Adenosine Triphosphate-binding Cassette Subfamily Research Articles

Limbal stem cells carried by a four-dimensional -printed chitosan-based scaffold for corneal epithelium injury in diabetic rabbits.

Methods: Herein, we obtained and characterized deltaN p63- and adenosine triphosphate-binding cassette subfamily G member 2-expressing limbal stem cells (LSCs). Chitosan and carboxymethyl chitosan (CTH) were cross-linked to be an in situ thermosensitive hydrogel (ACH), which was printed through four-dimensional (4D) printing to obtain a porous carrier with uniform pore diameter (4D-CTH). Rabbits were injected with alloxan to induce diabetes mellitus (DM). Following this, the LSC-carrying hydrogel was spread on the surface of the cornea of the diabetic rabbits to cure corneal epithelium injury. Results: Compared with the control group (LSCs only), rapid wound healing was observed in rabbits treated with LSC-carrying 4D-CTH. Furthermore, the test group also showed better corneal nerve repair ability. The results indicated the potential of LSC-carrying 4D-CTH in curing corneal epithelium injury. Conclusion: 4D-CTH holds potential as a useful tool for studying regenerative processes occurring during the treatment of various diabetic corneal epithelium pathologies with the use of stem cell-based technologies.

The impact of chrysanthemi indici flos-enriched flavonoid part on the model of hyperuricemia based on inhibiting synthesis and promoting excretion of uric acid

Ethnopharmacological relevanceIn recent years, in addition to hypertension, hyperglycemia, and hyperlipidemia, the prevalence of hyperuricemia (HUA) has increased considerably. Being the fourth major health risk factor, HUA can affect the kidneys and cardiovascular system. Chrysanthemi Indici Flos is a flavonoid-containing traditional Chinese patent medicine that exhibits a uric acid (UA)-lowering effect. However, the mechanisms underlying Chrysanthemi Indici Flos-enriched flavonoid part (CYM.E) mediated alleviation of HUA remain unelucidated. Aim of the studyThis study aimed to elucidate the efficacy of CYM.E in preventing and treating HUA and its specific effects on UA-related transport proteins, to explore possible mechanism. MethodsThe buddleoside content in CYM.E was determined through high-performance liquid chromatography. HUA was induced in mice models using adenine and potassium oxonate. Subsequently, mice were administered 10 mg/kg allopurinol, and 30, 60, and 90 mg/kg CYM.E to evaluate the effects of CYM.E on the of HUA mice model. Herein, plasma uric acid (UA), creatinine (CR), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol (LDL-c) contents, along with serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activities were measured. Additionally, xanthine oxidase (XOD) and adenosine deaminase (ADA) activities in the liver were determined. The histomorphologies of the liver and kidney tissues were examined through hematoxylin and eosin staining. The messenger RNA (mRNA) expression of facilitated glucose transporter 9 (GLUT9), organic anion transporter (OAT)1, OAT3, and adenosine triphosphate binding cassette subfamily G2 (ABCG2) in the kidney was assessed by real-time quantitative polymerase chain reaction. Furthermore, the expression of urate transporter 1 (URAT1), GLUT9, OAT1, and OAT3 in the kidney, OAT4, and ABCG2 proteins was determined by immunohistochemistry and western blotting. ResultsThe buddleoside content in CYM.E was approximately 32.77%. CYM.E improved body weight and autonomous activity in HUA mice. Additionally, it reduced plasma UA, BUN, and CR levels and serum ALT and AST activities, thus improving hepatic and renal functions, which further reduced the plasma UA content. CYM.E reduced histopathological damage to the kidneys. Furthermore, it lowered plasma TC, TG, and LDL-c levels, thereby improving lipid metabolism disorder. CYM.E administration inhibited hepatic XOD and ADA activities and reduced the mRNA expression of renal GLUT9. CYM.E inhibited the protein expression of renal URAT1, GLUT9, and OAT4, and increased the mRNA and protein expression of renal OAT1, OAT3, and ABCG2. Altogether, these results show that CYM.E could inhibit the production and promote reabsorption of UA and its excretion.

Searching for low phospholipid associated cholelithiasis among patients with post-cholecystectomy biliary pain.

