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Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.

BACKGROUND: To perform a detailed morphological analysis of the inorganic portion of two different clinical presentations of calcium-based deposits retrieved from subjects with SSc and identify a chemical dissolution of these deposits suitable for clinical use.
METHODS: Chemical analysis using Fourier Transform IR spectroscopy (\'FTIR\'), Raman microscopy, Powder X-Ray Diffraction (\'PXRD\'), and Transmission Electron Microscopy (\'TEM\') was undertaken of two distinct types of calcinosis deposits: paste and stone. Calcinosis sample titration with ethylenediaminetetraacetic acid (\'EDTA\') assessed the concentration at which the EDTA dissolved the calcinosis deposits in vitro.
RESULTS: FTIR spectra of the samples displayed peaks characteristic of hydroxyapatite, where signals attributable to the phosphate and carbonate ions were all identified. Polymorph characterization using Raman spectra were identical to a hydroxyapatite reference while the PXRD and electron diffraction patterns conclusively identified the mineral present as hydroxyapatite. TEM analysis showed differences of morphology between the samples. Rounded particles from stone samples were up to a few micron in size, while needle-like crystals from paste samples reached up to 0.5 µm in length. Calcium phosphate deposits were effectively dissolved with 3% aqueous solutions of EDTA, in vitro. Complete dissolution of both types of deposit was achieved in approximately 30 min using a molar ratio of EDTA/HAp of ≈ 300.
CONCLUSIONS: Stone and paste calcium-based deposits both comprise hydroxyapatite, but the constituent crystals vary in size and morphology. Hydroxyapatite is the only crystalline polymorph present in the SSc-related calcinosis deposits. Hydroxyapatite can be dissolved in vitro using a dosage of EDTA considered safe for clinical application. Further research is required to establish the optimal medium to develop the medical product, determine the protocol for clinical application, and to assess the effectiveness of EDTA for local treatment of dystrophic calcinosis.

Calcium supplementation has been shown to be efficacious in mitigating the progression of senile osteoporosis (SOP) and reducing the incidence of osteoporotic fractures resulting from prolonged calcium shortage. In this study, Grifola frondosa (GF) peptides-calcium chelate were synthesized through the interaction between peptide from GF and CaCl2. The chelation reaction was shown to involve the participation of the amino and carboxyl groups in the peptide, as revealed by scanning electron microscope, Fourier-transform infrared, and ultraviolet spectrophotometry. Furthermore, a mouse model of (SOP) induced by d-galactose was established (SCXK-2018-0004). Results demonstrated that low dosage of low-molecular weight GF peptides-calcium chelates (LLgps-Ca) could significantly improve serum index and pathological features of bone tissue and reduce bone injury. Further research suggested that LLgps-Ca could ameliorate SOP by modulating the disrupted metabolic pathway, which includes focal adhesion, extracellular matrix receptor interaction, and PI3K-Akt signaling pathway. Using Western blot, the differentially expressed proteins were further confirmed. Thus, calciumchelating peptides from GF could serve as functional calcium agents to alleviate SOP.

This study investigated the characteristics of Lactobacillus helveticus-derived whey-calcium chelate (LHWCC) and its effect on the calcium absorption and bone health of rats. Fourier-transform infrared spectroscopy showed that carboxyl oxygen atoms, amino nitrogen atoms, and phosphate ions were the major binding sites with calcium in LHWCC, which has a sustained release effect in simulated in vitro digestion. LHWCC had beneficial effects on serum biochemical parameters, bone biomechanics, and the morphological indexes of the bones of calcium-deficient rats when fed at a dose of 40 mg Ca/kg BW for 7 weeks. In contrast to the inorganic calcium supplement, LHWCC significantly upregulated the gene expression of transient receptor potential cation V5 (TRPV5), TRPV6, PepT1, calcium-binding protein-D9k (Calbindin-D9k), and a calcium pump (plasma membrane Ca-ATPase, PMCA1b), leading to promotion of the calcium absorption rate, whereas Ca3(PO4)2 only upregulated the TRPV6 channel in vivo. These findings illustrate the potential of LHWCC as an organic calcium supplement.

BACKGROUND: Ethylene diamine tetra-acetic acid (EDTA) is a chelating agent used to dissolve calcium deposits but evidence in decalcifying atherosclerotic lesions is limited.
OBJECTIVE: We assessed the feasibility and efficacy of EDTA delivered via porous balloon to target calcified lesions in cadaveric below-the-knee (BTK) arteries.
METHODS: Using porcine carotid arteries, EDTA concentration was measured in the arterial wall and outside the artery at the 0-, 0.5-, 4-, and 24-h circulation after the injection through a porous balloon. In cadaver BTK samples, the proximal and distal anterior tibial artery (ATA) and distal posterior tibial artery (PTA) were studied. EDTA-2Na/H2O or EDTA-3Na/H2O were administrated using a porous balloon, then circulated for 6 h for EDTA-3Na/H2O and 24 h for EDTA-2Na/H2O and EDTA-3Na/H2O. Micro-CT imaging of the artery segments before and after the circulation and cross-sectional analyses were performed to evaluate calcium burden.
RESULTS: In the porcine carotid study, EDTA was delivered through a porous balloon present in the arterial wall and was retained there for 24 h. In BTK arteries, cross-sectional analyses of micro-CT revealed a significant decrease in the calcium area in the distal ATA segment under 24-h circulation with EDTA-2Na/H2O and in the distal ATA segment under 24-h circulation with EDTA-3Na/H2O. The proximal ATA segment under 6-h circulation with EDTA-3Na/H2O showed no significant change in any parameters of calcium CONCLUSION: EDTA-3Na/H2O or EDTA-2Na/H2O with longer circulation times resulted in greater calcium reduction in atherosclerotic lesion. EDTA may have a potential therapeutic option for the treatment of atherosclerotic calcified lesions.

