Effect of exposures to multiple metals on blood pressure and hypertension in the elderly: a community-based study.

A chronic disease, hypertension (HTN) is prevalent among the elderly. Exploring the factors that influence HTN and blood pressure (BP) changes is of great public health significance. However, mixed exposure to multiple serum metals has had less research on the effects on BP and HTN for the elderly. From April to August 2019, 2372 people participated in the community physical examination program for the elderly in Tongling City, Anhui Province. We measured BP and serum levels of 10 metals and collected basic demographic information. We analyzed the relationship between metal levels and changes in BP and HTN by the least absolute shrinkage and selection operator regression, Bayesian kernel machine regression model, and generalized linear model. In multiple models, lead (Pb) and cadmium (Cd) were still significantly associated with HTN occurrence after adjusting for potential confounders (Pb: ORquartile 4 VS quartile 1 = 1.20, 95% CI 1.01-1.43; Cd: ORquartile 4 VS quartile 1 = 1.37, 95% CI 1.16-1.62). In the male subgroup, results were similar to those of the general population. In the female group, Cd was positively correlated with HTN and systolic blood pressure, while Pb was not. According to this study, Pb and Cd were correlated with BP and HTN positively, and there was a certain joint effect. To some extent, our findings provide clues for the prevention of hypertension in the elderly.

Joint and interactive effects of metal mixtures on liver damage: Epidemiological evidence from repeated-measures study.

BACKGROUND: The impact of heavy metals on liver function has been examined in numerous epidemiological studies. However, these findings lack consistency and longitudinal validation. METHODS: In this study, we conducted three follow-up surveys with 426 participants from Northeast China. Blood and urine samples were collected, along with questionnaire information. Urine samples were analyzed for concentrations of four metals (chromium [Cr], cadmium [Cd], lead [Pb], and manganese [Mn]), while blood samples were used to measure five liver function indicators (alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin [ALB], globulin [GLB], and total protein [TP]). We utilized a linear mixed-effects model (LME) to explore the association between individual heavy metal exposure and liver function. Joint effects of metal mixtures were investigated using quantile g-computation and Bayesian kernel machine regression (BKMR). Furthermore, we employed BKMR and Marginal Effect models to examine the interaction effects between metals on liver function. RESULTS: The LME results demonstrated a significant association between urinary heavy metals (Cr, Cd, Pb, and Mn) and liver function markers. BKMR results indicated positive associations between heavy metal mixtures and ALT, AST, and GLB, and negative associations with ALB and TP, which were consistent with the g-comp results. Synergistic effects were observed between Cd-Cr on ALT, Mn-Cr and Cr-Pb on ALB, while an antagonistic effect was found between Mn-Pb and Mn-Cd on ALB. Additionally, synergistic effects were observed between Mn-Cr on GLB and Cd-Cr on TP. Furthermore, a three-way antagonistic effect of Mn-Pb-Cr on ALB was identified. CONCLUSION: Exposure to heavy metals (Cr, Cd, Mn, Pb) is associated with liver function markers, potentially leading to liver damage. Moreover, there are joint and interaction effects among these metals, which warrant further investigation at both the population and mechanistic levels.

CsPbBr3 Perovskite Nanoparticles causes Colitis-Like Symptom via Promoting Intestinal Barrier Damage and Gut Microbiota Dysbiosis.

