Plants as potential sources of natural immunomodulators

In recent years, the immunomodulating properties of plants are being studied extensively with greater interest due to the growing awareness on immune system modulation and to achieve the desirable effects on disease prevention. Several plant remedies well-known in traditional medicine exert their anti-infective effects not only by directly affecting the pathogen, but also by stimulating natural and adaptive defense mechanisms of the host. Therefore plant-remedies have become versatile means with improved immunotherapy. The aim of this review is to highlight the efficacy of available literature evidences on natural immunomodulators of plant origin. In addition, several aspects on plants and their phytoconstituents responsible for immunomodulation have been discussed. A brief explanation has also been given on the use and efficacy of chemical immunomodulators. Moreover, this review also discusses biological screening methods for various plant-based immunodrugs that focus on revealing the mechanism involved in immunomodulation. Hence, botanicals, the diverse chemical complexes, could provide appropriate combinations of synergistic moieties useful in immune drug discovery. In this article, we reviewed the importance of traditional medicines as natural products related to immunodrugs.     

Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice

Several microRNAs have been implicated in neurogenesis, neuronal differentiation, neurodevelopment, and memory. Development of miRNA-based therapeutics, however, needs tools for effective miRNA modulation, tissue-specific delivery, and in vivo evidence of functional effects following the knockdown of miRNA. Expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer''s disease, Huntington''s disease, and spinocerebellar ataxias. The temporal expression pattern of miR-29b during development also correlates with its protective role in neuronal survival. Here, we report the cellular and behavioral effect of in vivo, brain-specific knockdown of miR-29. We delivered specific anti-miRNAs to the mouse brain using a neurotropic peptide, thus overcoming the blood-brain-barrier and restricting the effect of knockdown to the neuronal cells. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival. The mice showed characteristic features of ataxia, including reduced step length. However, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29. In contrast, another miR-29 target, voltage-dependent anion channel1 (VDAC1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown. Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells. Our study suggests that regulation of VDAC1 expression by miR-29 is an important determinant of neuronal cell survival in the brain. Loss of miR-29 results in dysregulation of VDAC1, neuronal cell death, and an ataxic phenotype.     

RNA and β-Hemolysin of Group B Streptococcus Induce Interleukin-1β (IL-1β) by Activating NLRP3 Inflammasomes in Mouse Macrophages

The inflammatory cytokine IL-1β is critical for host responses against many human pathogens. Here, we define Group B Streptococcus (GBS)-mediated activation of the Nod-like receptor-P3 (NLRP3) inflammasome in macrophages. NLRP3 activation requires GBS expression of the cytolytic toxin, β-hemolysin, lysosomal acidification, and leakage. These processes allow the interaction of GBS RNA with cytosolic NLRP3. The present study supports a model in which GBS RNA, along with lysosomal components including cathepsins, leaks out of lysosomes and interacts with NLRP3 to induce IL-1β production.     

α‐synuclein‐induced mitochondrial dysfunction in isolated preparation and intact cells: Implications in the pathogenesis of Parkinson's disease

This study has shown that purified recombinant human α‐synuclein (20 μM) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 μM), a proteasomal inhibitor, causes an accumulation of α‐synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down α‐synuclein expression by specific siRNA. Furthermore, in wild‐type (non‐transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 μM) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild‐type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 μM). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated α‐synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease.

     

Plant community dynamics relative to the changing distribution of a highly invasive species, <Emphasis Type="Italic">Eichhornia crassipes</Emphasis>: a remote sensing perspective

Eradicating or controlling invasive alien species has frequently had unintended consequences, such as proliferation of other invasive species or loss of ecosystem function. We explore this problem using a case study of a highly invasive floating aquatic macrophyte, water hyacinth (Eichhornia crassipes), in the Sacramento-San Joaquin Delta of California. We used 5 years of remote sensing data to perform change detection analysis to study plant community dynamics contemporaneous with changes in water hyacinth cover. Our results show that as water hyacinth cover decreased, submerged aquatic plant (SAP) cover increased and vice versa. This effect was strongest in large patches of water hyacinth. We found no evidence that the native floating aquatic species, pennywort (Hydrocotyle umbellata), benefitted from reducing cover of water hyacinth. In most years, pennywort cover either showed no trend or followed the same trajectory as water hyacinth cover. In this study a decrease in cover of water hyacinth most often resulted in colonization by SAP species with some habitat returning to open water.     

