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Background Exposure to particulate matter (PM) emitted from vehicle exhaust might disrupt systemic function and elevate the risk of cardiovascular disease. In this study, we examined the changes of cardiometabolic biomarkers among vehicle inspectors exposed daily to PM0.25 and components. Methods This cross-sectional study was conducted at two vehicle inspection centers, Pulogadung and Ujung Menteng, located in East Jakarta, Indonesia. The exposed respondents were 43 workers from vehicle inspection centers, and the unexposed group consisted of 22 staff officers working in the same locations. Vehicle exhaust particulate matter was measured for eight hours using a Leland Legacy personal pump attached to a Sioutas Cascade Impactor. The used filters were 25 and 37-mm quartz filters. The particulate matter concentration was analyzed using a gravimetric method, whereas trace elements were analyzed using energy dispersive X-ray fluorescence. An EEL Smoke Stain Reflectometer analyzed black carbon. Results The personal exposure concentrations of PM0.25 were 10.4-fold higher than those in unexposed groups. Calcium and sulfur were the major components in the obtained dust, and their levels were 3.3- and 7.2-fold higher, respectively, in the exposed group. Based on an independent-samples t-test, high-density lipoprotein, triglyceride, HbA1c, total immunoglobulin E, high-sensitivity C-reactive protein, tumor necrosis factor–alpha, and nitric oxide levels were significantly different between the groups. Conclusions In summary, it was suggested that PM0.25 exposure from vehicle exhaust might affect cardiometabolic biomarkers change.

Highlights • Injuries with embedded metal fragments are an increasing medical concern. • Metal pellets implanted in the leg muscles of rats solubilize and release metal. • The solubilized metals pass through the kidney and are excreted in the urine. • Several urinary biomarkers of renal health are affected by the excreted metals., Background Wounds with embedded metal fragments are an unfortunate consequence of armed conflicts. In many cases the exact identity of the metal(s) and their long-term health effects, especially on the kidney, are not known. Aim of study The aim of this study was to quantitate the urinary levels of metals solubilized from surgically implanted metal pellets and to assess the effect of these metals on the kidney using a battery of biomarker assays. Materials and methods Using a rodent model system developed in our Institute to simulate embedded fragment injuries, eight metals considered likely components of an embedded fragment wound were individually implanted into the gastrocnemius muscle of male Sprague-Dawley rats. The rats were followed for 12 months post-implantation with urine collected prior to surgery then at 1-, 3-, 6-, 9-, and 12-months post-implantation to provide a within-subjects cohort for examination. Urinary metal levels were determined using inductively coupled plasma-mass spectrometry and urinary biomarkers assessed using commercially available kits to determine metal-induced kidney effects. Results With few exceptions, most of the implanted metals rapidly solubilized and were found in the urine at significantly higher levels than in control animals as early as 1-month post-implantation. Surprisingly, many of the biomarkers measured were decreased compared to control at 1-month post-implantation before returning to normal at the later time points. However, two metals, iron and depleted uranium, showed increased levels of several markers at later time points, yet these levels also returned to normal as time progressed. Conclusion This study showed that metal pellets surgically implanted into the leg muscle of Sprague-Dawley rats rapidly solubilized with significant levels of the implanted metal found in the urine. Although kidney biomarker results were inconsistent, the changes observed along with the relatively low amounts of metal implanted, suggest that metal-induced renal effects need to be considered when caring for individuals with embedded metal fragment wounds.