Low phospholipid associated cholelithiasis (LPAC) is associated with variants of the adenosine triphosphate-binding cassette subfamily B, member 4 (ABCB4) gene and is characterized by reduced phosphatidylcholine secretion into bile, impairing the formation of micelles and thus exposing bile ducts to toxic bile acids and increasing cholesterol saturation. LPAC is present in 1% of patients with gallstones and post-cholecystectomy pain is common in this group. LPAC is an under-appreciated cause of post-cholecystectomy pain. The aim of this study is to assess a cohort of patients with post-cholecystectomy pain to identify those with clinical features suggesting that further investigations for LPAC would be beneficial. A retrospective chart review was performed of the first 2 years of post-operative follow-up for all patients under 40 years of age undergoing cholecystectomy for symptomatic gallstones at a tertiary centre between January 2016 and December 2017. 258 patients under the age of 40 underwent a cholecystectomy. 50 patients (19.4%) reported abdominal pain post-cholecystectomy. Five patients (1.9%) fulfilled the criteria for suspected LPAC. Family history of gallstones was documented in 33 of 258 (12.8%) of cases. Obstetric history was obtained in 69 of 197 (35%) female patients. None of the five patients identified above who satisfied the criteria of LPAC had the diagnosis of LPAC considered by their treating clinicians. LPAC is an under-recognized cause of post-cholecystectomy pain. Treatment can avoid long-term symptoms and complications. Clinicians should take a family history and obstetric history to alert them to the diagnosis of LPAC.

Clinical outcomes of ABCB4 heterozygosity in infants and children with cholestatic liver disease.

Biallelic variants in the adenosine triphosphatebinding cassette subfamily B member 4 (ABCB4) gene which encodes the multidrug resistance 3 protein (MDR3) leads to progressive familiar intrahepatic cholestasis type 3. However, monoallelic variants are increasingly recognized as contributing to liver disease in adults. Our aim was to describe the clinical characteristics of MDR3 heterozygous variants in a large cohort of infants and children with cholestatic liver disease. The clinical and genotypic data on pediatric patients seen at King's College Hospital, London, between 2004 and 2022 and found to harbour heterozygous variants in ABCB4 were reviewed. Ninety-two patients amongst 1568 tested were identified with a monoallelic variant (5.9%). The most common presenting problem was conjugated hyperbilirubinemia (n = 46; 50%) followed by cholelithiasis (n = 12; 13%) and cholestatic hepatitis (n = 10; 11%). The median values of liver biochemistry at presentation were: GGT 105 IU/L and total bilirubin 86 µmol/L. Thirty-two genetic variants were identified including 22 missense (69%), 4 deletions (13%), 5 splice site (16%) and 1 termination (3%). At a median follow up of 1 year there was resolution of liver disease. Rare variants in ABCB4 were found amongst infants and children with cholestatic liver disease. The presenting problems were variable and abnormalities tended to normalize over time. Those with severe mutations could develop liver disease later in life when exposed to further insult and should be counseled appropriately.

Outcomes Associated With ABCG2 and CD133 Expression in Patients With Gastric Cancer After Surgical Resection

Objectives: Adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) and CD133 are recognized stem cell markers of gastric cancer. Extensive research has examined the significance of these markers in different types of cancers and their impact on prognoses, linking them to unfavorable clinical outcomes in various tumors. However, the prognostic value of these markers for gastric cancer remains unclear. We investigated the expression of ABCG2 and CD133 and their relationship with clinical outcomes in gastric cancer.Methods: ABCG2 and CD133 expression levels were analyzed, using immunohistochemistry and tissue microarrays, in tumor samples from 459 patients who underwent surgical resections due to gastric cancer. ABCG2 and CD133 expression levels were defined by intensity and dichotomized as medians. The associations among the expression levels of these markers, disease severity, and patient survival were also determined.Results: In the 411 patients for whom we analyzed the expression levels of these markers, 74.9% and 80.5% were found to have high levels of ABCG2 and CD133, respectively. High expression levels of ABCG2 and CD133 were more commonly observed in well-differentiated (<i>p</i><0.001 and <i>p</i>=0.004, respectively) and intestinal lesions (<i>p</i><0.001 and <i>p</i>=0.002, respectively). High ABCG2 expression correlated with improved survival outcomes, whereas high CD133 expression was associated with poorer outcomes. Cox regression analysis confirmed that stage, high ABCG2 (overall survival [OS]: hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41–0.91; <i>p</i>=0.015; recurrencefree survival [RFS]: HR, 0.55; 95% CI, 0.34–0.88; <i>p</i>=0.012), and CD133 expression (OS: HR, 1.59; 95% CI, 1.00–2.51; <i>p</i>=0.049; RFS: HR, 2.29; 95% CI, 1.21–4.34; <i>p</i>=0.011) were predictors of survival. A subgroup analysis indicated that ABCG2 expression was also associated with an improved RFS rate in patients who received systemic chemotherapy.Conclusions: High ABCG2 expression and low CD133 expression in tumors correlated with improved survival outcomes in post-resection patients with gastric cancer, suggesting their potential utility as prognostic biomarkers.

