Distinctive modulation of hepcidin in cancer and its therapeutic relevance.

Hepcidin, a short peptide synthesized primarily by hepatocytes in response to increased body iron and inflammation, is a crucial iron-regulating factor. Hepcidin regulates intestinal iron absorption and releases iron from macrophages into plasma through a negative iron feedback mechanism. The discovery of hepcidin inspired a torrent of research into iron metabolism and related problems, which have radically altered our understanding of human diseases caused by an excess of iron, an iron deficiency, or an iron disparity. It is critical to decipher how tumor cells manage hepcidin expression for their metabolic requirements because iron is necessary for cell survival, particularly for highly active cells like tumor cells. Studies show that tumor and non-tumor cells express and control hepcidin differently. These variations should be explored to produce potential novel cancer treatments. The ability to regulate hepcidin expression to deprive cancer cells of iron may be a new weapon against cancer cells.

Role of the calcium-sensing receptor (CaSR) in cancer metastasis to bone: Identifying a potential therapeutic target.

Cancer is a major cause of morbidity and mortality worldwide due to its ability to evade immune surveillance and metastasize from its origin to a secondary point of contact. Though several treatment techniques have been developed to suppress or manage cancer spread, a strategy for total control over the disease continues to evade researchers. In considering ways to control or prevent cancer from metastasizing to the bone, we analyze the impact of the calcium-sensing receptor (CaSR), whose primary role is to maintain calcium (Ca2+) homeostasis in cellular and systemic physiological processes. CaSR is a pleiotropic receptor capable of enhancing the proliferation of some cancers such as breast, lung, prostate and kidney cancers at its primary site(s) and stimulating bone metastasis, while exerting a suppressive effect in others such as colon cancer. The activity of CaSR not only increases cancer cell proliferation, migration and suppression of apoptosis in the organs indicated, but also increases the secretion of parathyroid hormone-related protein (PTHrP) and epiregulin, which induce osteolytic activity and osteoblastic suppression. In addition, released cytokines and Ca2+ from bone resorption are critical factors that further promote cancer proliferation. In this review, we seek to highlight previous viewpoints on CaSR, discuss its role in a new context, and consider its potential clinical application in cancer treatment.

Dietary cadmium exposure causes elevation of blood ApoE with triglyceride level in mice.

Cadmium (Cd) is a widespread toxic occupational and environmental pollutant, and its effect on lipid metabolism dysregulation has been observed. In this study, we utilized two-dimensional electrophoresis (2-DE) and mass spectrometry (MS) technologies to explore changes in the blood plasma proteins of mice exposed to Cd. From the 2-DE, 8 protein spots were screened in response to Cd exposure, and the identities of these proteins were revealed by MALDI-TOF MS. Western blotting was applied to analyze the expression of the apolipoproteins in both plasma and liver, which were consistent with Cd-induced dyslipidemia of their composed lipid. Moreover, the Cd-induced apolipoprotein ApoE upregulation was due to inhibition of autopahgic flux in the Cd exposed mice. It was further observed from the mouse liver that Cd reduced the expression of the lipid uptake receptor low-density lipoprotein receptor (LDLR), which might be responsible for the coordinated elevation in blood triglycerides and abnormal apolipoproteins. This study may provide a new insight into the mechanism of Cd-induced dyslipidemia and the risk of cardiovascular diseases.

Calcimimetic compound NPS R-467 protects against chronic cadmium-induced mouse kidney injury by restoring autophagy process.

In the kidney, disturbance of calcium homeostasis can cause renal hemodynamic changes, leading to glomerulonephritis, tubular damage and renal vascular disease, and thus promotes the development of chronic kidney disease (CKD). Cadmium (Cd) is a toxic heavy metals proved to induce disturbances of calcium homeostasis and nephrotoxicity. Calcium sensing receptor (CaSR) is abundantly expressed in the kidney and plays an important role in maintaining body calcium homeostasis. Our previous study suggested that the activation of CaSR could act as a protective pathway to reduce Cd-induced cytotoxicity in renal proximal tubular cells. However, its application in animal models, its treatment efficacy and underlying mechanisms are still unclear. Therefore, an in vivo animal model (ICR male mouse, n = 5) subjected to Cd-induced nephrotoxicity was used in this study. In the present study, the results indicated that long-term (4 weeks) but not short-term (7 days) Cd exposure induced kidney injury, including induced glomerular atrophy, renal proximal tubule damage, increased malondialdehyde (MDA) level, elevated urine protein quantity, and upregulated kidney injury molecule 1 (KIM-1). It was further observed that chronic Cd exposure induced inhibition of autophagy flux, which triggered kidney apoptosis and injury. However, NPS R-467 restored Cd-inhibited autophagy flux and reduced Cd-induced kidney apoptosis and injury. Finding from this study indicated that activation of CaSR in prevention from nephrotoxicity and kidney injury caused by Cd, which might be helpful for the treatment of clinical CKD.