Hematopoiesis and the inosine modification in transfer RNA

Human promyelocytic leukemia (HL-60) cells were used to begin to evaluate the role in hematopoiesis of inosine biosynthesis in the tRNA anticodon wobble position; a reaction involving the enzymatic insertion of performed hypoxanthine. Dimethyl sulfoxide (DMSO) and hypoxanthine were found to induce the differentiation of HL-60 cells in a synergistic manner, and the induced differentiation was independent of changes in the purine catabolic enzymes adenosine deaminase and purine nucleoside phosphorylase. The short-term exposure of HL-60 cells to DMSO plus hypoxanthine resulted in enhanced leucine incorporation, and a model is presented showing how the inosine modification reaction in tRNA may be involved. A means by which hypoxanthine insertion into tRNA may modulate the synthesis of regulatory proteins (e.g., lymphokines and cell surface receptors) is also outlined.     

Maternal Magnesium Restriction Elevates Glucocorticoid Stress and Inflammation in the Placenta and Fetus of WNIN Rat Dams

Magnesium plays a major role in many vital functions in the body. We reported earlier that maternal magnesium restriction altered body composition, fat metabolism, and insulin resistance in WNIN rat offspring and was associated with increased glucocorticoid stress in the offspring in their later life. We hypothesize that increased glucocorticoid stress and inflammation which originate in Mg restricted rat dams is transmitted through placenta to the fetus and underlie the metabolic disturbances in the later life of the offspring. Female weanling WNIN rats received ad libitum, a control diet (MgC) or the same with 62% restriction of Mg (MgR) for 3 months, and their plasma magnesium, inflammatory cytokines, and corticosterone were determined (n = 6 per group) before mating. Following mating with control males, placentae, and fetuses were collected on gestational day 15 (GD 15) from MgC and MgR dams (eight dams from each group and three samples from each dam) and used to determine the levels of inflammatory cytokines, corticosterone, and expression of relevant genes. MgR placentae and fetuses had higher (than MgC) levels of corticosterone and proinflammatory cytokines. Expression of Hsd11b1 was increased (sixfold, p < 0.05), while that of Hsd11b2 was decreased (0.4-fold, p < 0.05) in MgR (than MgC) placenta, whereas expression of Hsd11b1was increased (3.4-fold, p < 0.05) in MgR fetus. Chronic dietary magnesium restriction in WNIN female rats increased their levels of corticosterone, leptin, and proinflammatory cytokines which appeared to be transmitted through placenta to the fetus and could thus be associated with increased stress, altered body composition, fat metabolism, and insulin resistance in the later life of the offspring.     

Burden of Liver Disease among Community-Based People Who Inject Drugs (PWID) in Chennai,India

Background and Objective

We characterize the burden of liver disease in a cohort of PWID in Chennai, India, with a high prevalence of HCV.

Materials and Methods

1,042 PWID were sampled through community outreach in Chennai. Participants underwent fasting blood draw, questionnaire and an examination that included liver stiffness assessment using transient elastography (Fibroscan) and assessment of steatosis via ultrasound.

Results

The median age was 39 years, all were male, 14.8% were HIV infected and 35.6% were HCV antibody positive, of whom 78.9% were chronically infected (HCV RNA positive). Median liver stiffness was 6.2 kPA; 72.9% had no evidence of or mild stiffness, 14.5% had moderate stiffness, and 12.6% had evidence of severe stiffness/cirrhosis. Prevalence of severe stiffness/cirrhosis was significantly higher among persons who were older, had a longer duration of injecting drugs, higher body mass index, higher prevalence of insulin resistance, higher prevalence of steatosis, higher HCV RNA levels and evidence of alcohol dependence. An estimated 42.1% of severe stiffness/cirrhosis in this sample was attributable to HCV. 529 (53.0%) had some evidence of steatosis. Prevalence of steatosis was higher among those who had larger waist circumference, insulin resistance, higher HDL cholesterol and a history of antiretroviral therapy.

Conclusions

We observed a high burden of liver disease in this relatively young cohort that was primarily driven by chronic HCV infection, metabolic factors (insulin resistance and steatosis) and heavy alcohol use. Interventions to improve access to HCV treatment and reduce alcohol use are needed to prevent further progression of liver disease.