Graphical abstract THQ of Cr in the meat was more than one. HI in chicken was more than one. CR was neglectable in the case of both Cd and Pb., Highlights • All of the samples were contaminated with Cd, Cr, Cu, Ni and Pb. • The highest concentration of Pb (0.11 mg/kg) was in the gizzard. • The concentration of Cd and Cu were highest in the liver, while the highest contents of Cr and Ni were in the chicken. • THQs of Cr in the muscle were more than one. • Consumption of chicken meat in both of adults and children may pose a significant health risk for consumers., The present study aimed to determine the average concentration of some metals, including cadmium (Cd), chromium (Cr), copper (Cu), nickel (Ni) and lead (Pb) in the chicken, hen’s liver, and gizzard in the east of Iran. Estimated daily intake (EDI), target hazard quotient (THQ), hazard index (HI) and carcinogenic risk (CR) were calculated. In this cross-sectional study, fifty one samples including chicken, hen’s liver and gizzard were obtained from Birjand, Iran. Measurement of Cd, Cr, Cu, Ni, and Pb was carried out by using an Inductively Coupled Plasma-Optic Emission Spectroscopy (ICP-OES). All of the measured metals were detected in 100 % of the samples. The metals had a different distribution pattern. The highest concentration of Cd and Cu was in the liver samples while the Cr and Ni had the highest levels in the chicken. Pb concentration was at the highest level in the gizzard. The least amount of Cr, Ni, and Pb was found in the liver while Cu had the least content in the muscle. EDI had an acceptable level, but the highest daily intake of all studied metals was through muscle. Cr had the highest THQ and it was more than one in the meat. HI in chicken was more than one. Liver and gizzard of hens had a neglectable HI. CR was neglectable in the case of both Cd and Pb, but it was considerable for Cr and Ni. The consumption of chicken in both adults and children may pose a significant health risk for consumers.

Graphical abstract, Highlights • Oxidative stress and apoptosis created by Cu2+ and Cd2+ insults were studied in ZFL. • Cu2+ and Cd2+ both created lipid peroxidation, causing oxidative stress in cytoplasm. • Mitochondrial superoxide was induced by Cd2+ but supressed by Cu2+. • Cu2+ suppressed Casp3 activity, resulting in suppressed the apoptosis. • Pre-treatments of low concentration of Cu2+ protected the cell from Cd2+ insults., Copper (Cu) and cadmium (Cd) are widely used in industrial activities, resulting in Cu and Cd contamination in aquatic systems worldwide. Although Cu plays an essential role in many biological functions, an excessive amount of the metal causes cytotoxicity. In contrast, Cd is a non-essential metal that usually co-exists with Cu. Together, they cause oxidative stress in cells, leading to cell damage. These metal ions are also believed to cause cell apoptosis. In this study, we used a zebrafish liver cell line, ZFL, to study combined Cu and Cd cytotoxicity. Although Cd is more toxic than Cu, both were found to regulate the expression of oxidative stress related genes, and neither significantly altered the activity of oxidative stress related enzymes. Co-exposure tests with the antioxidant N-acetyl-l-cysteine and the Cu chelator bathocuproinedisulfonic acid disodium salt demonstrated that Cd toxicity was due to the oxidative stress caused by Cu, and that Cu at a low concentration could in fact exert an antioxidant effect against the oxidative stress in ZFL. Excessive Cu concentration triggered the expression of initiator caspases (caspase 8 and caspase 9) but suppressed that of an executioner caspase (caspase 3), halting apoptosis. Cd could only trigger the expression of initiator caspases; it could not halt apoptosis. However, a low concentration of Cu reduced the mitochondrial superoxide level, suppressing the Cd-induced apoptotic effects in ZFL.

Without effective homeostatic systems in place, excess copper (Cu) is universally toxic to organisms. While increased utilization of anthropogenic Cu in the environment has driven the diversification of Cu-resistance systems within enterobacteria, little research has focused on how this change in bacterial architecture impacts host organisms that need to maintain their own Cu homeostasis. Therefore, we utilized a simplified host-microbe system to determine whether the efficiency of one bacterial Cu-resistance system, increasing Cu-efflux capacity via the ubiquitous CusRS two-component system, contributes to the availability and subsequent toxicity of Cu in host Caenorhabditis elegans nematode. We found that a fully functional Cu-efflux system in bacteria increased the severity of Cu toxicity in host nematodes without increasing the C.elegans Cu-body burden. Instead, increased Cu toxicity in the host was associated with reduced expression of a protective metal stress-response gene, numr-1, in the posterior pharynx of nematodes where pharyngeal grinding breaks apart ingested bacteria before passing into the digestive tract. The spatial localization of numr-1 transgene activation and loss of bacterially dependent Cu-resistance in nematodes without an effective numr-1 response support the hypothesis that numr-1 is responsive to the bacterial Cu-efflux capacity. We propose that the bacterial Cu-efflux capacity acts as a robust spatial determinant for a host's response to chronic Cu stress.

