Curcumin Increases the Pathogenicity of Salmonella enterica Serovar Typhimurium in Murine Model

Curcumin has gained immense importance for its vast therapeutic and prophylactic applications. Contrary to this, our study reveals that it regulates the defense pathways of Salmonella enterica serovar Typhimurium (S. Typhimurium) to enhance its pathogenicity. In a murine model of typhoid fever, we observed higher bacterial load in Peyer's patches, mesenteric lymph node, spleen and liver, when infected with curcumin-treated Salmonella. Curcumin increased the resistance of S. Typhimurium against antimicrobial agents like antimicrobial peptides, reactive oxygen and nitrogen species. This increased tolerance might be attributed to the up-regulation of genes involved in resistance against antimicrobial peptides - pmrD and pmrHFIJKLM and genes with antioxidant function - mntH, sodA and sitA. We implicate that iron chelation property of curcumin have a role in regulating mntH and sitA. Interestingly, we see that the curcumin-mediated modulation of pmr genes is through the PhoPQ regulatory system. Curcumin downregulates SPI1 genes, required for entry into epithelial cells and upregulates SPI2 genes required to intracellular survival. Since it is known that the SPI1 and SPI2 system can be regulated by the PhoPQ system, this common regulator could explain curcumin's mode of action. This data urges us to rethink the indiscriminate use of curcumin especially during Salmonella outbreaks

Celastrus paniculatus and memantine prevent alcohol dependence and improve decision making in alcohol dependent C57BL6 mice

Background: Alcohol use disorder poses a huge burden with only a handful of approved drugs. AUD is associated with impaired decision-making that leads to compulsive drinking despite negative consequences. A drug that decreases alcohol consumption as well as improves decision-making may thus prove more useful. This study was planned to evaluate the effect of two drugs, Celastrus paniculatus and memantine on alcohol preference and decision impairment in alcohol-dependent mice. Methods: In part 1, the effect of both the study drugs on alcohol consumption was studied using intermittent access model in 70 male C57BL6 mice. In part 2, effect of drugs on decision making was studied using the rodent version of Iowa gambling task. Mice were divided in seven study groups: Group 1-3: Celastrus paniculatus (140, 280, and 560 mg/kg), Group 4: memantine (25 mg/kg), Group 5: vehicle control 1 (Milk), Group 6: vehicle control 2 (normal saline) and Group 7: naltrexone(1mg/kg). Results: Percentage alcohol preference was lower in test groups i.e., Celastrus paniculatus at medium (40.90±15.18%) and high doses (31.79±7.46%) vs. milk (82.74±8.53%; p<0.05); and in memantine group (36.28±10.99%) vs. normal saline (83.27±5.51%; p<0.05). The results were not significantly different to Naltrexone (19.70±6.90%). Percentage preference to disadvantageous arms was also lower in Celastrus paniculatus, at medium (50.52±1.92%) and high doses (48.11±2.43%) compared to milk (54.47±2.73%; p<0.05) and memantine (47.45±1.67%) compared to normal saline (54.00±2.73%; p<0.05), indicating better decision-making ability in the test groups. The findings were comparable to Naltrexone group (45.43±2.52%). Conclusions: These results indicate that Celastrus paniculatus and memantine reduce alcohol consumption and improve decision making in alcohol-dependent mice

Differential modulation of intracellular survival of cytosolic and vacuolar pathogens by curcumin

Curcumin, a principal component of turmeric, acts as an immunomodulator regulating the host defenses in response to a diseased condition. The role of curcumin in controlling certain infectious diseases is highly controversial. It is known to alleviate symptoms of Helicobacter pylori infection and exacerbate that of Leishmania infection. We have evaluated the role of curcumin in modulating the fate of various intracellular bacterial pathogens. We show that pretreatment of macrophages with curcumin attenuates the infections caused by Shigella flexneri (clinical isolates) and Listeria monocytogenes and aggravates those caused by Salmonella enterica serovar Typhi CT18 (a clinical isolate), Salmonella enterica serovar Typhimurium, Staphylococcus aureus, and Yersinia enterocolitica. Thus, the antimicrobial nature of curcumin is not a general phenomenon. It modulated the intracellular survival of cytosolic (S. flexneri and L. monocytogenes) and vacuolar (Salmonella spp., Y. enterocolitica, and S. aureus) bacteria in distinct ways. Through colocalization experiments, we demonstrated that curcumin prevented the active phagosomal escape of cytosolic pathogens and enhanced the active inhibition of lysosomal fusion by vacuolar pathogens. A chloroquine resistance assay confirmed that curcumin retarded the escape of the cytosolic pathogens, thus reducing their inter- and intracellular spread. We have demonstrated that the membrane-stabilizing activity of curcumin is crucial for its differential effect on the virulence of the bacteria

Bactericidal/permeability increasing protein: A multifaceted protein with functions beyond LPS neutralization

Bactericidal permeability increasing protein (BPI), a 55-60kDa protein, first reported in 1975, has gone a long way as a protein with multifunctional roles. Its classical role in neutralizing endotoxin (LPS) raised high hopes among septic shock patients. Today, BPI is not just a LPS-neutralizing protein, but a protein with diverse functions. These functions can be as varied as inhibition of endothelial cell growth and inhibition of dendritic cell maturation, or as an anti-angiogenic, chemoattractant or opsonization agent. Though the literature available is extremely limited, it is fascinating to look into how BPI is gaining major importance as a signalling molecule. In this review, we briefly summarize the recent research focused on the multiple roles of BPI and its use as a therapeutic

Multifaceted roles of curcumin: two sides of a coin!