Lead-based perovskite nanoparticles (Pb-PNPs) with superior optoelectronic properties are promising alternatives for the next generation of photovoltaics materials. This raises a great concern about their potential exposure toxicity in biological systems. However, little is known about their adverse effects on the gastrointestinal tract system so far. Here, the aim is to investigate the biodistribution, biotransformation, potential gastrointestinal tract toxicity, and effect on the gut microbiota after oral exposure to the CsPbBr3 perovskite nanoparticles (CPB PNPs). The advanced synchrotron radiation based microscopic X-ray fluorescence scanning and X-ray absorption near-edge spectroscopy demonstrate that high doses of CPB (CPB-H) PNPs can gradually transform into different lead-based compounds, subsequently accumulating in the gastrointestinal tract, especially the colon. Meanwhile, the pathological changes of stomach, small intestine, and colon reveal that CPB-H PNPs have higher gastrointestinal tract toxicity than Pb(Ac)2 , consequently leading to colitis-like symptoms. More importantly, 16S rRNA gene sequencing analysis discloses that CPB-H PNPs cause more significant alterations in the richness and diversity of the gut microbiota related to inflammation, intestinal barrier, and immune function than Pb(Ac)2 . The findings may contribute to shedding light on understanding the adverse effects on gastrointestinal tract and gut microbiota of Pb-PNPs.

Lead exposure exacerbates adverse effects of HFD on metabolic function via disruption of gut microbiome, leading to compromised barrier function and inflammation.

PURPOSE: The toxicity of lead (Pb) has been intensively studied, while the adverse effects in the population on a high-fat diet (HFD) remain unclear. This study compared the different biologic effects of Pb in CHOW and HFD-fed mice and investigated the important role that gut microbiota may play. METHODS: C57BL/6 mice were fed a CHOW diet and HFD with or without 1 g/L Pb exposure through drinking water for 8 weeks. Using oral glucose tolerance test, histopathological observation, real-time fluorescence quantitative PCR, enzyme-linked immunosorbent assay, and 16S high-throughput sequencing to compare the Pb toxicity, fecal microbiota transplantation was conducted to investigate the key role of gut microbiota. RESULTS: The metabolic disorders induced by HFD were aggravated by chronic Pb intake, and HFD exacerbated the Pb accumulation in the colon by 96%, 32% in blood, 27% in the liver, and 142% in tibiae. Concomitantly, Pb induced more serious colonic injury, further disturbing the composition of gut microbiota in the HFD-fed mice. Moreover, altered fecal microbiota by HFD and Pb directly mediated metabolic disorders and colonic damage in recipient mice, which emphasized the importance of gut microbiota. CONCLUSION: These findings indicated that the population with HFD has lower resistance and would face more security risks under Pb pollution, and pointed out the importance of assessing the health impacts of food contaminants in people with different dietary patterns.

Anxiety, aggression, reward sensitivity, and forebrain dopamine receptor expression in a laboratory rat model of early-life disadvantage.

Despite early-life disadvantage (ELD) in humans being a highly heterogenous construct, it consistently predicts negative neurobehavioral outcomes. The numerous environmental contributors and neural mechanisms underlying ELD remain unclear, though. We used a laboratory rat model to evaluate the effects of limited resources and/or heavy metal exposure on mothers and their adult male and female offspring. Dams and litters were chronically exposed to restricted (1-cm deep) or ample (4-cm deep) home cage bedding postpartum, with or without lead acetate (0.1%) in their drinking water from insemination through 1-week postweaning. Restricted-bedding mothers showed more pup-directed behaviors and behavioral fragmentation, while lead-exposed mothers showed more nestbuilding. Restricted bedding-raised male offspring showed higher anxiety and aggression. Either restricted bedding or lead exposure impaired goal-directed performance in a reinforcer devaluation task in females, whereas restricted bedding alone disrupted it in males. Lead exposure, but not limited bedding, also reduced sucrose reward sensitivity in a progressive ratio task in females. D1 and D2 receptor mRNA in the medial prefrontal cortex and nucleus accumbens (NAc) were each affected by the early-life treatments and differently between the sexes. Most notably, adult males (but not females) exposed to both early-life treatments had greatly increased D1 receptor mRNA in the NAc core. These results illuminate neural mechanisms through which ELD threatens neurobehavioral development and highlight forebrain dopamine as a factor.

Reducing lead uptake by plants as a way to lead-free food.

