Bioenergetic Failure Drives Functional Exhaustion of Monocytes in Acute-on-Chronic Liver Failure.

Objective: The monocyte-macrophage system is central to the host's innate immune defense and in resolving injury. It is reported to be dysfunctional in acute-on-chronic liver failure (ACLF). The disease-associated alterations in ACLF monocytes are not fully understood. We investigated the mechanism of monocytes' functional exhaustion and the role of umbilical cord mesenchymal stem cells (ucMSCs) in re-energizing monocytes in ACLF. Design: Monocytes were isolated from the peripheral blood of ACLF patients (n = 34) and matched healthy controls (n = 7) and patients with compensated cirrhosis (n = 7); phagocytic function, oxidative burst, and bioenergetics were analyzed. In the ACLF mouse model, ucMSCs were infused intravenously, and animals were sacrificed at 24 h and day 11 to assess changes in monocyte function, liver injury, and regeneration. Results: Patients with ACLF (alcohol 64%) compared with healthy controls and those with compensated cirrhosis had an increased number of peripheral blood monocytes (p < 0.0001) which displayed significant defects in phagocytic (p < 0.0001) and oxidative burst capacity (p < 0.0001). ACLF patients also showed a significant increase in the number of liver macrophages as compared with healthy controls (p < 0.001). Bioenergetic analysis showed markedly reduced oxidative phosphorylation (p < 0.0001) and glycolysis (p < 0.001) in ACLF monocytes. Patients with monocytes having maximum mitochondrial respiration of <37.9 pmol/min [AUC = 0.822, hazard ratio (HR) = 4.5] and baseline glycolysis of ≤42.7 mpH/min (AUC = 0.901, HR = 9.1) showed increased 28-day mortality (p < 0.001). Co-culturing ACLF monocytes with ucMSC showed improved mitochondrial respiration (p < 0.01) and phagocytosis (p < 0.0001). Furthermore, ucMSC therapy increased monocyte energy (p < 0.01) and phagocytosis (p < 0.001), reduced hepatic injury, and enhanced hepatocyte regeneration in ACLF animals. Conclusion: Bioenergetic failure drives the functional exhaustion of monocytes in ACLF. ucMSCs resuscitate monocyte energy and prevent its exhaustion. Restoring monocyte function can ameliorate hepatic injury and promote liver regeneration in the animal model of ACLF.

Profiling of heavy metal and pesticide residues in medicinal plants.

Application of medicinal plant to cure ailments has been practiced by several civilizations. Nowadays, contamination of heavy metals and pesticide residues in medicinal plant is a serious concern, due to toxic effects on human health. The present study was designed with an aim to quantify the heavy metals and pesticide residues in the 20 medicinal herbs, frequently sold in the local market as raw material without any quality assurance. The concentrations of the elements are as follows: copper (2.42-19.14 µgg-1), cadmium (0.01-2.10 µgg-1), chromium (17.63-58.63 µgg-1), iron (7.61-322.6 µgg-1), and lead (13.00-54.47 µgg-1), whereas total metal concentration ranged between 44.73 and 385.15 µgg-1. Among the organic pesticides, HCH (1.63-6.44 µgg-1) and DDT (0.63-7.14 µgg-1) isomers were found to be present in medicinal plant material. Result showed that lead and chromium concentrations in the herbs were above the permissible limits set by WHO. These herbs should be regularly checked for quality assurance before using raw or as a herbal formulation to avoid chronic exposure of metal and pesticides to human being.

Potential of cyanobacterial biofilms in phosphate removal and biomass production.

Four cyanobacterial biofilms, raised from cyanobacterial mats and dominated by Phormidium and Oscillatoria spp., were successfully grown attached to polyester mesh discs, and were tested for their probable application in [Formula: see text] -P removal from domestic sewage and other nutrient enriched wastewaters. Biofilm # 2, dominated by Phormidium fragile, best removed [Formula: see text] -P; nevertheless, some of it also grew outside the substrate making harvesting difficult. Other biofilms also efficiently removed [Formula: see text] -P from the medium in the following order: Biofilm # 1 > Biofilm # 3 > Biofilm # 4. Their growths were restricted to discs and are therefore better candidates as they can be efficiently harvested after [Formula: see text] -P removal. [Formula: see text] -P removal was primarily due to its uptake during growth of the biofilm rather than because of precipitation as pH of the medium remained <8.5. [Formula: see text] -N concentration in the medium determined [Formula: see text] -P removal efficiency of the test biofilms and therefore optimum N:P ratio is necessary for optimizing [Formula: see text] -P removal. The test biofilms could also efficiently remove [Formula: see text] -N from the medium.

Recombinant Human Keratinocyte Growth Factor Induces Akt Mediated Cell Survival Progression in Emphysematous Mice.

INTRODUCTION: Emphysema has been associated with decreased VEGF and VEGFR-2 expression and the presence of high numbers of apoptotic alveolar cells. Keratinocyte growth factor stimulates VEGF synthesis which in turn confers normal lung structure maintenance via the Akt pathway. In this study the potential role of rHuKGF in the improvement of deregulated Akt mediated cell survival pathway in emphysematous mice was investigated. METHODS: Three experimental groups, i.e., emphysema, treatment and control groups, were prepared. Lungs of mice were treated on 3 occasions by oropharyngeal instillation of 10mg rHuKGF per kg body weight after induction of emphysema with porcine pancreatic elastase. Subsequently, lung tissues from mice were collected for histopathology and molecular biology studies. RESULTS AND DISCUSSION: Histopathology photomicrographs and destructive index analysis have shown that elastase-induced airspace enlargement and loss of alveoli recovered in the treatment group. rHuKGF stimulates VEGF production which in turn induces the Akt mediated cell survival pathway in emphysematous lungs. mRNA expression of VEGF, VEGFR, PI3K and Akt was significantly increased while Pten, Caspase-9 and Bad was notably decreased in treatment group when compared with emphysema group, being comparable with the control group. Moreover, VEGF protein expression was in accordance with that found for mRNA. CONCLUSION: Therapeutic rHuKGF supplementation improves the deregulated Akt pathway in emphysema, resulting in alveolar cell survival through activation of the endogenous VEGF-dependent cell survival pathway. Hence rHuKGF may prove to be a potential drug in the treatment of emphysema.