Molecular cloning, expression and characterization of secreted ferritin in the silkworm, Bombyx mori.

Ferritin is a ubiquitous iron storage protein which plays key role in regulating iron homeostasis and metabolism. In this paper, the ferritin heavy chain homologs (HCH) and light chain homologs (LCH) from Bombyx mori (BmFerHCH and BmFerLCH) were amplified through PCR and cloned into the expression vector pET-30a(+). The recombinant BmFerHCH and BmFerLCH expressed in Escherichia coli were in the form of insoluble inclusion bodies, indicating that the two proteins were not in their natural structural conformation. In order to obtain refolded ferritin in vitro, the inclusion bodies (BmFerHCH and/or BmFerLCH) were dissolved in denaturing buffer (100 mM Tris, 50 mM Glycine, 8 M urea, 5 mM DTT, pH 8.0) and then refolded in refolding buffer (100 mM Tris, 400 mM L-arginine, 0.2 mM PMSF, 0.5 mM DTT). The result showed that it was only when both BmFerHCH and BmFerLCH were present together in the denaturing buffer that refolding was successful and resulted in the formation of heteropolymers (H-L chain dimers) over homopolymers (H-H chain or L-L chain dimers). Moreover, the molecules (NaCl, Triton and glycerol) were found to enhance protein refolding. The optimum temperature, pH and ratios of BmFerHCH/BmFerLCH required for refolding were found to be 10 °C, pH 7, 1:1 or 1:2, respectively. Finally, the refolded ferritin had the ability to store iron, exhibited ferroxidase activity, and could withstand high temperatures and pH treatment, which is consistent with ferritin in other species.

Silver nanoparticle toxicity in silkworms: Omics technologies for a mechanistic understanding.

The widespread use of silver nanoparticles (AgNPs) has raised public concern due to their potential toxic effects on humans and the environment. Although some studies have evaluated the toxicity of nanomaterials in vertebrates, studies on their hazardous effects on insects are limited. Here we focused on different concentrations of AgNPs to silkworms, a promising model organism, to evaluate their toxic effects by omics analysis. After the silkworms were fed with 100 mg L-1 AgNPs, transcriptomics analysis showed differential expression of 43 genes: 39 upregulated and 4 downregulated. These differentially expressed genes (DEGs) were involved in the digestion process, various metabolic pathways, transmembrane transport and energy synthesis. Proteomic results for silkworms fed with 400 mg L-1 AgNPs revealed 14 significantly differentially expressed proteins: 11 downregulated and 3 upregulated. Reverse transcription-polymerase chain reaction (RT-PCR) results showed that the expression levels of eight proteins were similar to the transcription levels of their corresponding genes. As the AgNPs concentration was increased, the expression of digestive enzymes was downregulated, which damaged the silkworm tissue and suppressed the activity of the enzyme superoxide dismutase and the protein HSP 1, causing oxidative stress and the production of reactive oxygen species, which had toxic effects on the silkworm digestive system. Histopathological results showed that treatment with 400 mg L-1 AgNPs destroyed the basal lamina and the columnar cells, caused adverse effects on tissues and had the potential to induce harmful effects on the digestive system. The data presented herein provide valuable information on the hazards and risks of nanoparticle contamination. Main finding: AgNPs would downregulate some digestive enzymes, damage the tissue of midgut in silkworm, meantime induce the accumulation of reactive oxygen species which may cause oxidative stress.

Applying microarray-based technique to study and analyze silkworm (Bombyx mori) transcriptomic response to long-term high iron diet.

To investigate the biological processes affected by long-term iron supplementation, newly hatched silkworms were exposed to high iron mulberry diet (10 and 100 ppm) and its effect on silkworm transcriptom was determined. The results showed that the silkworm was responsive to iron by increasing iron concentration and ferritin levels in the hemolymph and by regulating the expression of many other genes. A total of 523 and 326 differentially expressed genes were identified in 10 and 100 ppm Fe group compared to the control, respectively. Of these genes, 249 were shared between in both the 10 ppm and 100 ppm Fe group, including 152 up-regulated and 97 down-regulated genes. These shared genes included 19 known Fe regulated, 24 immune-related, 12 serine proteases and serine proteases homologs, 41 cuticular and cuticle genes. Ten genes (carboxypeptidases A, serine protease homologs 85, fibrohexamerin/P25, transferrin, sex-specific storage-protein 2, fungal protease inhibitor F, insect intestinal mucin, peptidoglycan recognition protein B, cuticle protein CPH45, unknown gene) were involved in the regulation of iron overload responses.