In this research, an attempt was made to produce safe food from lead-contaminated soil. It was assumed that an increased amount of calcium (Ca) in plants would prevent them from lead (Pb) uptake. A new-generation agricultural product - an activator of Ca transport in plants "InCa" (from Plant Impact) - was used. The study was conducted on several crop species, Cucumis sativus L., Linum usitatissimum L., Medicago sativa L. and Solanum lycopersicum L., cultivated in mineral medium. The leaves were sprayed with InCa activator while the roots received Pb from the substrate in the form of Pb(NO3)2 dissolved in the medium. It was shown that spraying the leaves with InCa reduced Pb concentration in the roots of S. lycopersicum to 73%, in C. sativus to 60%, and in L. usitatissimum to 57%. Finally, it was found that foliar application of InCa reduced the concentration of Pb in plant roots by 53%, and in plant shoots by 57% (on average by about 55%). These observations were confirmed using histochemical and electron microscopy techniques. It was shown that one of the InCa activator components - Ca(NO3)2 - is responsible for such effects. This result was verified by using another experimental method - the Allium epidermis test. Visualization of Pb in epidermal cells of Allium cepa. L. using the Leadmium™Green fluorescent probe (confocal microscopy) showed a reduction in the amount of Pb that entered the epidermal cells after the application of the tested solutions. For the first time, it was shown that it is possible to reduce Pb uptake by plants by up to 55%. In the future, this offers the possibility of developing a foliar calcium preparation aimed at lowering the concentration of Pb in plants and thereby reducing the amount of Pb in the food chain.

Potential Protective Effects of Spirulina (Spirulina platensis) against In Vitro Toxicity Induced by Heavy Metals (Cadmium, Mercury, and Lead) on SH-SY5Y Neuroblastoma Cells.

Spirulina, a filamentous microalga, is used all over the world as a nutraceutical dietary supplement. Recent studies have focused on examining its chelating activity and antioxidant properties, especially as a candidate for protection against neurotoxicity caused by heavy metals. The MTT test and LDH assay were used to examine the viability of the SH-SY5Y cells for 24, 48, and 72 h, to Cd, Hg, and Pb, individually or in combination with Spirulina, and the effects of necrotic cell death. In comparison to the control group, the viability of SH-SY5Y cells decreased after 24 h of exposure, with Cd being more toxic than Hg and Pb being less lethal. The effects of heavy metal toxicity on cell survival were ranked in order after 72 h under identical experimental circumstances as follows: Hg, Pb, and Cd. The viability of the cells was then tested after being exposed to Spirulina at doses of 5 at 50 (%v/v) for 24, 48, and 72 h, respectively. SH-SY5Y cells that had been treated with mixtures of heavy metals and Spirulina underwent the same assay. Cell viability is considerably increased by using Spirulina treatments at the prescribed periods and doses. Instead, the same procedure, when applied to SH-SY5Y cells, caused the release of LDH, which is consistent with the reduction in cell viability. We demonstrated for the first time, considering all the available data, that Spirulina 5, 25, and 50 (%v/v) enhanced the number of viable SH-SY5Y cells utilized as a model system for brain cells. Overall, the data from the present study provide a first insight into the promising positive role of Spirulina against the potentially toxic effects of metals.

Mild hypothermia fails to protect infant macaques from brain injury caused by prolonged exposure to Antiseizure drugs.