Novel coronavirus disease 2019 (COVID-19) has spread across the globe; and surprisingly, no potentially protective or therapeutic antiviral molecules are available to treat severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. However, zinc (Zn) and copper (Cu) have been shown to exert protective effects due to their antioxidant, anti-inflammatory, and antiviral properties. Therefore, it is hypothesized that supplementation with Zn and Cu alone or as an adjuvant may be beneficial with promising efficacy and a favorable safety profile to mitigate symptoms, as well as halt progression of the severe form of SARS-CoV-2 infection. The objective of this review is to discuss the proposed underlying molecular mechanisms and their implications for combating SARS-CoV-2 infection in response to Zn and Cu administration. Several clinical trials have also included the use of Zn as an adjuvant therapy with dietary regimens/antiviral drugs against COVID-19 infection. Overall, this review summarizes that nutritional intervention with Zn and Cu may offer an alternative treatment strategy by eliciting their virucidal effects through several fundamental molecular cascades, such as, modulation of immune responses, redox signaling, autophagy, and obstruction of viral entry and genome replication during SARS-CoV-2 infection.

Clarifying the mechanisms of heavy metal (HM) accumulation and translocation from soil-root-leaf is crucial to coping with soil HM pollution. In this study, we analysed copper (Cu), manganese (Mn), zinc (Zn) and cadmium (Cd) accumulation characteristics in Chinese turnips and the effect of soil physicochemical properties on both HM accumulation and translocation. Our results indicate that Chinese turnips absorb and translocate Mn, Zn, and Cd at much higher levels than they do Cu. When we measured bioconcentration factors in Chinese turnips for different HMs in the same soil, we found Chinese turnip capacities for HM accumulation decrease from Zn > Mn > Cd > Cu. In addition, the translocation factor for these HMs decreases from Mn > Cd > Zn > Cu. Correlation analysis indicates that soil pH and various soil components are either negatively or positively correlated with Mn, Zn, and Cd accumulation; also, soil properties are correlated with Mn translocation from root to leaf. These findings may help evaluate HM accumulation and translocation mechanisms as well as artificially regulate HM uptake levels from soils to turnips. Keywords: Turnip, Heavy metal, Bioconcentration, Phytoremediation, Soil composition

Metal ions provide considerable functionality across biological systems, and their utilization within biomolecules has adapted through changes in the chemical environment to maintain the activity they facilitate. While ancient earth's atmosphere was rich in iron and manganese and low in oxygen, periods of atmospheric oxygenation significantly altered the availability of certain metal ions, resulting in ion replacement within biomolecules. This adaptation mechanism has given rise to the phenomenon of metal cofactor interchangeability, whereby contemporary proteins and nucleic acids interact with multiple metal ions interchangeably, with different coordinated metals influencing biological activity, stability, and toxic potential. The ability of extant organisms to adapt to fluctuating metal availability remains relevant in a number of crucial biomolecules, including the superoxide dismutases of the antioxidant defense systems and ribonucleotide reductases. These well-studied and ancient enzymes illustrate the potential for metal interchangeability and adaptive utilization. More recently, the ribosome has also been demonstrated to exhibit interchangeable interactions with metal ions with impacts on function, stability, and stress adaptation. Using these and other examples, here we review the biological significance of interchangeable metal ions from a new angle that combines both biochemical and evolutionary viewpoints. The geochemical pressures and chemical properties that underlie biological metal utilization are discussed in the context of their impact on modern disease states and treatments.

