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1.
J Clin Invest ; 133(17)2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37463052

RESUMO

The liver has a high demand for phosphatidylcholine (PC), particularly in overnutrition, where reduced phospholipid levels have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). Whether other pathways exist in addition to de novo PC synthesis that contribute to hepatic PC pools remains unknown. Here, we identified the lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain containing 2A (Mfsd2a) as critical for maintaining hepatic phospholipid pools. Hepatic Mfsd2a expression was induced in patients having NAFLD and in mice in response to dietary fat via glucocorticoid receptor action. Mfsd2a liver-specific deficiency in mice (L2aKO) led to a robust nonalcoholic steatohepatitis-like (NASH-like) phenotype within just 2 weeks of dietary fat challenge associated with reduced hepatic phospholipids containing linoleic acid. Reducing dietary choline intake in L2aKO mice exacerbated liver pathology and deficiency of liver phospholipids containing polyunsaturated fatty acids (PUFAs). Treating hepatocytes with LPCs containing oleate and linoleate, two abundant blood-derived LPCs, specifically induced lipid droplet biogenesis and contributed to phospholipid pools, while LPC containing the omega-3 fatty acid docosahexaenoic acid (DHA) promoted lipid droplet formation and suppressed lipogenesis. This study revealed that PUFA-containing LPCs drive hepatic lipid droplet formation, suppress lipogenesis, and sustain hepatic phospholipid pools - processes that are critical for protecting the liver from excess dietary fat.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Hipernutrição , Animais , Camundongos , Fosfolipídeos/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fígado/metabolismo , Lisofosfolipídeos/metabolismo , Fosfatidilcolinas/metabolismo , Gorduras na Dieta , Hipernutrição/patologia
2.
JGH Open ; 6(7): 470-476, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35822121

RESUMO

Background and Aim: Patients with inflammatory bowel disease (IBD) requiring infliximab frequently spend hours to attend treatment. Through quality improvement (QI) methodology, we aimed to shorten the time spent in the biologics infusion center using the accelerated infusion protocol and describe patient outcomes, safety, and associated cost savings. Methods: From September 2018 through December 2019, eligible IBD patients receiving infliximab were recruited. We implemented interventions including the accelerated infusion protocol, and modifying collection location of infliximab. Statistical process control charts were created. Patients' clinical outcome and cost savings data were analyzed using descriptive statistics and Pearson's chi-square. Results: During the study period, a total of 60 patients with IBD receiving infliximab were recruited. A total of 315 infusions were administered-152 were under accelerated infusion protocol and 163 under standard protocol. The mean infliximab infusion time was reduced by 47%, from 2.4 h (142 ± 14 min) to 1.2 h (75 ± 10 min) (142 min vs 75 min, P < 0.001), with total time spent in the infusion center reduced by 52%, from 3.6 h (214 ± 25 min) to 1.7 h (102 ± 14 min) (214 vs 106 min, P < 0.001). Three mild infusion-related reactions (3/152 = 1.97%) were recorded. Estimated cost savings over the 16-month project period was SGD $6721.4 (nursing) and SGD $23 560 (patients). A high level of satisfaction (4.84 out of 5) with the protocol was reported. Conclusion: Our QI project shortened the infliximab infusion time and total time spent in the infusion center, without compromising patient safety. Estimated cost savings were substantial. The protocol helps reduce work productivity loss.

3.
JGH Open ; 5(9): 1015-1018, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34584969

RESUMO

BACKGROUND AND AIM: Hepatocellular carcinoma (HCC) is a significant global problem. With advances in HCC diagnosis and therapy, our hypothesis is that there are significant differences in the clinical characteristics and treatment of HCC over the years. METHODS: Patients with HCC between 1980 and 2018 from three major tertiary hospitals in Singapore were enrolled into a Research Electronic Data Capture database. Clinical characteristics and treatment of HCC were compared between those diagnosed before 2008 (cohort A) and during the current decade (ie from 2008 onwards) (cohort B). RESULTS: There were 3013 patients. Mean age of HCC diagnosis was significantly older in cohort B (68.6 vs 61.2 years, P < 0.001). The most common etiology remained as chronic hepatitis B infection but the proportion due to hepatitis B was significantly lower in cohort B (46.6% vs 57.2%, P < 0.0001). The prevalence of cryptogenic/non-alcoholic steatohepatitis was significantly higher in cohort B than cohort A (27.1% vs 18.6%, P < 0.0001). More patients received curative therapy in cohort B (43.7% vs 27.1%, P < 0.0001. CONCLUSION: In this largest collection of HCC patients in Singapore, patients are diagnosed with HCC at an older age and cryptogenic/non-alcoholic steatohepatitis is becoming more important as an etiology of HCC in the current decade. More patients also received curative therapy in the current decade.