Barbiturates and benzodiazepines are GABAA-receptor agonists and potent antiseizure medications. We reported that exposure of neonatal macaques to combination of phenobarbital and midazolam (Pb/M) for 24 h, at clinically relevant doses and plasma levels, causes widespread apoptosis affecting neurons and oligodendrocytes. Notably, the extent of injury was markedly more severe compared to shorter (8 h) exposure to these drugs. We also reported that, in the infant macaque, mild hypothermia ameliorates the apoptosis response to the anesthetic sevoflurane. These findings prompted us explore whether mild hypothermia might protect infant nonhuman primates from neuro- and gliotoxicity of Pb/M. Since human infants with seizures may receive combinations of benzodiazepines and barbiturates for days, we opted for 24 h treatment with Pb/M. Neonatal rhesus monkeys received phenobarbital intravenously, followed by midazolam infusion over 24 h under normothermia (T > 36.5 °C-37.5 °C; n = 4) or mild hypothermia (T = 35 °C-36.5 °C; n = 5). Medication doses and blood levels measured were comparable to those in human infants. Animals were euthanized at 36 h and brains examined immunohistochemically and stereologically. Treatment was well tolerated. Extensive degeneration of neurons and oligodendrocytes was seen at 36 h in both groups within neocortex, basal ganglia, hippocampus and brainstem. Mild hypothermia over 36 h (maintained until terminal perfusion) conferred no protection against the neurotoxic and gliotoxic effects of Pb/M. This is in marked contrast to our previous findings that mild hypothermia is protective in the context of a 5 h-long exposure to sevoflurane in infant macaques. These findings demonstrate that brain injury caused by prolonged exposure to Pb/M in the neonatal primate cannot be ameliorated by mild hypothermia.

Lead suppresses interferon γ to induce splenomegaly via modification on splenic endothelial cells and lymphoid tissue organizer cells in mice.

Splenomegaly is a symptom characterized by the presence of an enlarged spleen. The impact of environmental factors on splenomegaly is largely unknown. In this study, C57BL/6 mice were treated with 125 ppm or 1250 ppm lead (Pb) via drinking water for 8 wk, and the process of splenomegaly was evaluated. Treatment with 1250 ppm Pb, but not 125 ppm Pb, caused splenomegaly, which was associated with increased capacity for erythrocyte clearance. Intriguingly, Pb-caused splenomegaly was independent of lymphoid tissue inducer (LTi) cells, which produce lymphotoxins α and ß (LTα/ß) to activate endothelial cells and LT organizer (LTo) cells and drive the development of spleen physiologically. A direct action of Pb on endothelial cells and LTo cells did not impact their proliferation. On the other hand, during steady state, a tonic level of interferon (IFN)γ acted on endothelial cells and LTo cells to suppress splenomegaly, as IFNγ receptor (IFNγR)-deficient mice had enlarged spleens relative to wild-type mice; during Pb exposure, splenic IFNγ production was suppressed, thus leading to a loss of the inhibitory effect of IFNγ on splenomegaly. Mechanically, Pb acted on splenic CD4+ T cells to suppress IFNγ production, which impaired the Janus kinase (Jak)1/ signal transducer and activator of transcription (STAT)1 signaling in endothelial cells and LTo cells; the weakened Jak1/STAT1 signaling resulted in the enhanced nuclear factor-κB (NF-κB) signaling in endothelial cells and LTo cells, which drove their proliferation and caused splenomegaly. The present study reveals a previously unrecognized mechanism for the immunotoxicity of Pb, which may extend our current understanding for Pb toxicology.

Effect of pyrolysis temperature of biochar on Cd, Pb and As bioavailability and bacterial community composition in contaminated paddy soil.

To further investigate the effect of pyrolysis temperature on bioavailable Cd, Pb and As, as well as the bacterial community structure in multi-metal(loid) contaminated paddy soil, six types of biochar derived from wood sawdust and peanut shell at 300 °C, 500 °C and 700 °C were prepared and incubated with Cd, Pb and As contaminated paddy soil for 45 days. The results showed that adding biochar decreased bioavailable Cd by 31.3%- 42.9%, Pb by 0.61-56.1%, while bioavailable As changed from 9.68 mg kg-1 to 9.55-10.84 mg kg-1. We found that pyrolysis temperature of biochar had no significant effect on Cd bioavailability while Pb bioavailability decreased obviously with pyrolysis temperature raising. Biochar reduced the proportion of soluble and exchangeable Cd from 45.0% to 11.2-15.4% in comparison with the control, while no significant effect on the speciation of Pb and As. Wood sawdust biochar (WSBs) had more potential in decreasing bioavailable Cd and Pb than peanut shell biochar (PSBs). Although high-temperature biochar resulted a larger increase in bacterial species than low-and mid- temperature biochar, feedstock played a more important role in altering soil bacterial diversity and community composition than pyrolysis temperature. PSBs increased the diversity of soil bacteria through elevating soil dissolved carbon (DOC). Biochar altered soil bacterial community structure mainly by altering the level of soil electricity conductivity, DOC and bioavailable Cd. In addition, applying high-temperature PSBs increased the genus of bacteria that relevant to nitrogen cycling, such as Nitrospira, Nitrosotaleaceae and Candidatus_Nitrosotalea.

