct effect of tranilast on the inhibition of apoptosis and fibrosis because of its antioxidant stress capacity may contribute to the protective effect of tranilast against DOX-induced myocardial hypertrophy.

14.
Gene ; 773: 145384, 2020 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-33383119

RESUMO

Porcine circovirus type 4 (PCV4), a novel circovirus, was identified in pigs with serious symptoms, including porcine dermatitis and nephropathy syndrome (PDNS)-like signs, in China in 2019. This study investigated the prevalence and genome diversity of PCV4 in pigs from Guangxi Province, China, between 2015 and 2019. Thirteen of 257 (5.1%) samples were positive for PCV4, 9 of these (69.2%) PCV4-positive samples were coinfected with PCV2 or PCV3, and one PCV4-positive sample was coinfected with both PCV2 and PCV3. Three complete PCV4 genomes shared 36.9-73.8% nucleotide similarity with other representative circovirus genomes. Phylogenetic analysis indicated that PCV4 was most closely related to bat-associated circovirus and mink circovirus. In summary, this is the first epidemiological investigation and evolutionary analysis of PCV4 in Guangxi Province, China, and the results provide insight into the molecular epidemiology of PCV4.

15.
BMJ Open ; 10(11): e039557, 2020 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-33275116

RESUMO

OBJECTIVES: The HIV epidemic is around 7%-20% among men who have sex with men (MSM) in Southwest China. The low HIV-testing rate highlights the need for tools to identify high-risk MSM in resource-limited regions. Our aim was, therefore, to evaluate the HIV RISK Assessment Tool for HIV prediction and to characterise the primary infection among MSM in Southwest China. DESIGN: A cross-sectional survey was conducted in Guizhou province between January and December 2018. Participants were recruited from gay communities, among whom the HIV RISK Assessment Tool was evaluated. Logistic regression was used to analyse items associated with HIV and the area under the curve (AUC) of the receiver operating curve was calculated to quantify discrimination performance. PARTICIPANTS: 1330 MSM participants, of which 83 (6.2%) tested as HIV positive. RESULTS: A higher composite score of the tool (adjusted OR (aOR) 9.33, 95% CI 4.57 to 19.05) was independently associated with HIV infection. Items positively associated with HIV infection included having 2-5 same sex partners (aOR 2.43, 95% CI 1.28 to 4.64), always (aOR 5.93, 95% CI 1.59 to 22.13) or sometimes (aOR 4.25, 95% CI 2.09 to 8.64) having unprotected anal intercourse, taking both insertive and receptive sex roles (aOR 4.95, 95% CI 2.57 to 9.53) or only the receptive sex role (aOR 2.26, 95% CI 1.21 to 4.24). The tool showed an optimal discrimination ability (AUC=0.827), with a specificity of 0.747 and sensitivity of 0.785. Five MSM were identified with primary infection and had similar sexual risk behaviors as HIV-positive participants. CONCLUSIONS: The HIV RISK Assessment Tool showed an overall good performance in predicting HIV risk among MSM in Guizhou province where the prevalence is still severe. This tool also demonstrated a potential to identify primary infection and is worth being promoted in resource-limited regions.

16.
Neurosci Bull ; 2020 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-33355899

RESUMO

Tweety-homolog 1 (Ttyh1) is expressed in neural tissue and has been implicated in the generation of several brain diseases. However, its functional significance in pain processing is not understood. By disrupting the gene encoding Ttyh1, we found a loss of Ttyh1 in nociceptors and their central terminals in Ttyh1-deficient mice, along with a reduction in nociceptor excitability and synaptic transmission at identified synapses between nociceptors and spinal neurons projecting to the periaqueductal grey (PAG) in the basal state. More importantly, the peripheral inflammation-evoked nociceptor hyperexcitability and spinal synaptic potentiation recorded in spinal-PAG projection neurons were compromised in Ttyh1-deficient mice. Analysis of the paired-pulse ratio and miniature excitatory postsynaptic currents indicated a role of presynaptic Ttyh1 from spinal nociceptor terminals in the regulation of neurotransmitter release. Interfering with Ttyh1 specifically in nociceptors produces a comparable pain relief. Thus, in this study we demonstrated that Ttyh1 is a critical determinant of acute nociception and pain sensitization caused by peripheral inflammation.

17.
J Ethnopharmacol ; 269: 113706, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33346024

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic cholestasis is a usual clinical pathological process in hepatopathy and has few treatment options; it is classified under the category of jaundice in Chinese medicine. Da-Huang-Xiao-Shi decoction (DHXSD) is a classic Chinese prescription which is used to treat jaundice. AIM OF THE STUDY: We aimed to examine the protective effect of DHXSD on liver and its potential mechanism of action against chronic cholestasis. MATERIALS AND METHODS: Chronic cholestasis was induced using 3, 5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) in mice. Mice were then administered DHXSD intragastrically at doses of 3.68, 7.35, and 14.70 g/kg for four weeks followed by further analyses. Serum biochemical indices and liver pathology were explored. Eighteen individual bile acids (BAs) in mice serum and liver were quantified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The expression of BA related metabolic enzymes, transporters, along with nuclear receptor farnesoid X receptor (FXR) was detected by real-time qPCR and Western blot. RESULTS: DHXSD treatment reduced the serum biochemical indices, ameliorated pathological injury, and improved the disordered BA homeostasis. Mice treated with DHXSD showed significantly upregulated expression of the metabolic enzymes, cytochrome P450 2b10 (Cyp2b10), Cyp3a11, and UDP-glucuronosyltransferase 1a1 (Ugt1a1); and the bile acid transporters, multidrug resistance protein 2 (Mdr2), bile salt export pump (Bsep), and multidrug resistance-associated protein 3 (Mrp3). DHXSD treatment also significantly upregulated FXR expression in mice with DDC-induced chronic cholestasis. CONCLUSIONS: DHXSD exerted protective effects on chronic cholestasis in DDC-treated mice by alleviating the disordered homeostasis of BAs through increased expression of BA related metabolic enzymes and efflux transporters.

