Zinc antagonizes cadmium-induced osteoporosis in mice by inhibiting Cd2+ deposition, enhancing antioxidant capacity and correcting bone metabolic disorders.

Cadmium (Cd) is a toxic metal leading to multiple forms of organ damage. Zinc (Zn) was reported as a potential antagonist against Cd toxicity. The present study investigates the antagonistic effect of Zn (20 μM) on Cd (20 or 50 μM) cytotoxicity in macrophages in vitro. The results shows that Cd exposure caused dose-dependent morphologic and ultrastructural alterations in RAW 264.7 macrophages. Zn supplement significantly inhibited Cd cytotoxicity in RAW 264.7 or HD-11 macrophages by mitigating cell apoptosis, excessive ROS output, and mitochondrial membrane depolarization. Notably, Zn supplement for 12 h remarkably prevented intracellular Cd2+ accumulation in 20 μM (95.99 ± 9.93 vs 29.64 ± 5.08 ng/106 cells; P = 0.0008) or 50 μM Cd (179.78 ± 28.66 vs 141.62 ± 22.15 ng/106 cells; P = 0.003) exposed RAW 264.7 cells. Further investigation found that Cd promoted metallothioneins (MTs) and metal regulatory transcription factor 1 (MTF-1) expression in RAW 264.7 macrophages. Twenty μM Zn supplement dramatically enhanced MTs and MTF-1 levels in Cd-exposed RAW 264.7 macrophages. Intracellular Zn2+ chelation or MTF-1 gene silencing inhibited MTs synthesis in Cd-exposed RAW 264.7 macrophages, which was accompanied by the declined expression of MTF-1, indicating that regulation of Zn on MTs was partially achieved by MTF-1 mobilization. In conclusion, this study demonstrates the antagonism of Zn against Cd cytotoxicity in macrophages and reveals its antagonistic mechanism by preventing Cd2+ bioaccumulation and promoting MTs expression.

As a common harmful pollutant, cadmium (Cd) can easily enter the human body through the food chain, posing a major threat to human health. Gut microbiota play a key role in Cd absorption. Docosahexaenoic acid (DHA) is thought to have a potential role in the treatment of Cd poisoning. This study investigated the therapeutic effect and mechanism of DHA in Cd-exposed mice from the perspective of the gut microbiota. The results showed that DHA significantly increased the Cd content in feces and decreased the Cd accumulation in the organs of mice. The gut microbiota results showed that DHA significantly restored the abundance of Parabacteroides in the gut microbiota of Cd-exposed mice. Parabacteroides distasonis (P. distasonis), a representative strain of the Parabacteroides, also showed Cd- and toxicity-reduction capabilities. P. distasonis significantly restored the gut damage caused by Cd exposure. At the same time, P. distasonis reduced the Cd content in the liver, spleen, lung, kidneys, gut, and blood to varying degrees and significantly increased the Cd content in feces. The succinic acid produced by P. distasonis plays an important role in promoting Cd excretion in Cd-exposed mice. Therefore, these results suggest that P. distasonis may have a potential role in DHA-mediated Cd excretion in Cd-exposed mice.

Nano-selenium alleviates cadmium-induced cerebellar injury by activating metal regulatory transcription factor 1 mediated metal response

Disruption of the zinc metabolism in rat fœtal brain after prenatal exposure to cadmium

Alleviative effect of melatonin against the nephrotoxicity induced by cadmium exposure through regulating renal oxidative stress, inflammatory reaction, and fibrosis in a mouse model

High cadmium exposure impairs adult hippocampal neurogenesis via disruption of store-operated calcium entry

Effect of zinc supplementation on bone metabolism in male rats chronically exposed to cadmium

Cadmium (Cd) is a respiratory toxicant. Previous reports have confirmed that chronic respiratory Cd exposure causes chronic obstructive pulmonary disease-like lesions in a murine model. This study aimed to evaluate the influence of short-term Cd exposure on lung function. Adult C57BL/6J mice were exposed to Cd through inhaling different concentrations of cadmium chloride aerosols (25mg/L or 100mg/L, 2h per day) for 5days. Serum Cd was quantified by ICP-MS. Lung histopathology and lung function were evaluated. Pulmonary inflammatory cytokines were measured by real-time RT-PCR. Untargeted metabolomics, transcriptome sequencing, and targeted lipidomics were used to explore the mechanism. Serum Cd level was slightly elevated and alveolar structure was mildly damaged in Cd-exposed mice. An obvious lung function decline was observed, accompanied by upregulation of inflammatory cytokines in Cd-exposed mouse lungs. Untargeted metabolomics and transcriptomics showed that pulmonary lipid metabolism was disrupted in Cd-exposed mice. Lipidomics confirmed that sphingolipids, including ceramides and sphingosine, were significantly increased in Cd-exposed mouse lungs. Pulmonary SPTLC1, an essential subunit of the rate-limiting enzyme for ceramide de novo synthesis, and ceramide synthases, such as CerS2 and CerS6, were elevated in Cd-exposed mice. The present results provide experimental data that short-term environmental exposure causes pulmonary function decline probably by upregulating pulmonary sphingolipid synthesis.