Morphological and Functional Alterations Induced by Two Ecologically Relevant Concentrations of Lead on Danio rerio Gills.

Lead (Pb), due to its high toxicity and bioaccumulation tendency, is one of the top three pollutants of concern for both humans and wildlife and occupies second place in the Priority List of Hazardous Substances. In freshwater fish, Pb is mainly absorbed through the gills, where the greatest accumulation occurs. Despite the crucial role of gills in several physiological functions such as gas exchange, water balance, and osmoregulation, no studies evaluated the effects of environmentally relevant concentrations of Pb on this organ, and existing literature only refers to high levels of exposure. Herein we investigated for the first time the molecular and morphological effects induced by two low and environmentally relevant concentrations of Pb (2.5 and 5 µg/L) on the gills of Danio rerio, a model species with a high translational value for human toxicity. It was demonstrated that Pb administration at even low doses induces osmoregulatory dysfunctions by affecting Na+/K+-ATPase and AQP3 expression. It was also shown that Pb upregulates MTs as a protective response to prevent cell damage. Modulation of SOD confirms that the production of reactive oxygen species is an important toxicity mechanism of Pb. Histological and morphometric analysis revealed conspicuous pathological changes, both dose- and time-dependent.

Exogenously Applied Sodium Nitroprusside Mitigates Lead Toxicity in Rice by Regulating Antioxidants and Metal Stress-Related Transcripts.

Sustainable agriculture is increasingly being put in danger by environmental contamination with dangerous heavy metals (HMs), especially lead (Pb). Plants have developed a sophisticated mechanism for nitric oxide (NO) production and signaling to regulate hazardous effects of abiotic factors, including HMs. In the current study, we investigated the role of exogenously applied sodium nitroprusside (SNP, a nitric oxide (NO) donor) in ameliorating the toxic effects of lead (Pb) on rice. For this purpose, plants were subjected to 1.2 mM Pb alone and in combination with 100 µM SNP. We found that under 1.2 mM Pb stress conditions, the accumulation of oxidative stress markers, including hydrogen peroxide (H2O2) (37%), superoxide anion (O2-) (28%), malondialdehyde (MDA) (33%), and electrolyte leakage (EL) (34%), was significantly reduced via the application of 100 µM SNP. On the other hand, under the said stress of Pb, the activity of the reactive oxygen species (ROS) scavengers such as polyphenol oxidase (PPO) (60%), peroxidase (POD) (28%), catalase (CAT) (26%), superoxide dismutase (SOD) (42%), and ascorbate peroxidase (APX) (58%) was significantly increased via the application of 100 µM SNP. In addition, the application of 100 µM SNP rescued agronomic traits such as plant height (24%), number of tillers per plant (40%), and visible green pigments (44%) when the plants were exposed to 1.2 mM Pb stress. Furthermore, after exposure to 1.2 mM Pb stress, the expression of the heavy-metal stress-related genes OsPCS1 (44%), OsPCS2 (74%), OsMTP1 (83%), OsMTP5 (53%), OsMT-I-1a (31%), and OsMT-I-1b (24%) was significantly enhanced via the application of 100 µM SNP. Overall, our research evaluates that exogenously applied 100 mM SNP protects rice plants from the oxidative damage brought on by 1.2 mM Pb stress by lowering oxidative stress markers, enhancing the antioxidant system and the transcript accumulation of HMs stress-related genes.

