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Zou Y, Zhou Z, Yin S, Huang C, Tang H, Yin Z. Targeting of gallbladder megalin receptors with DHA-conjugated limonene albumin nanoparticles. NANOSCALE 2022; 14:6052-6065. [PMID: 35380143 DOI: 10.1039/d1nr07767h] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Gallbladder stones are a major pathogenic factor leading to cholecystitis, and it is increasingly important to explore innovative drug delivery methods for gallstones. In the present study, docosahexaenoic acid-coupled limonene bovine serum albumin nanoparticles (LIM-DHA-BSA-NPs) were constructed. The LIM-DHA-BSA-NPs are spherical structures, and the distribution was relatively uniform, and, more importantly, it has low cytotoxicity and good safety. The LIM-DHA-BSA-NPs solution shows higher uptake rates by RAW264.7 cells when compared with free limonene (LIM). The fluorescence intensity of FITC-modified BSA NPs was significantly higher than that of free FITC, which further indicated that the uptake of DHA-conjugated BSA NPs by RAW264.7 cells was stronger than that of the free drugs. Moreover, the in vivo distribution experiment showed that the enrichment of DiD-loaded BSA NPs in the gallbladder was significantly enhanced when compared with that of free DiD. The semi-quantitative fluorescence intensity results showed that the uptake of DiD-DHA-BSA-NPs was 4.5 times higher when compared with the free DiD. It is preliminarily shown that the DHA-conjugated BSA NPs that were constructed, have an ability to target the gallbladder. Furthermore, the Pearson colocalization coefficient Rcoloc from in vivo colocalization results indicates that the DHA-BSA-NPs had a good colocalization effect on the gallbladder epithelial cells (GBECs). In addition, the LIM-DHA-BSA-NPs solution not only significantly reduced the concentration of nitric oxide (NO) secreted by inflammatory model cells and the number of peripheral blood leukocytes in guinea pigs with cholecystitis, but also significantly decreased the activities of the aspartate transaminase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), glutamyl endopeptidase (GGT), total bile acid (TBA), and total bilirubin (TBIL) enzymes. Collectively, the LIM-DHA-BSA-NPs could be used as an effective anti-inflammatory agent at the cellular and animal levels. This experiment, for the first time, showed that DHA-conjugated BSA NPs could be absorbed into GBECs by megalin receptor-mediated endocytosis and then they exert an anti-cholecystitis effect because of the LIM. The active uptake of DHA-conjugated BSA NPs by the megalin receptors of the GBECs is expected to become an effective therapeutic strategy for cholecystolithiasis.
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Affiliation(s)
- Ya Zou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Zishuo Zhou
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Shanmei Yin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Chengyuan Huang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
| | - Hesong Tang
- Sichuan Emeishan Pharmaceutical Co., Ltd, No.6 Yingbin Road, High-tech Development Zone, Leshan City, Sichuan Province, 614000, China
| | - Zongning Yin
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
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Ertugrul G, Yankol Y, Mecit N, Kirimlioglu H, Kanmaz T, Acarli K, Kalayoglu M. Liver Transplant and Improvements in Cholesterol Biosynthesis Defects: A Case Report of Smith-Lemli-Opitz Syndrome. EXP CLIN TRANSPLANT 2022; 20:104-107. [PMID: 30674241 DOI: 10.6002/ect.2018.0131] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic disease characterized by mental retardation and multiple congenital anomalies. The main pathology is the lack of the enzyme 3β-hydroxysterol Δ7-reductase, which is the last enzymatic step in cholesterol synthesis, ending with a low cholesterol level. Cholesterol is vitally important in cell membranes and myelination of the nervous system. The cholesterol level affects many systems of the body, especially the nervous system. The cause of liver involvement in Smith-Lemli-Opitz syndrome is unclear, and many hypotheses have been suggested. Here, we present the early results of a patient with Smith-Lemli-Opitz syndrome who underwent living-donor liver transplant due to cirrhosis. As a result of liver transplant, normal cholesterol levels were shown, as well as improvements in the patient's neurodevelopment and behavior. Early liver transplant may be considered for patients with a defect of cholesterol biosynthesis, even in the absence of cirrhosis, and may be a future treatment option to prevent risks of neurologic deterioration.