Plasma membrane transporters play pivotal roles in the import of nutrients, including sugars, amino acids, nucleobases, carboxylic acids, and metal ions, that surround fungal cells. The selective removal of these transporters by endocytosis is one of the most important regulatory mechanisms that ensures a rapid adaptation of cells to the changing environment (e.g., nutrient fluctuations or different stresses). At the heart of this mechanism lies a network of proteins that include the arrestin?related trafficking adaptors (ARTs) which link the ubiquitin ligase Rsp5 to nutrient transporters and endocytic factors. Transporter conformational changes, as well as dynamic interactions between its cytosolic termini/loops and with lipids of the plasma membrane, are also critical during the endocytic process. Here, we review the current knowledge and recent findings on the molecular mechanisms involved in nutrient transporter endocytosis, both in the budding yeast Saccharomyces cerevisiae and in some species of the filamentous fungus Aspergillus. We elaborate on the physiological importance of tightly regulated endocytosis for cellular fitness under dynamic conditions found in nature and highlight how further understanding and engineering of this process is essential to maximize titer, rate and yield (TRY)-values of engineered cell factories in industrial biotechnological processes., We are grateful to Dr. George Diallinas and Dr. Christos Gournas for their suggestions and critical reading of this manuscript. We thank Dr. Jack Pronk for his fruitful suggestions. Work at CBMA was supported by the ‘‘Contrato-Programa” UIDB/04050/2020 funded by Portuguese national funds through the FCT I.P. BA and RA acknowledge FCT for the PD/BD/135208/2017 and PD/BD/113813/2015 PhD grants, respectively., info:eu-repo/semantics/publishedVersion

Graphical abstract, Highlights • CTR1-overexpressing HepG2 and ZFL cell lines were created. • CTR1 overexpression in both HepG2 and ZFL cells increased Cd2+ uptake and toxicity. • CTR1 knockdown in HepG2 cells decreased Cd2+ uptake and toxicity. • CTR1 plays a significant role in Cd2+ uptake and toxicity., Cadmium (Cd2+) is considered a human carcinogen as it causes oxidative stress and alters DNA repair responses. However, how Cd2+ is taken up by cells remains unclear. We hypothesized that Cd2+ could be transported into cells via a membrane copper (Cu) transporter, CTR1. CTR1 expression was not affected by Cd2+ exposure at the mRNA or protein level. Stable cell lines overexpressing either hCTR1, in the human liver cell line HepG2, or zCTR1, in the zebrafish liver cell line ZFL, were created to study their responses to Cd2+ insult. It was found that both HepG2 and ZFL cells overexpressing CTR1 had higher Cd2+ uptake and thus became sensitive to Cd2+. In contrast, hCTR1 knockdown in HepG2 cells led to a reduced uptake of Cd2+, making the cells relatively resistant to Cd2+. Localization studies revealed that hCTR1 had a clustered pattern after Cd2+ exposure, possibly in an attempt to reduce both Cd2+ uptake and Cd2+-induced toxicity. These in vitro results indicate that CTR1 can transport Cd2+ into the cell, resulting in Cd2+ toxicity.

Highlights • A method to track the fate of materials in e-waste flows in EU is presented. • An extension to the current indicators to assess WEEE treatment systems is proposed. • Recovery performance of waste screens in France is assessed per target elements. • The type of screens collected impact the materials potentially available for recycling. • Tracking the quality of WEEE flows can boost (critical) raw materials recovery., Currently, in the European Union (EU), e-waste chain performance is assessed by technical indicators that aim to ensure system compliance with collection and recovery targets set by the WEEE Directive. This study proposes indicators to improve WEEE flow monitoring beyond the current overall weight-based approach, including complementary flows and treatment performance. A case study focused on the screen category in France is presented. In 2017, the collection rate of cathode-ray tube screens (CRT) was 68%, while for flat panel display (FPD) generated only 14% was collected. CRT screens have less precious and critical materials than FDP. Thus, elements like cobalt and gold highly concentrated in FPD, have a collection rate two to four times lower than elements such as copper (37%) which represents a high proportion in CRTs. Recycling is the main treatment in France. Nevertheless, the recycling rate per element varies significantly due to the low collection, and also the lack of technology and/or secondary raw materials market. The elements with higher recycling rates are base metals such as copper (28%), followed by precious metals like silver (23%), and gold (13%). Except for palladium, the recycling rate of the critical raw materials targeted in the study ranged from 6% (cobalt) to 0% (e.g. neodymium and indium). The results stress the need for indicators to support the development of WEEE chain from waste management to secondary (critical) raw materials suppliers.

