Amino acid transporters: Emerging roles in drug delivery for tumor-targeting therapy

Amino acid transporters,which play a vital role in transporting amino acids for the biosynthesis of mammalian cells,are highly expressed in types of tumors.Increasing studies have shown the feasibility of amino acid transporters as a component of tumortargeting therapy.In this review,we focus on tumor-related amino acid transporters and their potential use in tumor-targeting therapy.Firstly,the expression characteristics of amino acid transporters in cancer and their relationship with tumor growth are reviewed.Secondly,the recognition requirements are discussed,focusing on the“acidbase”properties,conformational isomerism and structural analogues.Finally,recent developments in amino acid transporter-targeting drug delivery strategies are highlighted,including prodrugs and nanocarriers,with special attention to the latest findings of molecular mechanisms and targeting efficiency of transporter-mediated endocytosis.We aim to offer related clues that might lead to valuable tumor-targeting strategies by the utilization of amino acid transporters.     

The association of red blood cell n‐3 and n‐6 fatty acids with bone mineral density and hip fracture risk in the women's health initiative

Omega‐3 (n‐3) and omega‐6 (n‐6) polyunsaturated fatty acids (PUFA) in red blood cells (RBCs) are an objective indicator of PUFA status and may be related to hip fracture risk. The primary objective of this study was to examine RBC PUFAs as predictors of hip fracture risk in postmenopausal women. A nested case‐control study (n = 400 pairs) was completed within the Women's Health Initiative (WHI) using 201 incident hip fracture cases from the Bone Mineral Density (BMD) cohort, along with 199 additional incident hip fracture cases randomly selected from the WHI Observational Study. Cases were 1:1 matched on age, race, and hormone use with non–hip fracture controls. Stored baseline RBCs were analyzed for fatty acids using gas chromatography. After removing degraded samples, 324 matched pairs were included in statistical analyses. Stratified Cox proportional hazard models were constructed according to case‐control pair status; risk of fracture was estimated for tertiles of RBC PUFA. In adjusted hazard models, lower hip fracture risk was associated with higher RBC α‐linolenic acid (tertile 3 [T3] hazard ratio [HR]: 0.44; 95% confidence interval [CI], 0.23–0.85; p for linear trend 0.0154), eicosapentaenoic acid (T3 HR: 0.46; 95% CI, 0.24–0.87; p for linear trend 0.0181), and total n‐3 PUFAs (T3 HR: 0.55; 95% CI, 0.30–1.01; p for linear trend 0.0492). Conversely, hip fracture nearly doubled with the highest RBC n‐6/n‐3 ratio (T3 HR: 1.96; 95% CI, 1.03–3.70; p for linear trend 0.0399). RBC PUFAs were not associated with BMD. RBC PUFAs were indicative of dietary intake of marine n‐3 PUFAs (Spearman's rho = 0.45, p < 0.0001), total n‐6 PUFAs (rho = 0.17, p < 0.0001) and linoleic acid (rho = 0.09, p < 0.05). These results suggest that higher RBC α‐linolenic acid, as well as eicosapentaenoic acid and total n‐3 PUFAs, may predict lower hip fracture risk. Contrastingly, a higher RBC n‐6/n‐3 ratio may predict higher hip fracture risk in postmenopausal women. © 2013 American Society for Bone and Mineral Research.     

Plasma and Mucosal Fatty Acid Pattern in Colectomized Ulcerative Colitis Patients