BACKGROUND: Peanut peptides have good chelating ability with metal ions. However, there are few studies on the chelation mechanism of peanut peptides with calcium and absorption properties of peptide-calcium complex.
RESULTS: Peptides with high calcium chelating rate were isolated and purified from peanut protein hydrolysate (PPH), and the chelation rate of component F21 was higher (81.4 ± 0.8%). Six peptides were identified from component F21 by liquid chromatography-tandem mass spectrometry, and the frequency of acidic amino acids and arginine in the amino acid sequence was higher in all six peptides. Peanut peptide-calcium complex (PPH21-Ca) was prepared by selecting component F21 (PPH21). Ultraviolet analysis indicated that the chelate reaction occurred between peanut peptide and calcium ions. Fourier transform infrared analysis showed that the chelating sites were carboxyl and amino groups on the amino acid residues of peptides. Scanning electron microscopy revealed that the surface of peanut peptide had a smooth block structure, but the surface of the complex had a granular morphology. Caco-2 cell model tests revealed that the bioavailability of PPH21-Ca was 58.4 ± 0.5%, which was significantly higher than that of inorganic calcium at 37.0 ± 0.4%.
CONCLUSIONS: Peanut peptides can chelate calcium ions by carboxyl and amino groups, and the peptide-calcium complex had higher bioavailability. This study provides a theoretical basis for the development of new calcium supplement products that are absorbed easily. © 2024 Society of Chemical Industry.

Oncology treatments cause infertility, and ovarian tissue cryopreservation and transplantation (OTCT) is the only option for fertility preservation in prepubertal girls with cancer. However, OTCT is associated with massive follicle loss. Here, we aimed to determine the effect of supplementation of slow freezing and vitrification media with BAPTA-AM and melatonin alone and in combination on ovarian tissue viability, reactive oxygen species (ROS) levels, total antioxidant capacity (TAC), and follicular morphology and viability. Our results indicated that BAPTA-AM and melatonin can significantly improve ovarian tissue viability and the TAC/ROS ratio and reduce ROS generation in frozen-thawed ovarian tissues in slow freezing and vitrification procedures. BAPTA-AM was also found to be less effective on TAC compared to melatonin in vitrified ovarian tissue. While supplementation of slow freezing and vitrification media with BAPTA-AM and/or melatonin could increase the percentage of morphologically intact follicles in cryopreserved ovarian tissues, the differences were not significant. In conclusion, supplementation of cryopreservation media with BAPTA-AM or melatonin improved the outcome of ovarian tissue cryopreservation in both vitrification and slow freezing methods. Our data provide some insight into the importance of modulating redox balance and intracellular Ca2+ levels during ovarian tissue cryopreservation to optimize the current cryopreservation methods.

Selective calcium chelator 1,2-Bis(2-aminophenoxy) ethane-N,N,N\',N\'-tetraacetic acid (BAPTA) is a common tool to investigate calcium signaling. However, BAPTA expresses various effects on intracellular calcium signaling, which are not related to its ability to bind Ca2+. In patch clamp experiments, we investigated calcium chelation independent effects of BAPTA on endogenous calcium-activated chloride channels ANO6 (TMEM16F) in HEK293T cells. We have found that application of BAPTA to intracellular solution led to two distinct effects on channels properties. On the one hand, application of BAPTA acutely reduced amplitude of endogenous ANO6 channels induced by 10 μM Ca2+ in single channel recordings. On the other hand, BAPTA application by itself induced ANO6 channel activity in the absence of the intracellular calcium elevation. Open channel probability was enhanced by increasing the intracellular BAPTA concentration from 0.1 to 1 and 10 mM. Another calcium chelator EGTA did not demonstrate chelation independent effects on the ANO6 activity in the same conditions. Due to off-target effects BAPTA should be used with caution when studying calcium-activated ANO6 channels.

The preservation of liquid semen is pivotal for both industrial livestock production and genetic management/conservation of species with sperm that are not highly cryo-tolerant. Nevertheless, with regard to poultry semen, even brief in vitro storage periods can lead to a notable decline in fertility, despite the in vivo capacity to maintain fertility for several weeks when within the hen\'s sperm storage tubules. For fertility in sperm, intracellular calcium ions ([Ca2+]i) play a key role in signaling towards modifying energy metabolism. While reducing [Ca2+]i has been found to enhance the preservation of sperm fertility in some mammals, the connection between semen fertility and calcium availability in avian sperm has received limited attention. In this study, we demonstrate that the use of extracellular and intracellular calcium chelators in liquid semen extenders, specifically EGTA and EGTA-AM, has distinct effects on prolonging the fertility of chicken sperm. These results were validated through in vivo fertility tests. Mechanistically, the effects observed were linked to coordination of mitochondrial metabolism and ATP catabolism. Despite both calcium chelators inducing hypoxia, they differentially regulated mitochondrial respiration and ATP accumulation. This regulation was closely linked to a bimodal control of dynein ATPase activity; a direct initial activation with reduction in [Ca2+]i, and subsequent suppression by cytoplasmic acidification caused by lactic acid. These findings not only contribute to advancing poultry liquid semen preservation techniques, but also elucidates biologically relevant mechanisms that may underlie storage within the female reproductive tract in birds.