Cadmium exposure induces histological damage and cytotoxicity in the cardiovascular system of mice.

Objective To investigate the effects of vitamin D deficiency on bone turnover and bone mineral density in patients with a blunted PTH response as compared to patients with vitamin D deficiency and secondary hyperparathyroidism.Method A total of 542 postmenopausal women [mean age (64.0 ± 10.8) years] were evaluated by assessing serum calcium,phosphate,alkaline phosphatase,25-hydroxy vitamin D (25-OHD),PTH,bone turnover markers such as osteocalcin,C-terminal telopeptide of type Ⅰ collagen(CTX) and procollagen type Ⅰ amino-terminal propeptide(PINP),and bone mineral density of lumber spine,total hip and femur neck etc.Result (1) The prevalence of vitamin D deficiency in this cohort was 24％.Mean 25-OHD varied across seasons (P =0.023) ; women who paid visits during winter and spring yielded significantly lower levels of 25-OHD than those who had their visit during the fall (P =0.012 and P =0.039).Serum PTH and bone turnover markers did not vary by season.(2) All subjects could be divided into four groups occording to their serum 25-OHD and PTH levels.Group 1:25-OHD＜ 10 ng/ml and PTH ≥ 65 pg/ml (7.0％),group 2:25-OHD ＜ 10 ng/ml and PTH ＜ 65 pg/ml (17.0％),group 3:25-OHD ≥ 10 ng/ml and PTH＜65 pg/ml (73.6％),group 4:25-OHD ≥ 10 ng/ml and PTH ≥ 65 pg/ml (2.4％).Blunted PTH response was found in 70.8％ of patients with vitamin D deficiency.Patients with vitamin D deficiency and a blunted PTH response were characterized by a lowered serum calcium,a reduction in bone turnover (serum CTX and serum osteocalcin),but protection in bone density as compared to those with vitamin D deficiency and secondary hyperparathyroidism.(3) As for spine bone mineral density,the significant independent predictors were body mass index(r2 =0.370,P＜0.01),age(r2 =-0.158,P＜0.01),PTH(r2 =-0.121,P＜0.05),and serum CTX(r2 =-0.118,P＜0.05).For femoral neck bone mineral density,the significant independent predictors were years since menopause(r2 =-0.201,P＜O.01) and body mass index(r2 =0.139,P＜0.05).And for hip bone mineral density,the significant independent predictors were age (r2 =-0.239,P＜0.01) and body mass index (r2 =0.239,P＜0.01).There was little correlation between 25-OHD and bone mineral density.Conclusion This study identifies a high prevalence of vitamin D deficiency in healthy postmenopausal women in shanghai,and a distinct group of patients with vitamin D deficiency and a blunted PTH response as shown by disruption in calcium homeostasis but protection against PTH-mediated bone loss.Compared with hip,spine bone mineral density is more sensitive to higher serum PTH and higher bone turnover. Key words: 25-hydroxy vitamin D; Serum parathyroid hormone; Hyperparathyroidism; Bone turnover; Bone mineral density

