Pristane cadmium chloride nanoemulsion accelerates the onset of systemic lupus erythematosus in a C57BL/6 mouse model.

OBJECTIVE: To accelerate the onset of systemic lupus erythematosus in C57BL/6 mice by injecting cadmium chloride nanoemulsion and shorten the traditional modeling time. METHODS: Pristane cadmium chloride nanoemulsion was prepared, and 66 C57BL/6 mice were randomly divided into four groups. The pristane group was intraperitoneally injected with 0.6 mL of pristane blank nanoemulsion, the model group was injected with 0.6 mL of pristane cadmium chloride nanoemulsion, the Cadmium chloride control group was injected with 0.6 mL of cadmium chloride nanoemulsion, and the control group was injected with the same amount of 0.9% sodium chloride solution. Urine protein content, anti-dsDNA antibody content, Th1 cell/Th2 cell ratio, and kidney staining were detected in each group. RESULTS: The model group began to develop disease in the 4th week, the anti-dsDNA antibody level reached 566.71 ± 1.44 ng/L, and the proteinuria reached 245.38 ± 30.54 ng/mL. The model group showed an onset at least 5 weeks earlier than that in the pristane group. There was no significant difference in anti-dsDNA antibody content between Cadmium chloride control group and blank group. At the 12th week, the Th1/Th2 cell ratio in the model group significantly decreased, and the pathological changes in the kidneys were consistent with the typical manifestations of lupus in mouse models. CONCLUSION: These results suggest that cadmium chloride promotes earlier onset of pristane-induced systemic lupus erythematosus in a C57BL/6 mouse model.

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

Chronic cadmium (Cd) exposure causes severe adverse health effects on the human body, especially the kidney tissue. Studies have demonstrated oxidative stress to be involved in renal pathological variations after exposure to Cd, but few effective treatments are available for the disease yet. Therefore, the present study was carried out to investigate the potential therapeutic intervention and its underlying molecular mechanisms of melatonin (MT), a natural antioxidant with multiple biological activities, against renal injury caused by Cd exposure in mice. C57BL/6 male mice (eight-week-old) were intragastrically administered with CdCl2, MT, or both for 30 days. Biochemical analysis showed that MT intervention significantly improved the SOD, GSH, and CAT activities while markedly decreasing the kidney MDA content of the mice exposed to Cd. Histological examination indicated that Cd exposure resulted in the atrophy of the renal glomerular, the degeneration and dilation of tubules, and the accumulation of fibrocytes. By contrast, MT administration effectively ameliorated the histological outcome of the injured kidney tissue. Moreover, administrating MT significantly inhibited proinflammatory cytokines TNF-α and iNOS expression in Cd-treated mice. Further, MT treatment markedly suppressed the expressions of renal fibrosis-related factors TGF-ß1, α-SMA, and collagen Ⅰ in the injured renal tissue and the accumulation and development of renal fibrosis. In addition, the administration of MT significantly reduced the expression of caspase-3 and cell apoptotic death in the kidney tissue of Cd-exposed mice. In all, the data showed that MT has a compelling therapeutic potential in alleviating the pathological variations of renal injury caused by Cd exposure.

Naphthaleneoxypropargyl-Containing Piperazine as a Regulator of Effector Immune Cell Populations upon an Aseptic Inflammation.

This study investigated the effects of aseptic inflammation and heavy metal exposure on immune responses, as well as the potential immunomodulatory properties of the newly synthesized 1-[1-(2,5-dimethoxyphenyl)-4-(naphthalene-1-yloxy)but-2-ynyl]-4-methylpiperazine complexed with ß-cyclodextrin (ß-CD). Aseptic inflammation was induced by a subcutaneous injection of turpentine in rats, while heavy metal exposure was achieved through a daily administration of cadmium chloride and lead acetate. The levels of immune cell populations, including cytotoxic T lymphocytes (CTL), monocytes, and granulocytes, were assessed in the spleen. The results showed that aseptic inflammation led to decreased levels of CTL, monocytes, and granulocytes on the 14th day, indicating an inflammatory response accompanied by a migration of effector cells to the inflamed tissues. The exposure to cadmium chloride and lead acetate resulted in systemic immunotoxic effects, with reduced levels of B cells, CD4+ Th cells, monocytes, and granulocytes in the spleen. Notably, piperazine complexed with ß-CD (the complex) exhibited significant stimulatory effects on CD4+, CD8+, and myeloid cell populations during aseptic inflammation, even in the presence of heavy metal exposure. These findings suggest the potential immunomodulatory properties of the complex in the context of aseptic inflammation and heavy metal exposure.