5.
Dig Liver Dis ; 49(12): 1314-1319, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28882540

RESUMO

BACKGROUND: Inflammatory bowel disease (IBD) frequently results in disability. The relevance of psychological effects in causing disability, and whether disability occurs similarly in non-Western cohorts is as yet unknown. AIM: We assessed the relationship between symptoms of anxiety and depression, quality of life and disability in a Singaporean IBD cohort and their predictors. METHODS: Cross-sectional study. We assessed consecutive IBD subjects' IBD-Disability Index (IBD-DI), Hospital Anxiety and Depression Scale (HADS), and IBD questionnaire (IBDQ). Clinical and demographic variables were collected. Non-parametric statistical analyses were performed. Independent predictors of disability were identified through multivariate logistic regression. RESULTS: 200 consecutive subjects were recruited (males: 69%; median age: 43.8 (±15.4) years; 95 had Crohn's disease (CD), 105 had ulcerative colitis (UC); median IBD duration: 10.8 (±9.0) years.) 27% of the cohort had anxiety and/or depression, which worsened disability (IBD-DI: -9 (±14) with anxiety vs 6 (±13) without anxiety, P<0.001; -12 (±16) with depression vs 5 (±13) without depression, P<0.001). Age at diagnosis, use of prednisolone, stricturing CD and active IBD were significant predictors of disability. IBDQ strongly correlated with IBD-DI(rs=0.82, P<0.01). CONCLUSION: Symptoms of anxiety and depression were common in this Asian cohort of IBD and were strongly associated with IBD-related disability. Recognizing psychological issues contributing to disability in IBD is important to ensure holistic care and appropriate treatment.


Assuntos
Ansiedade/epidemiologia , Depressão/epidemiologia , Avaliação da Deficiência , Doenças Inflamatórias Intestinais/psicologia , Qualidade de Vida , Adulto , Estudos de Coortes , Comorbidade , Estudos Transversais , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Escalas de Graduação Psiquiátrica , Fatores de Risco , Índice de Gravidade de Doença , Singapura/epidemiologia , Inquéritos e Questionários , Adulto Jovem
6.
Toxicol Appl Pharmacol ; 217(3): 322-31, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17097122

RESUMO

Diclofenac is a widely used nonsteroidal anti-inflammatory drug that has been associated with rare but serious hepatotoxicity. Experimental evidence indicates that diclofenac targets mitochondria and induces the permeability transition (mPT) which leads to apoptotic cell death in hepatocytes. While the downstream effector mechanisms have been well characterized, the more proximal pathways leading to the mPT are not known. The purpose of this study was to explore the role of free cytosolic calcium (Ca(2+)(c)) in diclofenac-induced cell injury in immortalized human hepatocytes. We show that exposure to diclofenac caused time- and concentration-dependent cell injury, which was prevented by the specific mPT inhibitor cyclosporin A (CsA, 5 microM). At 8 h, diclofenac caused increases in [Ca(2+)](c) (Fluo-4 fluorescence), which was unaffected by CsA. Combined exposure to diclofenac/BAPTA (Ca(2+) chelator) inhibited cell injury, indicating that Ca(2+) plays a critical role in precipitating mPT. Diclofenac decreased the mitochondrial membrane potential, DeltaPsi(m) (JC-1 fluorescence), even in the presence of CsA or BAPTA, indicating that mitochondrial depolarization was not a consequence of the mPT or elevated [Ca(2+)](c). The CYP2C9 inhibitor sulphaphenazole (10 microM) protected from diclofenac-induced cell injury and prevented increases in [Ca(2+)](c), while it had no effect on the dissipation of the DeltaPsi(m). Finally, diclofenac exposure greatly increased the mitochondria-selective superoxide levels secondary to the increases in [Ca(2+)](c). In conclusion, these data demonstrate that diclofenac has direct depolarizing effects on mitochondria which does not lead to cell injury, while CYP2C9-mediated bioactivation causes increases in [Ca(2+)](c), triggering the mPT and precipitating cell death.


Assuntos
Anti-Inflamatórios não Esteroides/toxicidade , Cálcio/metabolismo , Citosol/efeitos dos fármacos , Diclofenaco/toxicidade , Hepatócitos/efeitos dos fármacos , Mitocôndrias Hepáticas/efeitos dos fármacos , Membranas Mitocondriais/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/metabolismo , Apoptose/efeitos dos fármacos , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/biossíntese , Linhagem Celular Transformada , Ciclosporina/farmacologia , Citocromo P-450 CYP2C9 , Citosol/metabolismo , Diclofenaco/metabolismo , Relação Dose-Resposta a Droga , Antagonismo de Drogas , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Oxirredução , Permeabilidade , Sulfafenazol/farmacologia , Superóxidos/metabolismo , Desacopladores
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