Patients with inflammatory bowel disease (IBD)have increased plasma n3 polyunsaturated fatty acids(PUFAs), which in ulcerative colitis (UC) patientspersists six months after colectomy, suggesting aprimary abnormality in fatty acid (FA) metabolism inIBD. This finding needed to be confirmed in a largerseries of UC long-term colectomized patients. We aimedto assess the plasma FA pattern in UC colectomized patients with either Brooke's ileostomy (UC-BI)or ileal pouch anal anastomosis (UC-IPAA) and themucosal FA pattern in the ileal reservoir of the UC-IPAApatients. Plasma FAs were assessed in 63 UC colectomized patients (31 with BI and 32 with IPAA) and 30controls. In 26 UC-IPAA (8 with pouchitis and 18 withoutpouchitis) and in 13 healthy controls gut mucosal FAswere also investigated. FAs were detected by capillary column gas-liquid chromatography.Increased levels of saturated fatty acids (SFAs) anddecreased percentages of monounsaturated fatty acids(MUFAs) were observed in both groups of patients. There were no changes in plasma n3 and n6 PUFAs. Themucosal FA pattern of the ileal reservoir consisted ofincreased long-chain PUFAs, specially n6 PUFA, and adecrease of their essential precursors. High percentages of SFAs and low percentages of MUFAs were alsoseen. The plasma FA profile previously described in IBDis not observed long-term after colectomy in UC,suggesting that it is related with the presence of inflamed intestine. High concentrations of SFAsand decreased percentages of MUFAs might represent earlyevents in disturbed FA metabolism in IBD. The changes inFAs of the ileal reservoir, which closely resemble those found in human and experimentalIBD, probably represent a common pattern of intestinalinflammation.     

Methylprednisolone Administration in Primary Biliary Cirrhosis Increases Cholic Acid Turnover, Synthesis, and Deoxycholate Concentration in Bile

As immunosuppressive agents, corticosteroids maybe considered an appropriate treatment for primarybiliary cirrhosis, even if bone loss and other sideeffects may occur. We studied biliary lipid metabolism in 10 nonicteric patients, with histologicallyproven primary biliary cirrhosis (stage I-IV). Weadministered methylprednisolone (24 mg daily) for 30days to ascertain its effects on biliary lipidmetabolism, which are largely still unknown. All patientsunderwent a 30-day drug-washout period before enteringthe trial. The following parameters were studied beforeand after methylprednisolone treatment: serum biochemistry; cholic acid pool size, kineticsand synthesis; biliary lipid secretion; biliary bileacid pattern; biliary lipid molar percentage; andcholesterol saturation index. Methylprednisolone induced a statistically significant (Wilcoxon ranktest) increase in cholic acid turnover (from 0.26± 0.04 to 0.50 ± 0.05 K/day, P = 0.005)and synthesis (from 0.42 ± 0.12 to 0.78 ±0.11 mmol/day, P = 0.04), and in bile deoxycholic acid molarpercentage (from 19.4 ± 2.7 to 30.6 ± 4.4%molar, P = 0.01). On the other hand, a significantdecrease in biliary cholesterol molar percentage (from7.9 ± 0.7 to 6.4 ± 0.5 % molar, P =0.005), cholesterol saturation index (from 1.11 ±0.11 to 0.95 ± 0.07, P = 0.05), and biliarycholesterol secretion (from 64.7 ± 5.4 to 53.0± 4.5 mol/hr, P = 0.005) was observed. These findings show thatshort-term administration of methylprednisolone inpatients with primary biliary cirrhosis does not induceexpansion of the cholic acid pool but increases cholicacid synthesis and turnover, as well as intestinalproduction of deoxycholic acid. If long-term treatmentis considered, the beneficial immunosuppressive effectsof corticosteroids have to be weighed against the hepatotoxic properties of deoxycholicacid.     

产地对巴戟天化学成分含量的影响

本文对不同产地五年生巴戟天微量元素、糖类、总蒽醌、氨基酸含量进行分析。结果表明，德庆、高要产的巴戟天含量均较高。     

Pruritus in Chronic Hepatitis C (Association with High Serum Bile Acids, Advanced Pathology, and Bile Duct Abnormalities)