18.
J Cell Mol Med ; 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33263949

RESUMO

Hepatitis B virus (HBV) infection is a major public health problem. The high levels of HBV DNA and HBsAg are positively associated with the development of secondary liver diseases, including hepatocellular carcinoma (HCC). Current treatment with nucleos(t)ide analogues mainly reduces viral DNA, but has minimal, if any, inhibitory effect on the viral antigen. Although IFN reduces both HBV DNA and HBsAg, the serious associated side effects limit its use in clinic. Thus, there is an urgent demanding for novel anti-HBV therapy. In our study, viral parameters were determined in the supernatant of HepG2.2.15 cells, HBV-expressing Huh7 and HepG2 cells which transfected with HBV plasmids and in the serum of HBV mouse models with hydrodynamic injection of pAAV-HBV1.2 plasmid. RT-qPCR and Southern blot were performed to detect 35kb mRNA and cccDNA. RT-qPCR, Luciferase assay and Western blot were used to determine anti-HBV effects of MLN4924 and the underlying mechanisms. We found that treatment with MLN4924, the first-in-class neddylation inhibitor currently in several phase II clinical trials for anti-cancer application, effectively suppressed production of HBV DNA, HBsAg, 3.5kb HBV RNA as well as cccDNA. Mechanistically, MLN4924 blocks cullin neddylation and activates ERK to suppress the expression of several transcription factors required for HBV replication, including HNF1α, C/EBPα and HNF4α, leading to an effective blockage in the production of cccDNA and HBV antigen. Our study revealed that neddylation inhibitor MLN4924 has impressive anti-HBV activity by inhibiting HBV replication, thus providing sound rationale for future MLN4924 clinical trial as a novel anti-HBV therapy.

19.
Dermatology ; : 1-8, 2020 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-33352561

RESUMO

BACKGROUND: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment. OBJECTIVES: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment. METHODS: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving <20% of the body surface area were enrolled. Taz/BD cream was applied once daily for 4 weeks. Patients who achieved ≥90% improvement in the Psoriasis Area and Severity Index (PASI) from baseline to week 4 were followed up to investigate relapse after drug withdrawal. Relapsed patients underwent another 4-week treatment. RESULTS: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment. CONCLUSION: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.

20.
bioRxiv ; 2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33140051

RESUMO

The COVID-19 pandemic has caused significant morbidity and mortality. Currently, there is a critical shortage of proven treatment options and an urgent need to understand the pathogenesis of multi-organ failure and lung damage. Cytokine storm is associated with severe inflammation and organ damage during COVID-19. However, a detailed molecular pathway defining this cytokine storm is lacking, and gaining mechanistic understanding of how SARS-CoV-2 elicits a hyperactive inflammatory response is critical to develop effective therapeutics. Of the multiple inflammatory cytokines produced by innate immune cells during SARS-CoV-2 infection, we found that the combined production of TNF-α and IFN-γ specifically induced inflammatory cell death, PANoptosis, characterized by gasdermin-mediated pyroptosis, caspase-8-mediated apoptosis, and MLKL-mediated necroptosis. Deletion of pyroptosis, apoptosis, or necroptosis mediators individually was not sufficient to protect against cell death. However, cells deficient in both RIPK3 and caspase-8 or RIPK3 and FADD were resistant to this cell death. Mechanistically, the STAT1/IRF1 axis activated by TNF-α and IFN-γ co-treatment induced iNOS for the production of nitric oxide. Pharmacological and genetic deletion of this pathway inhibited pyroptosis, apoptosis, and necroptosis in macrophages. Moreover, inhibition of PANoptosis protected mice from TNF-α and IFN-γ-induced lethal cytokine shock that mirrors the pathological symptoms of COVID-19. In vivo neutralization of both TNF-α and IFN-γ in multiple disease models associated with cytokine storm showed that this treatment provided substantial protection against not only SARS-CoV-2 infection, but also sepsis, hemophagocytic lymphohistiocytosis, and cytokine shock models, demonstrating the broad physiological relevance of this mechanism. Collectively, our findings reveal that blocking the COVID-19 cytokine-mediated inflammatory cell death signaling pathway identified in this study may benefit patients with COVID-19 or other cytokine storm-driven syndromes by limiting inflammation and tissue damage. The findings also provide a molecular and mechanistic description for the term cytokine storm. Additionally, these results open new avenues for the treatment of other infectious and autoinflammatory diseases and cancers where TNF-α and IFN-γ synergism play key pathological roles.

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