Copper (Cu) is essential for all life forms; however, in excess, it becomes toxic. Toxic properties of Cu are known to be utilized by host species against various pathogenic invasions. Leishmania, in both free-living and intracellular forms, exhibits appreciable tolerance toward Cu stress. While determining the mechanism of Cu-stress evasion employed by Leishmania, we identified and characterized a hitherto unknown Cu-ATPase in Leishmania major and established its role in parasite survival in host macrophages. This novel L. major Cu-ATPase, LmATP7, exhibits homology with its orthologs at multiple motifs. In promastigotes, LmATP7 primarily localized at the plasma membrane. We also show that LmATP7 exhibits Cu-dependent expression patterns and complements Cu transport in a Cu-ATPase-deficient yeast strain. Promastigotes overexpressing LmATP7 exhibited higher survival upon Cu stress, indicating efficacious Cu export compared with Wt and heterozygous LmATP7 knockout parasites. We further explored macrophage-Leishmania interactions with respect to Cu stress. We found that Leishmania infection triggers upregulation of major mammalian Cu exporter, ATP7A, in macrophages, and trafficking of ATP7A from the trans-Golgi network to endolysosomes in macrophages harboring amastigotes. Simultaneously, in Leishmania, we observed a multifold increase in LmATP7 transcripts as the promastigote becomes established in macrophages and morphs to the amastigote form. Finally, overexpressing LmATP7 in parasites increases amastigote survivability within macrophages, whereas knocking it down reduces survivability drastically. Mice injected in their footpads with an LmATP7-overexpressing strain showed significantly larger lesions and higher amastigote loads as compared with controls and knockouts. These data establish the role of LmATP7 in parasite infectivity and intramacrophagic survivability.

Rare pleiotropic genetic disorders, Ataxia-telangiectasia (A-T), Bloom syndrome (BS) and Nijmegen breakage syndrome (NBS) are characterised by immunodeficiency, extreme radiosensitivity, higher cancer susceptibility, premature aging, neurodegeneration and insulin resistance. Some of these functional abnormalities can be explained by aberrant DNA damage response and chromosomal instability. It has been suggested that one possible common denominator of these conditions could be chronic oxidative stress caused by endogenous ROS overproduction and impairment of mitochondrial homeostasis. Recent studies indicate new, alternative sources of oxidative stress in A-T, BS and NBS cells, including NADPH oxidase 4 (NOX4), oxidised low-density lipoprotein (ox-LDL) or Poly (ADP-ribose) polymerases (PARP). Mitochondrial abnormalities such as changes in the ultrastructure and function of mitochondria, excess mROS production as well as mitochondrial damage have also been reported in A-T, BS and NBS cells. A-T, BS and NBS cells are inextricably linked to high levels of reactive oxygen species (ROS), and thereby, chronic oxidative stress may be a major phenotypic hallmark in these diseases. Due to the presence of mitochondrial disturbances, A-T, BS and NBS may be considered mitochondrial diseases. Excess activity of antioxidant enzymes and an insufficient amount of low molecular weight antioxidants indicate new pharmacological strategies for patients suffering from the aforementioned diseases. However, at the current stage of research we are unable to ascertain if antioxidants and free radical scavengers can improve the condition or prolong the survival time of A-T, BS and NBS patients. Therefore, it is necessary to conduct experimental studies in a human model., Graphical abstract fx1