301 Measuring ATPase activity of adenosine triphosphate–binding cassette subfamily C member 4, lamprey CFTR, and human CFTR using antimony-phosphomolybdate assay

301 Measuring ATPase activity of adenosine triphosphate–binding cassette subfamily C member 4, lamprey CFTR, and human CFTR using antimony-phosphomolybdate assay

Recurrent Harlequin Ichthyosis in a Family: A Case Report

Introduction: Harlequin ichthyosis is a severe form of erythrodermic ichthyosis that manifests in a distinctive and distressing appearance at birth. The newborn baby is covered in thick, plate-like scales with distorted surface features, resulting in limited mobility. Fortunately, this condition is rare, with an estimated incidence of approximately 1 in 300,000 births. It is inherited in an autosomal recessive manner and is caused by a mutation in the adenosine triphosphate binding cassette subfamily A member 12 (ABCA12) gene. This mutation affects lipid transport, and the activity of ABCA12 is crucial to produce long-chain ceramides, which are essential for the development of a normal skin barrier. Methods: We present a case report of a newborn who presented with thick, firmly adherent dense plaques covering the entire body, accompanied by deep fissures that extended into the dermis. The facial features included severe ectropion, conjunctival chemosis, eclabium, tethered ears, and a rudimentary nose. In addition, there was flexion contracture of the arms, legs, and digits, along with hypoplastic nails. Results: The baby experienced respiratory difficulty, poor sucking, and a severe cutaneous infection. Unfortunately, the baby’s condition deteriorated and passed away on the 20th day after delivery. Conclusion: Previously considered universally fatal, harlequin ichthyosis now has reported cases of survivors, although it remains a challenging condition. It is crucial to provide parents and family with comprehensive information about the implications of the condition. They should be encouraged to explore all available options and receive psychological support throughout the process. It is essential for the neonatal intensive care unit staff to be trained in providing specialized care for these babies. In addition, parents should be offered the option of antenatal counseling, particularly in cases where there is a previously affected sibling or a history of consanguinity.

Research Note: Heat stress affects immune and oxidative stress indices of the immune organs of broilers by changing the expressions of adenosine triphosphate-binding cassette subfamily G member 2, sodium-dependent vitamin C transporter-2, and mitochondrial calcium uniporter

This study aimed to determine the mechanisms of heat-induced oxidative stress in the thymus and spleen of broilers. After 28 d, 30 broilers were randomly divided into the control (25°C ± 2°C; 24 h/d) and heat-stressed (36°C ± 2°C; 8 h/d) groups; the experiment lasted for 1 wk. The broilers in each group were euthanized, and some samples were collected and analyzed at 35 d. The results showed that the birds subjected to heat stress reduced the weight (P < 0.01) and the indices of thymus (P < 0.01), the activities of T-AOC (P < 0.01) and SOD (P < 0.05) of spleen, and levels of IL-10 (P < 0.05) and the GSH-PX (P < 0.05) in thymus and spleen, and increased the IL-6 content of thymus (P < 0.05), the MDA content (P < 0.01), and the reactive oxygen species (ROS) levels (P < 0.01) in thymus and spleen. Moreover, the expression of the IgG gene in the thymus and spleen of heat-stressed broilers was increased (P < 0.05); however, the expression of the IgM gene in the spleen was increased (P < 0.05), with no difference (P > 0.05) in the thymus of heat-stressed broilers compared with the control. Furthermore, the relative expression of adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) in the thymus and spleen both increased (P < 0.05). The sodium-dependent vitamin C transporter-2 (SVCT-2) (P < 0.01) and mitochondrial calcium uniporter (MCU) (P < 0.01) mRNA levels in the thymus of heat-stressed broilers increased, and the expression of ABCG2 (P < 0.05), SVCT-2 (P < 0.01), and MCU (P < 0.01) proteins in the thymus and spleen of heat-stressed broilers increased compared with the control group. This study confirmed that heat stress-induced oxidative stress in the immune organs of broilers, further reducing immune function.

