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Iron is essential for many biological functions, including being a cofactor for enzymes involved in cell proliferation. In line, it has been shown that cancer cells can perturb their iron metabolism towards retaining an abundant iron supply for growth and survival. Accordingly, it has been suggested that iron deprivation through the use of iron chelators could attenuate cancer progression. While they have exhibited anti-tumor properties in vitro, the current therapeutic iron chelators are inadequate due to their low efficacy. Therefore, we investigated whether the bacterial catecholate-type siderophore, enterobactin (Ent), could be used as a potent anti-cancer agent given its strong iron chelation property. We demonstrated that iron-free Ent can exert cytotoxic effects specifically towards monocyte-related tumor cell lines (RAW264.7 and J774A.1), but not primary cells, i.e. bone marrow-derived macrophages (BMDMs), through two mechanisms. First, we observed that RAW264.7 and J774A.1 cells preserve a bountiful intracellular labile iron pool (LIP), whose homeostasis can be disrupted by Ent. This may be due, in part, to the lower levels of lipocalin 2 (Lcn2; an Ent-binding protein) in these cell lines, whereas the higher levels of Lcn2 in BMDMs could prevent Ent from hindering their LIP. Secondly, we observed that Ent could dose-dependently impede reactive oxygen species (ROS) generation in the mitochondria. Such disruption in LIP balance and mitochondrial function may in turn promote cancer cell apoptosis. Collectively, our study highlights Ent as an anti-cancer siderophore, which can be exploited as an unique agent for cancer therapy.

Mammalian siderophores are believed to play a critical role in maintaining iron homeostasis. However, the properties and functions of mammalian siderophores have not been fully clarified. In this study, we have employed Chrome Azurol S (CAS) assay which is a well-established method for bacterial siderophores study, to detect and quantify mammalian siderophores in urine samples. Our study demonstrates that siderophores in urine can be altered by diet, gut microbiota and inflammation. C57BL/6 mice, fed on plant-based chow diets which contain numerous phytochemicals, have more siderophores in the urine compared to those fed on purified diets. Urinary siderophores were up-regulated in iron overload conditions, but not altered by other tested nutrients status. Further, germ-free mice displayed 50% reduced urinary siderophores, in comparison to conventional mice, indicating microbiota biotransformation is critical in generating or stimulating host metabolism to create more siderophores. Altered urinary siderophores levels during inflammation suggest that host health conditions influence systemic siderophores level. This is the first report to measure urinary siderophores as a whole, describing how siderophores levels are modulated under different physiological conditions. We believe that our study opens up a new field in mammalian siderophores research and the technique we used in a novel manner has the potential to be applied to clinical purpose.

The data herein is related to the research article entitled “Microbiota-inducible innate immune siderophore binding protein Lipocalin 2 is critical for intestinal homeostasis” (Singh et al., 2016) [1]. In the present article, we monitored dextran sodium sulfate (DSS)-induced colitis development upon Lipocalin 2 (Lcn2) neutralization, and examined the survival of Lcn2 deficient (Lcn2KO) mice and their WT littermates upon DSS challenge. To dissect the relative contribution of immune and non-immune cells-derived Lcn2 in mediating protection against gut inflammation, we generated respective bone marrow chimera and evaluated their susceptibility to IL-10 receptor neutralization-induced chronic colitis.Neutralization of Lcn2 in WT mice resulted in exacerbated DSS-induced colitis. Notably, mice lacking Lcn2 exhibited 100% mortality whereas only 20% mortality was observed in WT mice upon DSS challenge. Further, data from bone marrow chimera showed that immune cell-derived Lcn2 is the major contributor in conferring protection against colitis. Keywords: Siderocalin, Gut microbiota, Inflammatory bowel disease, Bone marrow chimeras, Colitis

Inflammatory bowel disease (IBD) is a group of inflammatory disorders of the intestine caused by dysregulated T-cell mediated immune response against commensal microflora. Probiotics are reported as therapeutically effective against IBD. However, variable efficacy of the live probiotic strains, difference in survival and persistence in the gut between the strains and the lack of insight into the mechanisms of probiotic action limit optimal therapeutic efficacy. Our aims were to evaluate the lactobacillus strains isolated from the North Indian population for the generation of regulatory cells and cytokines in the intestine, to study their effects on pro-inflammatory mediators in the mouse model of inflammatory bowel disease and to explore the underlying mechanisms of their actions. Among the selected lactobacillus strains, Lactobacillus casei Lbs2 (MTCC5953) significantly suppressed lipopolysaccharide-induced pro-inflammatory cytokine (TNF-alpha, IL-6) secretion. Both live and heat-killed Lbs2 polarized Th0 cells to T-regulatory (Treg) cells in vitro, increased the frequency of FoxP3(+) Treg cells in the mesenteric lymph nodes (MLNs) and alleviated macroscopic and histopathological features of colitis in probiotic-fed mice. Moreover, the levels of IL-12, TNF-alpha and IL-17A were suppressed, while IL-10 and TGF-beta levels were augmented in the colonic tissues of Lbs2-treated mice. The induced Treg (iTreg) cells secreted IL-10 and TGF-beta and exerted suppressive effects on the proliferation of effector T-cells. Adoptive transfer of iTreg cells ameliorated the disease manifestations of murine colitis and suppressed the levels of TNF-alpha and IL-17A. Finally, Lbs2 effects were mediated by Toll-like receptor 2 (TLR2) activation on the dendritic cells. This study identified live and heat-killed Lbs2 as putative therapeutic candidates against IBD and highlighted their Toll-like receptor 2-dependent immunomodulatory and regulatory function.