Aging is a complex phenomenon and its impact is becoming more relevant due to the rising life expectancy and because aging itself is the basis for the development of age-related diseases such as cancer, neurodegenerative diseases and type 2 diabetes. Recent years of scientific research have brought up different theories that attempt to explain the aging process. So far, there is no single theory that fully explains all facets of aging. The damage accumulation theory is one of the most accepted theories due to the large body of evidence found over the years. Damage accumulation is thought to be driven, among others, by oxidative stress. This condition results in an excess attack of oxidants on biomolecules, which lead to damage accumulation over time and contribute to the functional involution of cells, tissues and organisms. If oxidative stress persists, cellular senescence is a likely outcome and an important hallmark of aging. Therefore, it becomes crucial to understand how senescent cells function and how they contribute to the aging process. This review will cover cellular senescence features related to the protein pool such as morphological and molecular hallmarks, how oxidative stress promotes protein modifications, how senescent cells cope with them by proteostasis mechanisms, including antioxidant enzymes and proteolytic systems. We will also highlight the nutritional status of senescent cells and aged organisms (including human clinical studies) by exploring trace elements and micronutrients and on their importance to develop strategies that might increase both, life and health span and postpone aging onset., Graphical abstract fx1

Aims To examine the associations of plasma copper concentrations and superoxide dismutase 1 (SOD1) polymorphisms as well as their gene-environment interaction with newly diagnosed impaired glucose regulation (IGR) and type 2 diabetes (T2D). Methods We performed a large case-control study in 2520 Chinese Han subjects: 1004 newly diagnosed T2D patients, 512 newly diagnosed IGR patients and 1004 individuals with normal glucose tolerance. Results After multivariable adjustment, the ORs (95% CIs) of T2D across tertiles of plasma copper were 1.00 (reference), 1.85 (95% CI: 1.39, 2.45), and 4.21 (95% CI: 3.20, 5.55) (P-trend, Graphical abstract Image 1, Highlights • Plasma copper concentrations are positively and significantly associated with IGR as well as T2D. • Compared with the GG genotype of rs2070424, the risk of T2D associated with AG and AA genotypes were higher. • The associations between copper and T2D as well as IGR may be modified by SOD1 rs2070424 polymorphism. • Evaluating the interaction of copper and gene polymorphisms may shed etiologic insight into the copper-diabetes relation.

Cryptococcus neoformans is an opportunistic fungal pathogen whose pathogenic lifestyle is linked to its ability to cope with fluctuating levels of copper (Cu), an essential metal involved in multiple virulence mechanisms, within distinct host niches. During lethal cryptococcal meningitis in the brain, C. neoformans senses a Cu-deficient environment and is highly dependent on its ability to scavenge trace levels of Cu from its host and adapt to Cu scarcity to successfully colonize this niche. In this study, we demonstrate for this critical adaptation, the Cu-sensing transcription factor Cuf1 differentially regulates the expression of the SOD1 and SOD2 superoxide dismutases in novel ways. Genetic and transcriptional analysis reveals Cuf1 specifies 5’-truncations of the SOD1 and SOD2 mRNAs through specific binding to Cu responsive elements within their respective promoter regions. This results in Cuf1-dependent repression of the highly abundant SOD1 and simultaneously induces expression of two isoforms of SOD2, the canonical mitochondrial targeted isoform and a novel alternative cytosolic isoform, from a single alternative transcript produced specifically under Cu limitation. The generation of cytosolic Sod2 during Cu limitation is required to maintain cellular antioxidant defense against superoxide stress both in vitro and in vivo. Further, decoupling Cuf1 regulation of Sod2 localization compromises the ability of C. neoformans to colonize organs in murine models of cryptococcosis. Our results provide a link between transcription factor–mediated alteration of protein localization and cell proliferation under stress, which could impact tissue colonization by a fungal pathogen.