Chronic Rhinosinusitis with Nasal Polyposis in an Adult with Homozygous Variants of Uncertain Significance in ABCA3 Gene

IntroductionThe role of surfactant proteins in pulmonary diseases has been studied extensively. However, little is known about its contribution in diseases involving the nasal mucosa. Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common disease characterized by persistent inflammation of the nasal passage and paranasal sinuses. We present a case of CRSwNP and interstitial lung disease (ILD) with variants of uncertain significance (VUS) in adenosine triphosphate binding cassette subfamily A member 3 (ABCA3) identified as potential genetic etiology. Case DescriptionPatient was a 42-year-old female with chronic obstructive pulmonary disease (COPD) with oxygen-dependance, bronchiectasis, history of hospitalization for bronchiolitis obliterans organizing pneumonia (BOOP) in infancy, who presented for evaluation of CRSwNP and anosmia. Nasal polyps were first discovered around three years of age, requiring more than 25 nasal polypectomies in her lifetime. Evaluation for cystic fibrosis during childhood was unremarkable. She reported only one episode of wheezing and denied aspirin sensitivity. Despite her significant history of BOOP in infancy, the patient remained without pulmonary infections until four years prior to presentation. Since then, she had two episodes of pneumonia and was diagnosed with COPD, leading to chronic oxygen use. Recent spirometry showed severe airflow obstruction, hyperinflation and decreased diffusing capacity for carbon monoxide. Chest CT revealed diffuse bronchiectasis, mucous plugging, and mild ground glass opacity. Patient had negative sweat test and normal alpha-1 antitrypsin level. Genetic testing with Invitae PCD panel and Neonatal Respiratory Distress panel revealed homozygous VUS [c.155C>T (p. Pro52Leu)] in ABCA3 gene. ConclusionOur patient had an atypical course of ILD, remaining asymptomatic most of her life, and CRSwNP. ABCA3 variants are associated with autosomal recessive pulmonary diseases, such as pulmonary surfactant metabolism dysfunction, pediatric ILD and pulmonary fibrosis1. Surfactant phospholipids are known to lower the surface tension in the alveoli, but they also decrease mucus viscosity and help to eliminate inhaled pathogens2,3,4. The pathophysiology of CRSwNP is unclear and the clinical phenotype of the disease varies widely. While the pathogenicity of the variant is not defined, this case raises a possibility that patient’s ABCA3 genotype may contribute to CRSwNP with recalcitrant nasal polyps.

Morphophysiological, proteomic and metabolomic analyses reveal cadmium tolerance mechanism in common wheat (Triticum aestivum L.).

Soil cadmium (Cd) contamination can reduce wheat yield and quality, thus threatening food security and human health. Herein, morphological physiology, Cd accumulation and distribution, proteomic and metabolomic analyses were performed (using wheat cultivars 'Luomai23' (LM, Cd-sensitive) and 'Zhongyu10' (ZY, Cd-tolerant) at the seedling stage with sand culture) to reveal Cd tolerance mechanism. Cd inhibited wheat growth, caused oxidative stress, hindered carbon and nitrogen metabolism, and altered the quantity and composition of root exudates. The root Cd concentration was lower in ZY than in LM by about 35% under 15μMCd treatments. ZY reduced Cd uptake through root exudation of amino acids and alkaloids. ZY also reduced Cd accumulation through specific up-regulation (twice) of major facilitator superfamily (MFS) proteins. Furthermore, ZY enhanced Cd cell wall fixation and vacuolar compartmentalization by increasing pectin contents, hemicellulose1 contents, and adenosine triphosphate binding cassette subfamily C member 1 (ABCC1) transporter expression, thus reducing the Cd organelle fraction of ZY by about 12% and 44% in root and shoot, respectively, compared with LM. Additionally, ZY had enhanced resilience to Cd due to increased antioxidant capacity, plasma membrane stability, nitrogen metabolism, and endoplasmic reticulum homeostasis, indicating that the increased Cd tolerance could be because of multi-level coordination. These findings provide a reference for exploring the molecular mechanism of Cd tolerance and accumulation, providing a basis for safe utilization of Cd-contaminated soil by breeding Cd-tolerant and low Cd-accumulating wheat varieties.