Discovery of Bispecific Lead Compounds from Azadirachta indica against ZIKA NS2B-NS3 Protease and NS5 RNA Dependent RNA Polymerase Using Molecular Simulations.

Zika virus (ZIKV) has been characterized as one of many potential pathogens and placed under future epidemic outbreaks by the WHO. However, a lack of potential therapeutics can result in an uncontrolled pandemic as with other human pandemic viruses. Therefore, prioritized effective therapeutics development has been recommended against ZIKV. In this context, the present study adopted a strategy to explore the lead compounds from Azadirachta indica against ZIKV via concurrent inhibition of the NS2B-NS3 protease (ZIKVpro) and NS5 RNA dependent RNA polymerase (ZIKVRdRp) proteins using molecular simulations. Initially, structure-based virtual screening of 44 bioflavonoids reported in Azadirachta indica against the crystal structures of targeted ZIKV proteins resulted in the identification of the top four common bioflavonoids, viz. Rutin, Nicotiflorin, Isoquercitrin, and Hyperoside. These compounds showed substantial docking energy (-7.9 to -11.01 kcal/mol) and intermolecular interactions with essential residues of ZIKVpro (B:His51, B:Asp75, and B:Ser135) and ZIKVRdRp (Asp540, Ile799, and Asp665) by comparison to the reference compounds, O7N inhibitor (ZIKVpro) and Sofosbuvir inhibitor (ZIKVRdRp). Besides, long interval molecular dynamics simulation (500 ns) on the selected docked poses reveals stability of the respective docked poses contributed by intermolecular hydrogen bonds and hydrophobic interactions. The predicted complex stability was further supported by calculated end-point binding free energy using molecular mechanics generalized born surface area (MM/GBSA) method. Consequently, the identified common bioflavonoids are recommended as promising therapeutic inhibitors of ZIKVpro and ZIKVRdRp against ZIKV for further experimental assessment.

Hepatorenal Protective Effect of Fenugreek Aqueous Extract against Lead Toxicity in Experimental Rats.

In this study, aqueous extract of germinated fenugreek seeds was investigated to assess its therapeutic effect on hepatorenal lead toxicity in experimental rats. After overnight fasting, rats were injected intraperitoneally with 0.5 mL of lead acetate at a dose of 35 mg/kg body weight for five consecutive days. Animals were divided into four groups of ten rats each: normal control; untreated negative control and rats treated with 200 or 400 mg/kg body weight of the aqueous extract. Treatments were performed by intraperitoneal injection of 1mL of the extract once a day for 28 consecutive days. Results showed significant differences between treated and control groups during the whole period of the experiment. This was demonstrated by improving body weight and level of serum total protein, decreasing levels of serum ALT, AST, total bilirubin, blood urea nitrogen, and creatinine. As well, histological analysis revealed a marked reduction in inflammation and structural alterations of liver and kidney organs of fenugreek-treated rats. This hepatoprotective effect can be attributed to the anti-inflammatory, anti-oxidant and regenerative capacity of the high content of the phytochemical constituents in the extract.

Identification of a Potential Inhibitor of the FIV p24 Capsid Protein and Characterization of Its Binding Site.