Introduction: Curcumin has been a front-line topic of mainstream scientific research for a variety of diseases from cancer to Alzheimer's to infectious diseases. Curcumin suppresses the type 1 immune response, which might lead to alleviation of type 1 immune response disorders. However, the inhibition of type 1 immune response might invite infections with opportunistic pathogens. Considering its low bioavailability, several curcumin derivatives have been designed to improve its functionality. Areas covered: This is a consolidated review which aims to compare and contrast diverse aspects of curcumin in variety of diseases. The intricate underlying mechanisms and the functional determinants of curcumin are discussed. Expert opinion: Curcumin being considered as a spicy panacea, is not a remedy for all diseases. However, its ability to act differentially as an antioxidant or pro-oxidant akin to that of a double-edged sword/friend turning foe can be either beneficial or harmful for the host. It exhibits antioxidant properties at concentrations achievable in the body, making the host vulnerable to infections due to the suppression of innate immune responses. With the increase in knowledge of its functional groups, production of analogues of curcumin is underway to enhance its bioavailability and hence its therapeutic potency

Typhoid fever & vaccine development: a partially answered question

Typhoid fever is a systemic disease caused by the human specific Gram-negative pathogen Salmonella enterica serovar Typhi (S Typhi). The extra-intestinal infections caused by Salmonella are very fatal. The incidence of typhoid fever remains very high in impoverished areas and the emergence of multidrug resistance has made the situation worse. To combat and to reduce the morbidity and mortality caused by typhoid fever, many preventive measures and strategies have been employed, the most important being vaccination. In recent years, many Salmonella vaccines have been developed including live attenuated as well as DNA vaccines and their clinical trials have shown encouraging results. But with the increasing antibiotic resistance, the development of potent vaccine candidate for typhoid fever is a need of the hour. This review discusses the latest trends in the typhoid vaccine development and the clinical trials which are underway

Immunomodulation using agonists and antagonists: potential clinical applications

Introduction: Extensive studies have gone into understanding the differential role of the innate and adaptive arms of the immune system in the context of various diseases. Receptor-ligand interactions are responsible for mediating cross-talk between the innate and adaptive arms of the immune system, so as to effectively counter the pathogenic challenge. While TLRs remain the best studied innate immune receptor, many other receptor families are now coming to the fore for their role in various pathologies. Research has focused on the discovery of novel agonists and antagonists for these receptors as potential therapeutics. Areas covered: In this review, we present an overview of the recent advances in the discovery of drugs targeting important receptors such as G-protein coupled receptors, TRAIL-R, IL-1 beta receptor, PPARs, etc. All these receptors play a critical role in the modulation of the immune response. We focus on the recent paradigms applied for the generation of specific and effective therapeutics for these receptors and their status in clinical trials. Expert opinion: Non-specific activation by antagonist/agonist is a difficult problem to dodge. This demands innovation in ligand designing with the use of strategies such as allosterism and dual-specific ligands. Rigorous preclinical and clinical studies are required in transforming a compound to a therapeutic

Curcumin reduces the antimicrobial activity of ciprofloxacin against Salmonella Typhimurium and Salmonella Typhi

Typhoidal and non-typhoidal infection by Salmonella is a serious threat to human health. Ciprofloxacin is the last drug of choice to clear the infection. Ciprofloxacin, a gyrase inhibitor, kills bacteria by inducing chromosome fragmentation, SOS response and reactive oxygen species (ROS) in the bacterial cell. Curcumin, an active ingredient from turmeric, is a major dietary molecule among Asians and possesses medicinal properties. Our research aimed at investigating whether curcumin modulates the action of ciprofloxacin. We investigated the role of curcumin in interfering with the antibacterial action of ciprofloxacin in vitro and in vivo. RTPCR, DNA fragmentation and confocal microscopy were used to investigate the modulation of ciprofloxacin-induced SOS response, DNA damage and subsequent filamentation by curcumin. Chemiluminescence and nitroblue tetrazolium reduction assays were performed to assess the interference of curcumin with ciprofloxacin-induced ROS. DNA binding and cleavage assays were done to understand the rescue of ciprofloxacin-mediated gyrase inhibition by curcumin. Curcumin interferes with the action of ciprofloxacin thereby increasing the proliferation of Salmonella Typhi and Salmonella Typhimurium in macrophages. In a murine model of typhoid fever, mice fed with curcumin had an increased bacterial burden in the reticuloendothelial system and succumbed to death faster. This was brought about by the inhibition of ciprofloxacin-mediated downstream signalling by curcumin. The antioxidant property of curcumin is crucial in protecting Salmonella against the oxidative burst induced by ciprofloxacin or interferon (IFN), a pro-inflammatory cytokine. However, curcumin is unable to rescue ciprofloxacin-induced gyrase inhibition. Curcumins ability to hinder the bactericidal action of ciprofloxacin and IFN might significantly augment Salmonella pathogenesis

Direct detection of Salmonella without pre-enrichment in milk, ice-cream and fruit juice by PCR against hilA gene

A novel PCR based assay was devised to specifically detect contamination of any Salmonella serovar in milk, fruit juice and ice-cream without pre-enrichment. This method utilizes primers against hilA gene which is conserved in all Salmonella serovars and absent from the close relatives of Salmonella. An optimized protocol, in terms time and money, is provided for the reduction of PCR contaminants from milk, ice-cream and juice through the use of routine laboratory chemicals. The simplicity, efficiency (time taken 3-4 h) and sensitivity (to about 5-10 CFU/ml) of this technique confers a unique advantage over other previously used time consuming detection techniques. This technique does not involve pre-enrichment of the samples or extensive sample processing, which was a pre-requisite in most of the other reported studies. Hence, this assay can be ideal for adoption, after further fine tuning, by food quality control for timely detection of Salmonella contamination as well as other food-borne pathogens (with species specific primers) in food especially milk, ice-cream and fruit juice. (C) 2011 Elsevier Ltd. All rights reserved