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Inflammation and reduced albumin synthesis associated with stable decline in serum albumin in hemodialysis patients. The concentration of albumin in serum is maintained by its rates of synthesis, catabolism, and distribution between vascular and extravascular compartments. Albumin synthesis is suppressed when there is inflammation or inadequate protein intake. This study was conducted to establish whether a decline in serum albumin of >0.3g/dL was accompanied by a change in albumin synthesis and if so whether these changes were associated with increased levels of acute phase proteins and/or with a decrease in equilibrated normalized protein catabolic rate (enPCR). Seventy-nine patients in the National Institutes of Health (NIH)-sponsored HEMO Study had baseline measurements of albumin synthesis (measured kinetically as the disappearance of [125]I human serum albumin), the serum concentrations of albumin, transferrin, C-reactive protein (CRP), α1 acid glycoprotein (α1AG), ceruloplasmin, interleukin-6 (IL-6), plus monthly measurements of enPCR. The plasma levels of all proteins and enPCR were measured regularly over 2years or until serum albumin decreased by >0.3g/dL on two sequential measurements. Albumin synthesis was measured a second time when serum albumin declined by >0.3g/dL or after 2years. Fifty-nine patients [21 with a significant decrease in serum albumin (decliners) and 38 with stable values of serum albumin] had albumin synthesis measured twice. A decline in albumin concentration and synthesis was associated with an increase in α1AG when data from all patients were analyzed as a group. In decliners, albumin synthesis decreased significantly but was unchanged in stable. Likewise, in decliners, IL-6, CRP, α1AG, and ceruloplasmin increased significantly but were unchanged in stable. enPCR was unchanged in both groups and was not associated with either changes in albumin level or synthesis in the whole group. A decrease in serum albumin of >0.3g/dL that persists for a period of 6weeks is associated a decrease in albumin synthesis. This response is associated with evidence of activation of the acute phase response (inflammation) but not with changes in enPCR. In well-dialyzed patients, inflammation is the principal cause of a decrease in serum albumin while protein intake plays an insignificant role.

Grains from cereals contribute an important source of protein to human food, and grain protein content (GPC) is an important determinant of nutritional quality in cereals. Here we show that the quantitative trait locus (QTL) qPC1 in rice controls GPC by regulating the synthesis and accumulation of glutelins, prolamins, globulins, albumins and starch. qPC1 encodes a putative amino acid transporter OsAAP6 , which functions as a positive regulator of GPC in rice, such that higher expression of OsAAP6 is correlated with higher GPC. OsAAP6 greatly enhances root absorption of a range of amino acids and has effects on the distribution of various amino acids. Two common variations in the potential cis -regulatory elements of the OsAAP6 5′-untranslated region seem to be associated with GPC diversity mainly in indica cultivars. Our results represent the first step toward unravelling the mechanism of regulation underlying natural variation of GPC in rice. Grain protein content (GPC) contributes to the nutritional quality of cereals. Here, the authors show that the OsAAP6 quantitative trait locus in rice controls GPC by regulating the synthesis and accumulation of several grain storage proteins and starch.

The functional maturation and preservation of hepatic cells derived from human induced pluripotent stem cells (hiPSCs) are essential to personalized in vitro drug screening and disease study. Major liver functions are tightly linked to the 3D assembly of hepatocytes, with the supporting cell types from both endodermal and mesodermal origins in a hexagonal lobule unit. Although there are many reports on functional 2D cell differentiation, few studies have demonstrated the in vitro maturation of hiPSC-derived hepatic progenitor cells (hiPSC-HPCs) in a 3D environment that depicts the physiologically relevant cell combination and microarchitecture. The application of rapid, digital 3D bioprinting to tissue engineering has allowed 3D patterning of multiple cell types in a predefined biomimetic manner. Here we present a 3D hydrogel-based triculture model that embeds hiPSC-HPCs with human umbilical vein endothelial cells and adipose-derived stem cells in a microscale hexagonal architecture. In comparison with 2D monolayer culture and a 3D HPC-only model, our 3D triculture model shows both phenotypic and functional enhancements in the hiPSC-HPCs over weeks of in vitro culture. Specifically, we find improved morphological organization, higher liver-specific gene expression levels, increased metabolic product secretion, and enhanced cytochrome P450 induction. The application of bioprinting technology in tissue engineering enables the development of a 3D biomimetic liver model that recapitulates the native liver module architecture and could be used for various applications such as early drug screening and disease modeling.