Feline immunodeficiency virus (FIV) is a veterinary infective agent for which there is currently no efficient drug available. Drugs targeting the lentivirus capsid are currently under development for the treatment of human immunodeficiency virus 1 (HIV-1). Here we describe a lead compound that interacts with the FIV capsid. This compound, 696, modulates the in vitro assembly of and stabilizes the assembled capsid protein. To decipher the mechanism of binding of this compound to the protein, we performed the first nuclear magnetic resonance (NMR) assignment of the FIV p24 capsid protein. Experimental NMR chemical shift perturbations (CSPs) observed after the addition of 696 enabled the characterization of a specific binding site for 696 on p24. This site was further analyzed by molecular modeling of the protein:compound interaction, demonstrating a strong similarity with the binding sites of existing drugs targeting the HIV-1 capsid protein. Taken together, we characterized a promising capsid-interacting compound with a low cost of synthesis, for which derivatives could lead to the development of efficient treatments for FIV infection. More generally, our strategy combining the NMR assignment of FIV p24 with NMR CSPs and molecular modeling will be useful for the analysis of future compounds targeting p24 in the quest to identify an efficient treatment for FIV.

Open Reading Frame 1 Protein of the Human Long Interspersed Nuclear Element 1 Retrotransposon Binds Multiple Equivalents of Lead.

The human long interspersed nuclear element 1 (LINE1) has been implicated in numerous diseases and has been suggested to play a significant role in genetic evolution. Open reading frame 1 protein (ORF1p) is one of the two proteins encoded in this self-replicating mobile genetic element, both of which are essential for retrotransposition. The structure of the three-stranded coiled-coil domain of ORF1p was recently solved and showed the presence of tris-cysteine layers in the interior of the coiled-coil that could function as metal binding sites. Here, we demonstrate that ORF1p binds Pb(II). We designed a model peptide, GRCSL16CL23C, to mimic two of the ORF1p Cys3 layers and crystallized the peptide both as the apo-form and in the presence of Pb(II). Structural comparison of the ORF1p with apo-(GRCSL16CL23C)3 shows very similar Cys3 layers, preorganized for Pb(II) binding. We propose that exposure to heavy metals, such as lead, could influence directly the structural parameters of ORF1p and thus impact the overall LINE1 retrotransposition frequency, directly relating heavy metal exposure to genetic modification.

Preclinical study of 212Pb alpha-radioimmunotherapy targeting CD20 in non-Hodgkin lymphoma.

BACKGROUND: Despite therapeutic advances, Non-Hodgkin lymphoma (NHL) relapses can occur. The development of radioimmunotherapy (RIT) with α-emitters is an attractive alternative. In this study, we investigated the potential of α-RIT in conjunction with 212Pb-rituximab for the treatment of NHL. METHODS: EL4-hCD20-Luc cells (mouse lymphoma cell line) were used for in vitro and in vivo studies. Biodistribution and efficacy studies were performed on C57BL/6 mice injected intravenously with 25 × 103 cells. RESULTS: 212Pb-rituximab (0.925-7.4 kBq/mL) inhibit proliferation of EL4-hCD20-Luc cells in vitro. Biodistribution of 203/212Pb-rituximab in mice showed a significant tumour uptake and suggested that the liver, spleen, and kidneys were the organs at risk. For efficacy studies, mice were treated at either 11 days (early stage) or 20-30 days after injection of tumour cells (late stage). Treatment with 277.5 kBq 212Pb-rituximab significantly prolonged survival. Even at an advanced tumour stage, significant tumour regression occurred, with an increase in the median survival time to 28 days, compared with 9 days in the controls. CONCLUSIONS: These results show the efficacy of 212Pb-rituximab in a murine syngeneic lymphoma model, in terms of significant tumour regression and increased survival, thereby highlighting the potency of α-RIT for the treatment of NHL.

Effects of Zinc, Mercury, or Lead on [3H]MK-801 and [3H]Fluorowillardiine Binding to Rat Synaptic Membranes.