Effective amphibian conservation requires an understanding of how populations respond to specific natural and anthropogenic factors. Chemical contaminants are among the known sources of acute and chronic stress and have been linked with habitat degradation and amphibian declines. Manipulative experiments were conducted to investigate the performance (i.e., growth, survival) of amphibians that metamorphose from chemically-contaminated aquatic breeding sites. The heavy metal cadmium (Cd) was selected as the focal contaminant because it bioaccumulates, is highly toxic, and occurs in polluted water bodies around the world. Effects of larval exposure to Cd on amphibian metamorphosis and juvenile performance were tested using the southern leopard frog (Rana sphenocephala) and American toad (Bufo americanus), two common North American habitat generalists that utilize Cd-contaminated breeding sites. It was expected that Cd exposure would decrease the growth and survival of tadpoles and juveniles because Cd affects the physiological processes and body condition of amphibians and other taxa. In the first experiment, southern leopard frog and American toad tadpoles were reared separately in cattle tank mesocosms (1325-L volume) that had been dosed once at 0, 5, 18, 60, or 200 [mu]g Cd/L. The experimental endpoints were survival, mass and age at metamorphosis, and whole body Cd content. Both species had a decrease in survival and increase in larval period and Cd content with increasing aqueous Cd concentration. However, southern leopard frog mass increased and American toad mass decreased with Cd exposure. A subset of metamorphs from the first experiment was subsequently reared in terrestrial enclosures (2 m2) located in a field along a forest edge. Metamorphs were obtained from all five Cd concentrations (American toads) or just the 0, 5, and 18 [mu]g Cd/L treatments (southern leopard frogs). Juveniles were monitored for survival and growth in their first autumn and the following spring. There were no significant effects of Cd exposure history on the mass or growth rate of either species, but there a deleterious effect on American toad survival. Southern leopard frogs from the 18 [mu]g Cd/L concentration were larger than the controls throughout the study. A laboratory experiment was conducted on the terrestrial performance of southern leopard frog juveniles that metamorphosed from cattle tank mesocosms dosed once with 0, 5, or 18 [mu]g Cd/L. Individuals were kept in separate containers for two months and fed either a low or high level diet of mealworms (Tenebrio molitor). Overall survival was 99 percent, indicating neither Cd nor diet were lethal. Initial differences in mass among Cd treatments were maintained within each diet level and those on the high diet weighed more than twice those on the low diet. The effect of Cd exposure history on juvenile mass depended on food abundance.A fourth study was conducted to determine the combined effects of Cd concentration and interspecific competition on amphibian metamorphosis. Southern leopard frogs were the focal species and American toads were the competitor. Metamorphs were collected from cattle tank mesocosms that had been dosed once at 0, 5, or 18 [mu]g Cd/L. Cadmium exposure decreased survival, increased mass and age at metamorphosis, and resulted in significant body burdens for the southern leopard frogs. Interspecific competition from the American toads increased survival and shortened the larval period, decreased mass at metamorphosis, and had no effect on contaminant uptake. The effect of Cd on metamorph age depended on whether American toads were present. A subset of southern leopard frog metamorphs from the fourth study was reared in terrestrial enclosures (9 m2) in two habitat types for the final experiment. Enclosures were located in deciduous forests or open fields and juvenile growth and survival was determined in the first autumn following metamorphosis. Cadmium exposure history affected growth rate, mass, and survival. Initial differences in mass due to larval Cd exposure were maintained over time in each habitat type, but growth was highest in field enclosures and survival was highest in forest enclosures. The forest sites were cooler and wetter, which may have improved juvenile survival. This research suggests that aquatic breeding sites polluted with Cd produce fewer, older, and contaminated amphibian metamorphs relative to uncontaminated sites. Those that survive to metamorphosis do not appear to be hindered by reduced terrestrial survival or growth as juveniles. However, Cd exposure influenced juvenile performance through interactions with terrestrial habitat quality. Assessments of the effects of contaminants on amphibians that incorporate multiple routes of exposure and other potential stressors may produce different outcomes than assessments that only manipulate the aquatic concentration.

Objective To study the effect of ossotide injection on bone metabolism and bone mineral density after internal fixation of closed reduction and proximal femoral anti rotation intramedullary nail in patients with femoral intertrochanteric fracture(PFNA). Methods 90 patients with PFNA were randomly divided into two groups according to the digital table, each group in 45 cases.The control group underwent internal fixation of closed reduction and proximal femoral anti rotation intramedullary nail for PFNA.The observation group was given ossotide injection after internal fixation of closed reduction and proximal femoral anti rotation intramedullary nail for PFNA.The healing time, postoperative hospitalization time and recovery rate were compared, and the serum osteocalcin level, serum alkaline phosphatase level, bone density, serum calcium and phosphorus levels were compared between the two groups before and after treatment. Results The average healing time and postoperative hospital stay of the observation group were significantly shorter than those of the control group (t=5.924, 8.824, all P<0.05). The recovery rate of the observation group was significantly higher than that of the control group(χ2=5.075, P<0.05). Before treatment, there were no significant differences between the two groups in serum osteocalcin level, serum alkaline phosphatase level, bone mineral density, serum calcium and phosphorus levels.After treatment, the serum osteocalcin level, serum alkaline phosphatase level, bone mineral density, serum calcium and phosphorus levels in the observation group respectively(5.69±0.56)μg/L, (92.52±10.59)IU/L, (0.88±0.48)g/cm2, (2.89±0.87)mmol/L, (1.93±0.59)mmol/L, significantly better than those in the control group(t=5.423, 5.413, 4.633, 5.883, 5.734, all P<0.05). Conclusion Femoral intertrochanteric fracture patients underwent closed reduction and internal fixation with PFNA application of ossotide injection can effectively improve the bone metabolism, increase bone density, accelerate fracture healing, shorten the hospitalization time, postoperative effect, it is worthy of promotion. Key words: Femoral fractures; Perioperative period; Bone peptide injection; Bone density