Recurrent Abdominal Pain After Cholecystectomy: Low Phospholipid-Associated Cholelithiasis

ABSTRACT Low phospholipid-associated cholelithiasis (LPAC) is a rare genetic syndrome characterized by the development of intrahepatic cholelithiasis in young adults. It is associated with a mutation of adenosine triphosphate-binding cassette subfamily B member 4 that leads to impaired solubilization of biliary cholesterol, which in turn precipitates as cholesterol crystals in the intrahepatic bile ducts. We present a young woman who underwent cholecystectomy in her 20s followed by recurrent episodes of right upper quadrant pain and liver enzyme abnormalities. She later developed intrahepatic cholestasis of pregnancy and was started on ursodeoxycholic acid, with improvement of her liver biochemistries. Subsequently, genetic testing confirmed adenosine triphosphate-binding cassette subfamily B member 4 mutation. The case highlights the importance of recognition of adult-onset genetic cholestatic syndromes.

Targeted liver ultrasound performed by an expert is the pivotal imaging examination for low phospholipid-associated cholelithiasis.

Low phospholipid-associatedcholelithiasis (LPAC) is a clinical syndrome that can be associated with variants in the adenosinetriphosphate-binding cassette subfamily B, member 4 (ABCB4) transporter gene, in a proportion of patients. The diagnosis of LPAC is defined by clinical as well as imaging criteria of intrahepatic hyperechoic foci or microlithiasis and biliary sludge on ultrasound. The aim of the study was to assess the role of imaging in investigating patients presenting with clinical features suggesting a diagnosis of LPAC. Imaging findings in 51 patients with clinical LPAC were retrospectively reviewed. Most patients had been referred with difficult-to-manage biliary pain postcholecystectomy and some with intrahepatic dilated ducts and stones. The diagnosis of LPAC was made on clinical features. The patients were young with symptom onset at median age 24 years and were mainly female (75%). Ultrasound was performed by an expert in 48/51 and magnetic resonance cholangiopancreatography (MRCP) in 47/51 patients. Targeted liver ultrasound found small hyperechoic foci with comet tail artifacts or posterior acoustic shadowing typical of LPAC in 30/48 (63%) of examinations. However, ultrasound examinations performed before referral for investigation did not report these findings. Intrahepatic duct dilatation was seen in 26/51 (51%) of cases. MRCP did not reliably detect microlithiasis. Targeted liver ultrasound performed by an expert aware of the possible diagnosis is the pivotal investigation for patients with clinical features suggesting LPAC. The findings in ultrasound performed before referral suggest LPAC is under-recognized and under-diagnosed.