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Affiliation(s)
- Gokhan Ertugrul
- The Organ Transplantation Center, Memorial Sisli Hospital, Istanbul, Turkey
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An observational study on the effect of hypercholesterolemia developed after living donor liver transplantation on cardiac event and graft failure. Sci Rep 2021; 11:959. [PMID: 33441656 PMCID: PMC7806822 DOI: 10.1038/s41598-020-79673-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 12/10/2020] [Indexed: 11/08/2022] Open
Abstract
This study sought to evaluate the association between newly-developed significant hypercholesterolemia within one year following living donor liver transplantation (LDLT) and long term outcomes in light of cardiovascular events and graft failure. From October 2003 to July 2017, 877 LDLT recipients were stratified according to development of significant hypercholesterolemia within one year following LDLT. The primary outcome was occurrence of a major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction, and coronary revascularization after LDLT. The incidence of graft failure, defined as all-cause death or retransplantation, was also compared. A total of 113 (12.9%) recipients developed significant hypercholesterolemia within one year. The differences in incidences of cardiac related events and graft related events began emerging significantly higher in the hypercholesterolemia group after 24 months and 60 months since the LDLT, respectively. After adjustment using the inverse probability of weighting, the hazard ratio (HR) for MACE was 2.77 (95% confidence interval (CI) 1.16–6.61; p = 0.02), while that for graft failure was 3.76 (95% CI 1.97–7.17, p < 0.001). A significant hypercholesterolemia after LDLT may be associated with cardiac and graft-related outcome; therefore, a further study and close monitoring of cholesterol level after LDLT is needed.
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Yaplito‐Lee J, Pai G, Hardikar W, Hong KM, Pitt J, Marum J, Amor DJ. Successful treatment of lathosterolosis: A rare defect in cholesterol biosynthesis-A case report and review of literature. JIMD Rep 2020; 56:14-19. [PMID: 33204591 PMCID: PMC7653246 DOI: 10.1002/jmd2.12158] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/05/2022] Open
Abstract
Lathosterolosis is a rare autosomal recessive disorder of cholesterol biosynthesis. It is caused by defects in the SC5D (sterol C5-desaturase) gene which encodes for the 3-beta-hydroxysteroid-delta-5-desaturase (also called sterol-C5-desaturase or lathosterol dehydrogenase). Only six cases have been described in the literature, but it is possible that a number of patients with milder forms of the condition might have been missed. Lathosterolosis manifests as microcephaly, bilateral cataracts, dysmorphism, limb anomalies, and developmental delay/intellectual disability. Liver involvement is variable and can range from normal liver function tests to portal fibrosis and cirrhosis. Diagnosis is made by demonstration of specific mutations in the SC5D gene and by plasma sterol analysis to confirm elevated lathosterol levels. In this report, we describe a girl with transaminitis in association with developmental delay/intellectual disability, facial dysmorphism, limb anomalies, and bilateral cataracts. Fibroscan showed severe liver fibrosis. Plasma sterol analysis and exome sequencing confirmed the diagnosis of lathosterolosis. Simvastatin treatment resulted in lowering of plasma lathosterol levels, improvement in transaminitis, and liver fibrosis grade, suggesting that children with this condition should be actively treated in order to prevent progression of liver disease.
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Affiliation(s)
- Joy Yaplito‐Lee
- Department of PaediatricsUniversity of MelbourneMelbourneVictoriaAustralia
- Department of Metabolic MedicineRoyal Children's HospitalMelbourneVictoriaAustralia
| | - Gautham Pai
- Department of Gastroenterology and Clinical NutritionRoyal Children's HospitalMelbourneVictoriaAustralia
| | - Winita Hardikar
- Department of PaediatricsUniversity of MelbourneMelbourneVictoriaAustralia
- Department of Gastroenterology and Clinical NutritionRoyal Children's HospitalMelbourneVictoriaAustralia
- Murdoch Children's Research InstituteUniversity of MelbourneMelbourneVictoriaAustralia
| | - Kai M. Hong
- Victorian Clinical Genetics ServicesMurdoch Children's Research InstituteMelbourneVictoriaAustralia
| | - James Pitt
- Department of PaediatricsUniversity of MelbourneMelbourneVictoriaAustralia
- Victorian Clinical Genetics ServicesMurdoch Children's Research InstituteMelbourneVictoriaAustralia
| | - Justine Marum
- Victorian Clinical Genetics ServicesMurdoch Children's Research InstituteMelbourneVictoriaAustralia
| | - David J. Amor
- Department of PaediatricsUniversity of MelbourneMelbourneVictoriaAustralia
- Murdoch Children's Research InstituteUniversity of MelbourneMelbourneVictoriaAustralia
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Lathosterolosis: An Extremely Rare Inherited Condition Associated With Progressive Liver Disease. J Pediatr Gastroenterol Nutr 2019; 69:e142-e145. [PMID: 31259789 DOI: 10.1097/mpg.0000000000002434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
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Mawson AR, Croft AM. Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:E3543. [PMID: 31546693 PMCID: PMC6801530 DOI: 10.3390/ijerph16193543] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/09/2019] [Accepted: 09/15/2019] [Indexed: 12/16/2022]
Abstract
Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.