Groundwater based irrigation is one of the key factors for rapid agricultural development in India. Therefore, understanding the sustainability of irrigation water management is utmost important for agriculture. This study investigated the sustainability of groundwater based irrigation by identifying recent (1996–2017) trend in groundwater depth using Mann-Kendall (MK) test or Modified MK and Sen's slope analysis. This study also explored the relationships of groundwater depth with rainfall and irrigated areas in lower Ganga River basin in India with an area 195,601 km2. Results showed that almost 81.78%, 66.22%, 74.38% and 66.79% wells for pre-monsoon, monsoon, post-monsoon and winter seasons respectively showed increasing trends in groundwater depth. The rapid increasing trend (slope: 8.95–104.46 cm/year) in monsoon season indicates shallow groundwater resource depletion and groundwater abstraction exceeds the groundwater recharge. Moreover, dry seasons increasing trends infer that shallow pumps will not functioning in future as a result irrigation cost will increase. Although irrigated areas remain almost same (1997–2014), decreasing rainfall along with abstraction of groundwater during dry season is primarily identified as main driving force for groundwater depletion. Further study is necessary to characterize the groundwater depletion. Planned water management is urgent for ensuring sustainable irrigation water management.

Commensal microbiota within a holobiont contribute to the overall health of the host via mutualistic symbiosis. Disturbances in such symbiosis is prominently correlated with a variety of diseases affecting the modern society of humans including cardiovascular diseases, which are the number one contributors to human mortality. Given that a hallmark of all cardiovascular diseases is changes in vascular function, we hypothesized that depleting microbiota from a holobiont would induce vascular dysfunction. To test this hypothesis, young mice of both sexes raised in germ-free conditions were examined vascular contractility and structure. Here we observed that male and female germ-free mice presented a decrease in contraction of resistance arteries. These changes were more pronounced in germ-free males than in germ-free females mice. Furthermore, there was a distinct change in vascular remodeling between males and females germ-free mice. Resistance arteries from male germ-free mice demonstrated increased vascular stiffness, as shown by the leftward shift in the stress-strain curve and inward hypotrophic remodeling, a characteristic of chronic reduction in blood flow. On the other hand, resistance arteries from germ-free female mice were similar in the stress-strain curves to that of conventionally raised mice, but were distinctly different and showed outward hypertrophic remodeling, a characteristic seen in aging. Interestingly, we observed that reactive oxygen species (ROS) generation from bone marrow derived neutrophils is blunted in female germ-free mice, but it is exacerbated in male germ-free mice. In conclusion, these observations indicate that commensal microbiota of a holobiont are central to maintain proper vascular function and structure homeostasis, especially in males.

Leishmaniasis is caused by protozoan parasites of the genus Leishmania and causes a wide spectrum of clinical manifestations ranging from self-healing cutaneous lesions to the fatal visceral form. The use of pentavalent antimony, the mainstay of therapy of Leishmaniasis is now limited by its toxicity and alarming increase in unresponsiveness, especially in the Indian subcontinent. Furthermore, other anti-leishmanial drugs are unaffordable in many affected countries and as vaccination based approaches have not yet proved to be effective, chemotherapy remains the only alternative, emphasizing the need for identifying novel drug targets. In this review, we have described the different host immune signaling pathways that could be considered as potential drug targets for Leishmania chemotherapy.

In Arunachal Pradesh and other sub-Himalayan areas of India, accidental consumption of Senecio plants by yaks is often fatal as the plant contains toxic alkaloids like Seneciophylline. The present investigation was undertaken to demonstrate the pro-oxidant effects of an ethanolic extract of Senecio chrysanthemoides (S-EtOH). S-EtOH impaired viability in macrophages, the IC(50) being 13.8+/-1.11 microg/mL. The effect of S-EtOH (1 microg/mL) on generation of reactive oxygen species (ROS) in macrophages was measured by flow cytometry using 2',7'-dichlorofluorescein diacetate (H(2)DCFDA) where it caused a significant increase in the mean fluorescence channel (MFC) from 8.55+/-0.03 to 47.32+/-2.25 (p

Stopped-flow kinetic measurements were used to compare the reactivities of [Ru(medtra)(H2O)] (medtra3− = N-methylethylenediaminetriacetate) (1) and [Ru(hedtra)(H2O)] (2) (hedtra3− = N-hydroxyethylethylenediaminetriacetate) with NO in aqueous solution at 15 °C, pH 7.2 (phosphate buffer). The measured second-order rate constants (3 × 103 and 6 × 104 M−1 s−1 for 1 and 2, respectively) are three to four order of magnitudes lower than that for the reaction between [RuIII(edta)(H2O)]− (3) with NO. However, NO scavenging studies of complexes 1–3, conducted by measuring the difference in nitrite production between treated and untreated murine macrophage cells, revealed that despite being less kinetically reactive toward NO, the [Ru(medtra)(H2O)] complex exhibited the highest NO scavenging ability and lowest toxicity of compounds 1–3.