Erratum

Journal of Gastroenterology and HepatologyVolume 37, Issue 4 p. 774-774 ErratumFree Access Erratum This article corrects the following: ePoster Volume 36Issue S2Journal of Gastroenterology and Hepatology pages: 74-283 First Published online: August 26, 2021 First published: 22 March 2022 https://doi.org/10.1111/jgh.15810AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat The abstract entitled “PP-0509 Anthocyanin Extracts from Black Rice Bran Influence the Adenosine Triphosphate-Binding Cassette Subfamily A Member 1 Gene Expression and Colorectal Cancer Cell Proliferation” by Iswanti et al.1 was missing in the published ePoster abstracts. The complete content is presented below. PP-0509 Anthocyanin Extracts from Black Rice Bran Influence the Adenosine Triphosphate-Binding Cassette Subfamily A Member 1 Gene Expression and Colorectal Cancer Cell Proliferation Authors: WIZA ISWANTI1, KARINA RAHMADIA EKAWIDYANI1,2, RINA AGUSTINA1,3, ASMARINAH4,5, SLAMET BUDIJANTO6, MURDANI ABDULLAH1,3,7,8 Affiliations: 1Department of Nutrition, Faculty of Medicine, Universitas Indonesia-Dr Cipto Mangunkusumo General Hospital, Jakarta 10430, Indonesia, 2Department of Community Nutrition, Faculty of Human Ecology, IPB University, Dramaga, Bogor 16680, Indonesia, 3Human Nutrition Research Center, Indonesian Medical Education and Research Institute (IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia, 4Department of Medical Biology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia, 5Molecular Biology Unit, Integrated Laboratory Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia, 6Department of Food Science and Technology, Faculty of Agricultural Technology, IPB University, Dramaga Bogor 16680, Indonesia, 7Human Cancer Research Center, Indonesian Medical Education and Research Institute (IMERI), Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia, 8Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia-Dr. Cipto Mangunkusumo General Hospital, Jakarta 10430, Indonesia Background and Aim: Adenosine triphosphate-binding cassette subfamily A member 1 (ABCA1) gene expression is lower in colon cancer, suggesting increased cell proliferation. This study assessed the ABCA1 gene expression and colorectal cancer cell proliferation in the HT-29 cell line after given anthocyanin supplement extracted from Indonesian black rice bran. Methods: This experimental study involved three administration groups of anthocyanin extract into cell line: anthocyanin extract with a dosage of 1.6 mg/mL (D1), a dosage of 2.0 mg/mL (D2), and a control group without anthocyanin (C). The dosage was obtained after determining the half-maximal inhibitory concentration (IC50) value. Each group was triplicated and evaluated after 24 and 48 hours of cell incubation. The cell proliferation and IC50 value were defined based on 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and spectrophotometry. Gene expression was analyzed with relative quantification using quantitative polymerase chain reaction (qPCR). Results: The average proliferation proportion of HT-29 cells after 24 hours for D1 was 55.0%, and D2 was 41.4% as compared to the control group that was considered 100%. While, for the 48 hours, the proliferations were 53.1% (D1) and 25.8% (D2) as compared to 100% (C). The dosage of IC50 was set at 1.7 mg/mL. The ABCA1 gene expression in HT-29 cell after supplementation of anthocyanin extract from black rice bran with IC50 dosage and with above IC50 dosage (2.0 mg/mL) was 1.2 and 2.3 times higher than the control group, respectively. Conclusion: Increase dosage of anthocyanin supplement extracted from black rice bran may increase ABCA1 gene expression and decrease proliferation of HT-29 cell line. Further study should explore the influence of anthocyanin extract on these outcomes in more dosage variations. Keywords: anthocyanin, cell proliferation, colorectal neoplasm, functional food, mRNA Reference 1.Asia Pacific Digestive Week (APDW), Kuala Lumpur, Malaysia, 19–22 August 2021|Virtual. J. Gastroenterol. Hepatol. 2021; 36(Suppl. 2): 74– 283. https://doi.org/10.1111/jgh.15607Google Scholar Volume37, Issue4April 2022Pages 774-774 ReferencesRelatedInformation

Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma: Bioinformatics-driven prognostic value.

Aberrant expression of adenosine triphosphate-binding cassette subfamily C (ABCC), one of the largest superfamilies and transporter gene families of membrane proteins, is associated with various tumors. However, its relationship with liver hepatocellular carcinoma (LIHC) remains unclear.We used the Oncomine, UALCAN, Human Protein Atlas, GeneMANIA, GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER, and Kaplan–Meier Plotter databases. On May 20, 2021, we searched these databases for the terms ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC10, ABCC11, ABCC12, ABCC13, and “liver cancer.” The exposure group comprised LIHC patients, and the control group comprised normal patients (those with noncancerous liver tissue). All patients shown in the retrieval language search were included. We compared the mRNA expression of these proteins in LIHC and control patients to examine the potential role of ABCC1–13 in LIHC.Relative to the normal liver tissue, mRNA expression of ABCC1/2/3/4/5/6/10 was significantly upregulated (P < .001), and that of ABCC9/11 significantly downregulated (both P < .001), in LIHC. ABCC mRNA expression varied with gender (P < .05), except for ABCC11–13; with tumor grade (P < 0.05), except for ABCC7/12/13; with tumor stage (P < .05), except for ABCC11–13; and with lymph node metastasis status (P < .05), except for ABCC7/8/11/12/13. Based on KEGG enrichment analysis, these genes were associated with the following pathways: ABC transporters, Bile secretion, Antifolate resistance, and Peroxisome (P < .05). Except for ABCC12/13, the ABCCs were significantly associated with B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (P < .05). High mRNA expression of ABCC1/4/5/8 (P < .05) and low expression of ABCC6/7/9/12/13 (P < .05) indicated poor prognosis. Prognostic significance was indicated for ABCC2/13 for both men and women (P < .05); for ABCC1/6/12/13 for tumor grades 1–3 (P < .05); for ABCC5/11/12/13 for all tumor stages (P < .05); for ABCC1/11/12/13 for American Joint Committee on Cancer T stages 1–3 (P < .05); and for ABCC1/5/6/13 for vascular invasion. None showed prognostic significance for microvascular invasion (P < .05).We identified ABCC1/2/3/4/5/6/9/10/11 as potential diagnostic markers, and ABCC1/4/5/6/7/8/9/12/13 as prognostic markers, of LIHC. Our future work will promote the use of ABCCs in the diagnosis and treatment of LIHC.