Human serum albumin (HSA) is widely used in clinical and cell culture applications. Conventional production of HSA from human blood is limited by the availability of blood donation and the high risk of viral transmission from donors. Here, we report the production of Oryza sativa recombinant HSA (OsrHSA) from transgenic rice seeds. The level of OsrHSA reached 10.58% of the total soluble protein of the rice grain. Large-scale production of OsrHSA generated protein with a purity >99% and a productivity rate of 2.75 g/kg brown rice. Physical and biochemical characterization of OsrHSA revealed it to be equivalent to plasma-derived HSA (pHSA). The efficiency of OsrHSA in promoting cell growth and treating liver cirrhosis in rats was similar to that of pHSA. Furthermore, OsrHSA displays similar in vitro and in vivo immunogenicity as pHSA. Our results suggest that a rice seed bioreactor produces cost-effective recombinant HSA that is safe and can help to satisfy an increasing worldwide demand for human serum albumin.

Hypoalbuminemia is frequently observed in hospitalized patients and it can be associated with several different diseases, including cirrhosis, malnutrition, nephrotic syndrome and sepsis. Regardless of its cause, hypoalbuminemia has a strong predictive value on mortality and morbidity. Over the years, the rationale for the use of albumin has been extensively debated and the indications for human serum albumin supplementation have changed. As the knowledge of the pathophysiological mechanisms of the pertinent diseases has increased, the indications for intravenous albumin supplementation have progressively decreased. The purpose of this brief article is to review the causes of hypoalbuminemia and the current indications for intravenous administration of albumin. Based on the available data and considering the costs, albumin supplementation should be limited to well-defined clinical scenarios and to include patients with cirrhosis and spontaneous bacterial peritonitis, patients with cirrhosis undergoing large volume paracentesis, the treatment of type 1 hepatorenal syndrome, fluid resuscitation of patients with sepsis, and therapeutic plasmapheresis with exchange of large volumes of plasma. While albumin supplementation is accepted also in other clinical situations such as burns, nephrotic syndrome, hemorrhagic shock and prevention of hepatorenal syndrome, within these contexts it does not represent a first-choice treatment nor is its use supported by widely accepted guidelines.

Cellular therapies for liver diseases and in vitro models for drug testing both require functional human hepatocytes (Hum-H), which have unfortunately been limited due to the paucity of donor liver tissues. Human pluripotent stem cells (hPSCs) represent a promising and potentially unlimited cell source to derive Hum-H. However, the hepatic functions of these hPSC-derived cells to date are not fully comparable to adult Hum-H and are more similar to fetal ones. In addition, it has been challenging to obtain functional hepatic engraftment of these cells with prior studies having been done in immunocompromised animals. In this report, we demonstrated successful engraftment of human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iPS-H) in immunocompetent mice by pre-engineering 3D cell co-aggregates with stromal cells (SCs) followed by encapsulation in recently developed biocompatible hydrogel capsules. Notably, upon transplantation, human albumin and α1-antitrypsin (A1AT) in mouse sera secreted by encapsulated iPS-H/SCs aggregates reached a level comparable to the primary Hum-H/SCs control. Further immunohistochemistry of human albumin in retrieved cell aggregates confirmed the survival and function of iPS-H. This proof-of-concept study provides a simple yet robust approach to improve the engraftment of iPS-H and may be applicable to many stem cell-based therapies.

In the present study, rat liver acellular scaffolds were used as biological support to guide the differentiation of human liver stem-like cells (HLSC) to hepatocytes. Once recellularized, the scaffolds were maintained for 21 days in different culture conditions to evaluate hepatocyte differentiation. HLSC lost the embryonic markers (alpha-fetoprotein, nestin, nanog, sox2, Musashi1, Oct 3/4, and pax2), increased the expression of albumin, and acquired the expression of lactate dehydrogenase and three subtypes of cytochrome P450. The presence of urea nitrogen in the culture medium confirmed their metabolic activity. In addition, cells attached to tubular remnant matrix structures expressed cytokeratin 19, CD31, and vimentin. The rat extracellular matrix (ECM) provides not only a favorable environment for differentiation of HLSC in functional hepatocytes (hepatocyte like) but also promoted the generation of some epithelial-like and endothelial-like cells. When fibroblast growth factor–epidermal growth factor or HLSC-derived conditioned medium was added to the perfusate, an improvement of survival rate was observed. The conditioned medium from HLSC potentiated also the metabolic activity of hepatocyte-like cells repopulating the acellular liver. In conclusion, HLSC have the potential, in association with the natural ECM, to generate in vitro a functional “humanized liver-like tissue.”