Glutamate (Glu) is considered the most important excitatory amino acid neurotransmitter in the mammalian Central Nervous System. Zinc (Zn) is co-released with Glu during synaptic transmission and interacts with Glutamate receptors and transporters. We performed binding experiments using [3H]MK-801 (NMDA), and [3H]Fluorowillardine (AMPA) as ligands to study Zn-Glutamate interactions in rat cortical synaptic membranes. We also examined the effects of mercury and lead on NMDA or AMPA receptors. Zinc at 1 nM, significantly potentiates [3H]MK-801 binding. Lead inhibits [3H]MK-801 binding at micromolar concentrations. At millimolar concentrations, Hg also has a significant inhibitory effect. These effects are not reversed by Zn (1 nM). Zinc displaces the [3H]FW binding curve to the right. Lead (nM) and Hg (µM) inhibit [3H]FW binding. At certain concentrations, Zn reverses the effects of these metals on [3H]FW binding. These specific interactions serve to clarify the role of Zn, Hg, and Pb in physiological and pathological conditions.

Soil cadmium and lead affecting biochemical properties of Matricaria chamomilla L. at different growth stages in the greenhouse and field.

Heavy metals bioremediation by medicinal plants is an important research issue, which has yet to be investigated. Matricaria chamomilla accumulation of soil cadmium (Cd, 0, 10 and 40 mg/kg) and lead (Pb, 0, 60 and 180 mg/kg) affecting plant biochemical properties L. at different growth stages in the greenhouse and field was investigated. The 10-kg experimental pots (located in the greenhouse and field with 80% of field capacity moisture) were filled with the treated soils, and were planted with M. chamomilla L. seeds (three replicates). Plants were sampled to determine their biochemical properties including Cd and Pb contents, pigments, proline (Pro), leaf relative water (LRW), lipid peroxidation (LX), and superoxide dismutase (SOD, EC 1.15. 1.1), and catalase (CAT, EC 1.11.1.6) activities. Soil final concentration of Cd and Pb was also determined. Heavy metal stress significantly decreased plant pigment contents; however, it significantly increased plant PRO, LRW, LX and SOD, and not CAT. Heavy metal, growth stage, growth location, and their interactions significantly affected plant heavy metal concentrations. Interestingly, although significantly higher concentration of Cd was observed in plant aerial part under greenhouse conditions, plant roots had significantly higher concentrations of Cd under field conditions, and it was reverse for Pb. Increased concentration of Cd and Pb significantly enhanced plant Pro content and the highest one was resulted by Pb3 (913.46 mg/g fresh weight) significantly higher than other treatments including Cd3 (595.34 mg/g fresh weight). M. chamomilla is a suitable species for the bioremediation of soils polluted with Cd and Pb.

Changes induced by lead in root system architecture of Arabidopsis seedlings are mediated by PDR2-LPR1/2 phosphate dependent way.

As sessile organisms, plants respond to changing environments modulating their genetic expression, metabolism and postembryonic developmental program (PDP) to adapt. Among environmental stressor, lead (Pb) is one of the most hazardous pollutants which limits crop productivity. Here, we describe in detail the effects of a wide range of concentrations of Pb on growth and development and a possible convergence with phosphate (Pi) starvation response. We found that the response to Pb presents a biphasic curve dose response in biomass accumulation: below 400 µM show a stimulatory effect meanwhile at Pb doses up to 600 µM effects are inhibitory. We found that +Pb (800 µM) modifies root system architecture (RSA) and induces acidification media, according to in silico ion interaction, in the growing medium Pb and Pi coprecipitate and plants grow in both Pi deficiency and Pb stress at the same time, however in spite of seedlings are under Pi starvation AtPT2 expression are Pb downregulated indicating that in addition to Pi starvation stress, Pb regulates physiological responses in root system. Using the mutants stop1, lpr1/2 and lpi3, which are affected in Pi starvation response, we found that changes in RSA by +Pb is genetically regulated and there are shared pathways with Pi starvation response mediated by PDR2-LPR1/2 and LPI3 pathways since lpr1/2 and lpi3 mutants are insensitive to +Pb and Pi starvation. Taking together, these results indicate that similar changes in RSA induced by independent environmental stimuli +Pb and Pi starvation are due to similar mediated response by PDR2-LPR1/2 pathway.