ABCC9 Is Downregulated and Prone to Microsatellite Instability on ABCC9tetra in Canine Breast Cancer.

Tumorigenesis is associated with metabolic abnormalities and genomic instability. Microsatellite mutations, including microsatellite instability (MSI) and loss of heterozygosity (LOH), are associated with the functional impairment of some tumor-related genes. To investigate the role of MSI and LOH in sporadic breast tumors in canines, 22 tumors DNA samples and their adjacent normal tissues were evaluated using polyacrylamide gel electrophoresis and silver staining for 58 microsatellites. Quantitative real-time polymerase chain reaction, promoter methylation analysis and immunohistochemical staining were used to quantify gene expression. The results revealed that a total of 14 tumors (6 benign tumors and 8 breast cancers) exhibited instability as MSI-Low tumors. Most of the microsatellite loci possessed a single occurrence of mutations. The maximum number of MSI mutations on loci was observed in tumors with a lower degree of differentiation. Among the unstable markers, FH2060 (4/22), ABCC9tetra (4/22) and SCN11A (6/22) were high-frequency mutation sites, whereas FH2060 was a high-frequency LOH site (4/22). The ABCC9tetra locus was mutated only in cancerous tissue, although it was excluded by transcription. The corresponding genes and proteins were significantly downregulated in malignant tissues, particularly in tumors with MSI. Furthermore, the promoter methylation results of the adenosine triphosphate binding cassette subfamily C member 9 (ABCC9) showed that there was a high level of methylation in breast tissues, but only one case showed a significant elevation compared with the control. In conclusion, MSI-Low or MSI-Stable is characteristic of most sporadic mammary tumors. Genes associated with tumorigenesis are more likely to develop MSI. ABCC9 protein and transcription abnormalities may be associated with ABCC9tetra instability.

Role of ATP-binding Cassette Transporters in Sorafenib Therapy for Hepatocellular Carcinoma: An Overview.

Molecular therapy with sorafenib remains the mainstay for advancedstage hepatocellular carcinoma. Notwithstanding, treatment efficacy is low, with few patients obtaining long-lasting benefits due to the high chemoresistance rate. To perform, for the first time, an overview of the literature concerning the role of adenosine triphosphate-binding cassette (ABC) transporters in sorafenib therapy for hepatocellular carcinoma. Three online databases (PubMed, Web of Science, and Scopus) were searched, from inception to October 2020. Study selection, analysis, and data collection were independently performed by two authors. The search yielded 224 results; 29 were selected for inclusion. Most studies were pre-clinical, using HCC cell lines; three used human samples. Studies highlight the effect of sorafenib in decreasing ABC transporters expression. Conversely, it is described the role of ABC transporters, particularly multidrug resistance protein 1 (MDR-1), multidrug resistance-associated proteins 1 and 2 (MRP-1 and MRP-2) and ABC subfamily G member 2 (ABCG2) in sorafenib pharmacokinetics and pharmacodynamics, being key resistance factors. Combination therapy with naturally available or synthetic compounds that modulate ABC transporters may revert sorafenib resistance by increasing absorption and intracellular concentration. A deeper understanding of ABC transporters' mechanisms may provide guidance for developing innovative approaches for hepatocellular carcinoma. Further studies are warranted to translate the current knowledge into practice and paving the way to individualized therapy.

ABA homeostasis and long-distance translocation are redundantly regulated by ABCG ABA importers.