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Affiliation(s)
- Anthony R Mawson
- Department of Epidemiology and Biostatistics, School of Public Health, College of Health Sciences, Jackson State University, Jackson, MS 39213, USA.
| | - Ashley M Croft
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK.
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Corso G, Dello Russo A, Gelzo M. Liver and the defects of cholesterol and bile acids biosynthesis: Rare disorders many diagnostic pitfalls. World J Gastroenterol 2017; 23:5257-5265. [PMID: 28839426 PMCID: PMC5550775 DOI: 10.3748/wjg.v23.i29.5257] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 05/01/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
In recent decades, biotechnology produced a growth of knowledge on the causes and mechanisms of metabolic diseases that have formed the basis for their study, diagnosis and treatment. Unfortunately, it is well known that the clinical features of metabolic diseases can manifest themselves with very different characteristics and escape early detection. Also, it is well known that the prognosis of many metabolic diseases is excellent if diagnosed and treated early. In this editorial we briefly summarized two groups of inherited metabolic diseases, the defects of cholesterol biosynthesis and those of bile acids. Both groups show variable clinical manifestations but some clinical signs and symptoms are common in both the defects of cholesterol and bile acids. The differential diagnosis can be made analyzing sterol profiles in blood and/or bile acids in blood and urine by chromatographic techniques (GC-MS and LC-MS/MS). Several defects of both biosynthetic pathways are treatable so early diagnosis is crucial. Unfortunately their diagnosis is made too late, due either to the clinical heterogeneity of the syndromes (severe, mild and very mild) that to the scarcity of scientific dissemination of these rare diseases. Therefore, the delay in diagnosis leads the patient to the medical observation when the disease has produced irreversible damages to the body. Here, we highlighted simple clinical and laboratory descriptions that can potentially make you to suspect a defect in cholesterol biosynthesis and/or bile acids, as well, we suggest appropriate request of the laboratory tests that along with common clinical features can help to diagnose these defects.
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Nemes K, Åberg F, Gylling H, Isoniemi H. Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications. World J Hepatol 2016; 8:924-932. [PMID: 27574546 PMCID: PMC4976211 DOI: 10.4254/wjh.v8.i22.924] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/07/2016] [Accepted: 07/13/2016] [Indexed: 02/06/2023] Open
Abstract
The aim of this review is to enlighten the critical roles that the liver plays in cholesterol metabolism. Liver transplantation can serve as gene therapy or a source of gene transmission in certain conditions that affect cholesterol metabolism, such as low-density-lipoprotein (LDL) receptor gene mutations that are associated with familial hypercholesterolemia. On the other hand, cholestatic liver disease often alters cholesterol metabolism. Cholestasis can lead to formation of lipoprotein X (Lp-X), which is frequently mistaken for LDL on routine clinical tests. In contrast to LDL, Lp-X is non-atherogenic, and failure to differentiate between the two can interfere with cardiovascular risk assessment, potentially leading to prescription of futile lipid-lowering therapy. Statins do not effectively lower Lp-X levels, and cholestasis may lead to accumulation of toxic levels of statins. Moreover, severe cholestasis results in poor micellar formation, which reduces cholesterol absorption, potentially impairing the cholesterol-lowering effect of ezetimibe. Apolipoprotein B-100 measurement can help distinguish between atherogenic and non-atherogenic hypercholesterolemia. Furthermore, routine serum cholesterol measurements alone cannot reflect cholesterol absorption and synthesis. Measurements of serum non-cholesterol sterol biomarkers - such as cholesterol precursor sterols, plant sterols, and cholestanol - may help with the comprehensive assessment of cholesterol metabolism. An adequate cholesterol supply is essential for liver-regenerative capacity. Low preoperative and perioperative serum cholesterol levels seem to predict mortality in liver cirrhosis and after liver transplantation. Thus, accurate lipid profile evaluation is highly important in liver disease and after liver transplantation.
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Poliakov E, Koonin EV, Rogozin IB. Impairment of translation in neurons as a putative causative factor for autism. Biol Direct 2014; 9:16. [PMID: 25011470 PMCID: PMC4099083 DOI: 10.1186/1745-6150-9-16] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 07/01/2014] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage. PRESENTATION OF THE HYPOTHESIS We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins. TESTING THE HYPOTHESIS A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models. IMPLICATIONS OF THE HYPOTHESIS It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence. REVIEWERS This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.
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Affiliation(s)
- Eugenia Poliakov
- Laboratory of Retinal Cell & Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA
| | - Eugene V Koonin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
| | - Igor B Rogozin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA
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