Pruritus is a common symptom of chroniccholestatic liver diseases but is considered rare inchronic hepatitis. We observed pruritus to be anunusually common complaint in patients with advancedchronic hepatitis C. We reviewed the records of 175chronic hepatitis C patients to identify patients withsevere, diffuse, unexplained pruritus; 12 consecutiveprospective patients undergoing liver biopsy for chronic hepatitis C served as controls.Assessment included laboratory biochemical tests andassessment of liver pathology by stage, grade, hepaticactivity index, and a bile duct score. Pruritus waspresent in nine (5.1%) patients. Serum AST, ALT,alkaline phosphatase, GGTP, total bilirubin, andferritin were similar in pruritics and controls.Pruritics had higher serum bile acids (2028.4 ±223.1 mmol/liter vs 423.1 ± 194.3, P < 0.001), highertransferrin saturation (57.5 ± 6.8% vs 33.2± 3.3, P < 0.01), and lower HCV RNA by bDNA(24.5 ± 12.7 ± 10 vs 172.7 ± 54.1× 10⁵, P < 0.05). Pathology revealedcirrhosis in 6/9 (66.6%) pruritics vs 1/12 (8.3%) controls (P < 0.01).Pruritics had higher pathologic stage (3.7 ± 0.2vs 2.2 ± 0.4, P < 0.01), grade (4.4 ±0.2 vs 2.1 ± 0.2, P < 0.001), activity index(14.3 ± 1.9 vs 8.6 ± 1.9, P < 0.025),and bile duct score (7.6 ± 0.6 vs 4.7 ± 0.4, P <0.01). Of eight pruritics treated withIFN-_2b, two had complete ALT responseand one relapsed. Pruritus followed a relapsing courseand only three patients partially responded despite a variety of interventions. Inconclusion, pruritus is a common complication ofadvanced CHC. Its presence is associated with high serumbile acids, advanced pathology and bile ductabnormalities. The clinical course of pruritus is relapsingand response to therapy is inconsistent. These featuressuggest that pruritus in CHC has a pathogenesis that mayvary from that of chronic cholestaticdiseases.     

赐百龄胶囊质量标准的实验研究

赐百龄胶囊系选用螺旋藻为原料直接精制而成。本研究采用吸收光谱法鉴别蓝藻蛋白，可见６２０ｎｍ的特征吸收峰。采用三氯化锑试管反应鉴别β－胡萝卜素，显蓝绿色。采用ＴＬＣ鉴别氨基酸，可显７个斑点。采用ＴＬＣ鉴别多糖水解液，可显３个斑点，其中２个斑点与葡萄糖、半乳糖对应．采用氨基酸分析仪测定游离、水解氨基酸，含丰富的人体必需的氨基酸，总量高达５５％以上。采用凯氏定氮法测定总氮量，提示蛋白质总量高达６０％以上。采用柱层析－ＵＶ法测定β－胡萝卜素，含量为４４ｍｇ％。     

Effect of Amino Acids on Lower Esophageal Sphincter Characteristics and Gastroesophageal Reflux in Humans

The effect of a commercially available mixedamino acids solution, when given either intravenously orintragastrically, on lower esophageal sphincter (LES)pressure, frequency of transient LES relaxations (TLESRs) and gastroesophageal reflux (GER) wasinvestigated in six healthy volunteers. LES pressure andesophageal pH were simultaneously recorded on threeseparate occasions 1 hr before (basal) and 3 hr during intravenous or intragastric infusion ofamino acids (250 mg protein/kg/hr) or saline (control).No significant changes in LES pressure were seen in thecontrol experiment. Intravenous amino acids caused a rapid and sustained (P < 0.01)decrease in LES pressure whereas intragastric aminoacids decreased LES pressure only gradually andtemporarily (P < 0.01). In the three experiments nosignificant differences were observed in TLESR frequency,the number of GER episodes, the mechanism of reflux, orduration of acid exposure. In healthy subjects bothintragastric and, especially, intravenous infusion of amino acids significantly decrease LESpressure but do not affect the frequency of TLESRs orGER episodes during a continuous liquid gastricload.     

Polyunsaturated Fatty Acids in Human Milk and Their Role in Early Infant Development

The lipid fraction of human milk represents themain source of energy for the newborn infant andsupplies essential nutrients such as fat-solublevitamins and polyunsaturated fatty acids(PUFA).³ The essential fatty acids linoleic and-linolenic acids are precursors of long-chainpolyunsaturated fatty acids (LC-PUFA), such asarachidonic (C20:4 n-6) and docosahexaenoic (C22:6 n-3)acids, present in human milk in considerable amounts.LC-PUFA are indispensable structural components of allcellular membranes, and they are incorporated inrelatively large amounts during early growth of the brain and the retina. Moreover, some LC-PUFAare precursors of eicosanoids, molecules with potentbiological activity that modulates various cellular andtissue processes. The supply of long-chain fatty acids has been associated with functionaloutcomes of the recipient infants such as visual acuityand development of cognitive functions during the firstyear of life. Here we discuss the PUFA composition of human milk, factors which determine andmodulate milk PUFA content, and possible effects of milkLC-PUFA on infant growth and development.