Toxic heavy metals such as cadmium (Cd) and copper (Cu) are global problems that are a growing threat to the environment. Despite some heavy metals are required for plant growth and development, others are considered toxic elements and do not play any known physiological role in plant cells. Elevated doses of Cd or Cu cause toxicity in plants and generate damages due to the stress condition and eventually cause a significant reduction in quantity and quality of crop plants. The nitric oxide (NO) donor sodium nitroprusside (SNP) is reported to alleviate the toxicity of some heavy metals like Cd and Cu. In the current study, the role of NO in alleviating stresses of Cd and Cu was investigated in in vitro-grown tobacco (Nicotiana tabacum) Based on plant growth, total chlorophyll contents, contents and activities of rubisco and rubisco activase. According to the results of this study, the growth and total chlorophyll contents of Cd/Cu stressed plants were hugely decreased in the absence of SNP, while the supplementation of SNP resulted in a significant increase of both fresh weight and total chlorophyll contents. Remarkable reductions of Rubisco and rubisco activase contents and activities were observed in Cd and Cu-induced plants. SNP supplementation showed the highest contents and activities of rubisco and rubisco activase compared to the control and Cu/Cd-stressed plants. Taken together, our findings suggest that SNP could play a protective role in regulation of plant responses to abiotic stresses such as Cd and Cu by enhancing Rubisco and Rubisco activase., Graphical abstract, Highlights • Heavy metal ions are believed to act as growth inhibitors and environmental disruptors. • Nitric oxide (NO) plays a functional role in regulation of plant responses to abiotic stresses. • Rubisco involved in the process of atmospheric carbon fixation in photosynthesis. • Rubisco Catalyzes 2 types of reactions (carboxylation and oxygenation). • Rubisco activase removes bound RuBP from inactive, decarboxylated Rubisco in an ATP-dependent reaction.

Iron (Fe) is an important trace element found in nearly all organisms, and is used as a cofactor in many biological reactions. One role for Fe in some invertebrates is in stabilization of extracellular matrices. The human blood fluke, Schistosoma japonicum, is responsible for significant human disease in developing and tropical nations. Disease in humans arises from host immunological reaction to parasite eggs that lodge in tissues. Schistosomes require Fe for development in their hosts, and store abundant Fe in vitelline (eggshell-forming) cells of the female system. The understanding of Fe metabolism and functionality are aspects of its biology that may be exploited in future therapeutics. The biology of Fe stores in vitelline cells of S. japonicum was investigated to illuminate possible functions of this element in early development of these parasites. Vitelline Fe is stored in yolk ferritin that is upregulated in females and is also expressed at low levels in egg-stages and adult males. Laser microdissection microscopy, coupled with reverse transcriptase- and real time-PCR amplification of schistosome ferritin sequences, confirmed that the vitelline cells are the likely progenitor cells of yolk ferritin. Assessment of Fe concentrations in whole male and whole female adult worms, eggs and purified eggshells by colorimetric assays and mass spectroscopy demonstrated higher levels of Fe in the female parasite, but also high levels of the element in whole parasite eggs and purified eggshell. Qualitative energy dispersive spectroscopy of purified eggshells, revealed that Fe is abundant in the eggshell, the matrix of which is composed of heavily cross-linked eggshell precursor proteins. Thus, vitelline stores of Fe are implicated in eggshell cross-linking in platyhelminths. These observations emphasise the importance of Fe in schistosome metabolism and egg formation and suggest new avenues for disruption of egg formation in these pathogenic parasites. Crown Copyright © 2007.

Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity., Graphical abstract, Highlights • Multiple myeloma (MM) displays intrinsic/adaptive resistance to bortezomib (BTZ). • An up-regulation of antioxidant levels is observed in BTZ-resistant MM cell lines. • Inhibition of CuZnSOD increases BTZ cytotoxicity in BTZ naïve/resistant cells. • We propose disulfiram as a combination chemotherapy drug to inhibit relapse in MM.