Patients with peritoneal dialysis are at risk for malnutrition and hypoalbuminemia, which are indicators of poor outcome. Recently, it was shown that dialysis solutions containing amino acids (AAs) and glucose improve protein anabolism in peritoneal dialysis patients. We determined if the same solutions could increase the fractional synthesis rate of albumin along with whole-body protein synthesis. Changes in the fractional albumin synthetic rate reflect acute change in hepatic albumin synthesis. A random-order cross-over study compared the effects of Nutrineal® (AA source) plus Physioneal® (glucose) dialysate with Physioneal® alone dialysate. Eight patients in the overnight fasting state were compared to 12 patients in the daytime-fed state. Fractional albumin synthetic rate and whole-body protein synthesis were determined simultaneously using a primed-continuous infusion of L-[1-13C]-leucine. Fractional albumin synthesis on AAs plus glucose dialysis did not differ significantly from that on glucose alone in the fasting or the fed state. Protein intake by itself (fed versus fasting) failed to induce a significant increase in the fractional synthetic rate of albumin. Conversely, the oral protein brought about a significant stimulation of whole-body protein synthesis. Our findings show that the supply of AAs has different effects on whole-body protein synthesis and the fractional synthetic rate of albumin.

Background Alterations in blood–brain barrier permeability have been proposed to represent a relevant factor contributing to Parkinson’s disease progression. However, few studies have addressed this issue in patients at different stages of disease. Methods Albumin was measured in cerebrospinal fluid and serum samples obtained from 73 non-demented subjects with idiopathic Parkinson’s disease and 47 age-matched control subjects. The albumin ratio (AR) was calculated to assess blood-cerebrospinal fluid and blood–brain barrier function. The group of patients with Parkinson’s disease included 46 subjects with Hoehn-Yahr staging between 1 and 2 and 27, with a score ranging from 2.5 to 4. Results Statistically significant differences in albumin ratio were found between patients with advanced disease, and both early-stage and unaffected groups. Conversely, early-phase patients did not differ from healthy subjects. Additionally, dopaminergic treatment seems to exert a possible effect on AR values . Conclusions Our study demonstrates that possible dysfunction of the blood-cerebrospinal fluid barrier, blood–brain barrier, or both, characterize Parkinson’s disease progression. The associations between clinical scores, treatments and biochemical findings suggest a progressive impairment of barrier integrity during the course of the disease.

Serum alanine aminotransferase (ALT) is a marker of liver injury. The 2005 American Gastroenterology Association Future Trends Committee report states that serum ALT levels remain constant with age. This study examines the association between serum ALT and age in a community-dwelling cohort in the United States. A cross-sectional study of 2,364 (54% female) participants aged 30-93 years from the Rancho Bernardo Study cohort who attended a research clinic visit in 1984-87. Demographic, metabolic co-variates, ALT, bilirubin, gamma glutamyl transferase (GGT), albumin, and adiposity signaling biomarkers (leptin, IL-6, adiponectin, ghrelin) were measured. Participants were divided into four-groups based upon age quartile, and multivariable-adjusted least squares of means (LSM) were examined (p for trend <0.05). ALT decreased with increasing age, with mean ALT levels (IU/L) of 23, 21, 20, and 17 for those between quartile ages 30-62, 63-71, 72-77, and 78-93 years (p<0.0001). Trends of decreasing LSM ALT with age and the decreasing prevalence of categorically defined elevated serum ALT with age remained robust after adjusting for sex, alcohol use, metabolic syndrome components, and biomarkers of adiposity (p-value <0.0001), and was not materially changed after adjusting for bilirubin, GGT, and albumin. ALT levels decrease with age in both men and women independent of metabolic syndrome components, adiposity signaling biomarkers, and other commonly used liver function tests. Further studies are needed to understand the mechanisms responsible for a decline in ALT with age, and to establish the optimal cut-point of normal ALT in the elderly.