Cadmium (Cd) is a toxic heavy metal that can cause ovarian damage, but the mechanism is unknown. Ferroptosis is a newly identified type of programmed cell death. In our study, we explored whether ferroptosis is involved in Cd-induced ovarian damage and the underlying mechanism. Our histopathological results after acute Cd exposure showed significant damage to granulosa cells, and superovulation results showed that the first polar body extrusion (PBE) rate and the number of MII oocytes were significantly reduced. Transcriptomics analysis showed differences in lipid metabolism and amino acid pathways in the ovaries of Cd-exposed mice. Targeted metabolomics showed that oxidized ARA metabolites were increased in the ovaries of Cd-exposed mice. Further examination of oxidative markers revealed oxidative stress and abnormal iron metabolism in Cd-exposed mouse ovaries. Ultrastructure results showed that mitochondria of oocytes from Cd-exposed mice were significantly crumpled, cristae disappeared and showed an ferroptosis morphology. Further findings showed that acute Cd exposure up-regulated the mRNA and protein levels of the Acsl4 gene and down-regulated the mRNA and protein levels of the Gpx4 and Fsp1 genes, suggesting that Cd exposure induces ovarian ferroptosis. Ferritin-1 (Fer- 1), a specific inhibitor of ferroptosis, significantly alleviated ovarian oxidative stress and ferroptosis in mice and partially attenuated Cd-induced ovarian damage. In summary, Cd exposure leads to ovarian injury by inducing ovarian ferroptosis in mice. Our study provides a theoretical basis for finding potential strategies for Cd-related ovarian diseases based on ferroptosis process intervention.

Osteoporosis is a common skeletal disease in post-menopausal women. Palmul-tang, an herbal medicine, has been treated for gynecological disease such as anemia, anorexia, anti-fatigue, unspecified menstruation and female infertility in East Asia. In this study, ameliorative effects of Palmul-tang soft extracts (PMT), a Korean Medicine, on osteoporosis were investigated. Ovariectomized (OVX) osteoporotic ICR mice were intragastrically administrated PMT for 4 weeks. The level of bone mineral density (BMD) was analyzed in bone tissues by dual X-ray absorptiometry. The bone medullary cavity and deposition of collagen were investigated by histological analysis. In addition, the BMP-2 signaling-related molecules, osteoblastic differentiation and formation markers, were determined in femoral tissues. The levels of BMD and bone mineral content were significantly increased in tibia, femurs and LV by treatment of PMT. PMT replenished bone marrow cavity and increased collagen deposition in bone marrow cells of femur. In addition, administration of PMT recovered serum ALP, bALP, osteocalcin and calcium levels in osteoporotic mice. Moreover, PMT treatment up-regulated the expressions of BMP-2, RUNX2 and OSX with its downstream factors, ALP, OPN and BSP-1, in the femoral tissues. Taken together, PMT restored the bone minerals and improvement of bone integrity by bone-forming BMP-2 signaling pathway. These results demonstrate that PMT could be an ameliorative agent for osteoporosis.

Cadmium (Cd) can easily enter the body through the food chain and threaten health since Cd pollution is prevalent in the environment. Gut microbiota is necessary for the reduction of metal ions. To reduce Cd-induced harmful impacts and Cd accumulation in the body, we investigated the effect of amino acids on gut microbiota and Cd excretion in (fecal Cd) Cd-exposed mice. The screening of 20 amino acids showed that threonine (Thr) effectively increased fecal Cd, and reduced Cd-induced intestinal structural damage. The abundance of Escherichia-Shigella genus and KF843036_g significantly increased after the oral administration of Thr. As the type species of the Escherichia-Shigella genus, Escherichia coli exhibited high similarity to KF843036_g species and significantly decreased Cd-induced gut damage. Cd contents in the liver, kidney, and gut of Cd-exposed mice were also significantly (p < 0.05) decreased after E. coli treatment, while the contents in the feces were increased. The results demonstrated the potential roles that gut E. coli might play in Thr-mediated Cd excretion in Cd-exposed mice. The findings may provide important data for better understanding the molecular biological mechanism of Thr in reducing Cd accumulation in the body.