The effects of abscisic acid (ABA) on plant growth, development, and response to the environment depend on local ABA concentrations. Here, we show that in Arabidopsis, ABA homeostasis is regulated by two previously unknown ABA transporters. Adenosine triphosphate–binding cassette subfamily G member 17 (ABCG17) and ABCG18 are localized to the plasma membranes of leaf mesophyll and cortex cells to redundantly promote ABA import, leading to conjugated inactive ABA sinks, thus restricting stomatal closure. ABCG17 and ABCG18 double knockdown revealed that the transporters encoded by these genes not only limit stomatal aperture size, conductance, and transpiration while increasing water use efficiency but also control ABA translocation from the shoot to the root to regulate lateral root emergence. Under abiotic stress conditions, ABCG17 and ABCG18 are transcriptionally repressed, promoting active ABA movement and response. The transport mechanism mediated by ABCG17 and ABCG18 allows plants to maintain ABA homeostasis under normal growth conditions.

ABCB1 in dermatology: roles in skin diseases and their treatment.

Adenosine triphosphate–binding cassette subfamily B member 1 (ABCB1), also known as permeability glycoprotein, multidrug-resistant protein 1, or cluster of differentiation 243 (CD243), is a crucial protein for purging foreign substances from cells. The functions of ABCB1 have been investigated extensively for their roles in cancer, stem cells, and drug resistance. Abundant pharmacogenetic studies have been conducted on ABCB1 and its association with treatment responsiveness to various agents, particularly chemotherapeutic and immunomodulatory agents. However, its functions in the skin and implications on dermatotherapeutics are far less reported. In this article, we reviewed the roles of ABCB1 in dermatology. ABCB1 is expressed in the skin and its appendages during drug delivery and transport. It is associated with treatment responsiveness to various agents, including topical steroids, methotrexate, cyclosporine, azathioprine, antihistamines, antifungal agents, colchicine, tacrolimus, ivermectin, tetracycline, retinoid acids, and biologic agents. Moreover, genetic variation in ABCB1 is associated with the pathogenesis of several dermatoses, including psoriasis, atopic dermatitis, melanoma, bullous pemphigoid, Behçet disease, and lichen planus. Further investigation is warranted to elucidate the roles of ABCB1 in dermatology and the possibility of enhancing therapeutic efficacy through ABCB1 manipulation.

Pharmacogenomics and Morphine.

Morphine is an opioid analgesic indicated in the treatment of acute and chronic moderate to severe pain. From a pharmacodynamic standpoint, morphine exerts its effects by agonizing mu‐opioid receptors predominantly, resulting in analgesia and sedation. Pharmacokinetically, morphine is primarily metabolized in the liver via glucuronidation by the enzyme uridine diphosphate glucuronosyltransferase family 2 member B7 and encounters the transporter proteins organic cation transporter isoform 1 and P‐glycoprotein (adenosine triphosphate–binding cassette subfamily B member 1) as it is being distributed throughout the body. The genes coding for the proteins impacting either the pharmacokinetics or pharmacodynamics of morphine may bear genetic variations, also known as polymorphisms, which may alter the function of the proteins in such a manner that an individual may have disparate treatment outcomes. The purpose of this review is to highlight some of the genes coding for proteins that impact morphine pharmacokinetics and pharmacodynamics and present some treatment considerations.

Anti-hyperuricemic and nephroprotective effects of whey protein hydrolysate in potassium oxonate induced hyperuricemic rats.

Hyperuricemia (HUA) is a serious public health concern globally that needs to be solved. It is closely related to gout and other metabolic diseases. To develop a safe and effective dietary supplementation for alleviating HUA, we investigated the effects of whey protein hydrolysate (WPH) on HUA and associated renal dysfunction and explored their underlying mechanism. Potassium oxonate was used to induce HUA in model rats, who were then administered WPH for 21 days. The results showed that WPH significantly inhibited xanthine oxidase and adenosine deaminase activity in serum and liver, decreased uric acid (UA), creatinine, and blood urea nitrogen levels in serum, and increased the UA excretion in urine. In addition, WPH downregulated the expression of urate transporter 1 and upregulated the expression of organic anion transporter 1, adenosine triphosphate binding cassette subfamily G member 2, organic cation/carnitine transporters 1 and 2, and organic cation transporter 1 in kidneys. These findings demonstrated for the first time that WPH could alleviate HUA by inhibiting UA production and promoting UA excretion, and improve the renal dysfunction caused by HUA. Thus, WPH may be a potential functional ingredient for the prevention and treatment of HUA and associated renal dysfunction. © 2021 Society of Chemical Industry.