Cadmium chloride generates cytotoxic reactive species that cause oxidative damage and morphological changes in human erythrocytes.

Cadmium chloride (CdCl2) is a widely used industrial compound that exhibits multiple organ toxicity. Cadmium is transported through blood where erythrocytes are exposed to its action. Here the effect of CdCl2 on human erythrocytes was examined under in vitro conditions. Human erythrocytes were treated with 0.01-0.5 mM CdCl2 for 24 h at 37 °C. Lysates were made from CdCl2 treated and untreated (control) cells and used for further analysis. CdCl2 treatment resulted in marked hemolysis of erythrocytes and oxidation of hemoglobin to methemoglobin. This will result in anemia and also reduce the oxygen carrying ability of erythrocytes. Hemoglobin oxidation was accompanied by degradation of heme and release of free ferrous iron moiety. Further analysis showed elevated lipid hydroperoxides and formation of advanced oxidation protein products along with reduction in total sulfhydryl content, indicating the generation of oxidative stress condition in the cell. Incubation of erythrocytes with CdCl2 enhanced generation of reactive oxygen and nitrogen species, decreased the antioxidant power and inhibited pathways of glucose metabolism. Plasma membrane was damaged as indicated by enhanced osmotic fragility and inhibition of membrane bound enzymes. This was confirmed by electron microscopy which showed formation of echinocytes. These results show that CdCl2 generates reactive species which impair the antioxidant system resulting in oxidative damage to erythrocytes.

Cadmium chloride-induced apoptosis of HK-2 cells via interfering with mitochondrial respiratory chain.

Cadmium could induce cell apoptosis, probably related to the dysfunction of the mitochondrial respiratory chain. The human renal proximal tubule (HK-2) was used to explore the mechanism of mitochondrial respiratory chain dysfunction during apoptosis induced by cadmium chloride (CdCl2). Cell viability was evaluated by cell proliferation assay and different concentrations of 60, 80 and 100 µM were selected to evaluate the mitochondrial toxicity of CdCl2 respectively. Under the CdCl2 treatment for 24 h, the mitochondrial reactive oxygen species (ROS) of HK-2 cells increased and the superoxide dismutase (SOD) activity was inhibited at the above three concentrations separately. Both ATP content and mitochondrial membrane potential decreased significantly at 100 µM concentration. The levels of procaspase-3 and Bcl-2 had fallen in a concentration-dependent manner and Bax was significantly increased at 60, 80 and 100 µM concentration compared with no CdCl2 treatment respectively, which activated the mitochondrial apoptosis pathway. N-acetyl-cysteine (NAC) could partially resist CdCl2-induced cell apoptosis, while myxothiazol (Myx) promoted the process. Mitochondria relative alterations manifested as inhibition of complex III and V. In addition, both the quantity of mitochondrial coenzyme Q-binding protein CoQ10 homolog B (CoQ10B) and cytochrome c (Cyt c) had decreased significantly. Taken together, CdCl2 induced HK-2 apoptosis due to the mitochondrial respiratory chain dysfunction by reducing the CoQ10B level, offering a novel evaluating indicator for the environmental toxicity of CdCl2.

Ameliorative effects of a curcumin vitamin E nanocomposite coated with olive oil against cadmium chloride-induced testicular damage.

In the current study, we synthesized and prepared a curcumin and vitamin E nanocomposite coated with olive oil (CEONC). Curcumin, vitamin E, and olive oil are fundamental organic antioxidants, and forming nanoparticles from these components endows them with special characteristics. We investigated the protective effect of CEONC on reproductive toxicity induced by cadmium chloride (CdCl2 ) in male rats. Forty rats (170-180 g) were randomly assigned to four groups: Group 1 (control) received oral distilled water; Group 2 intraperitoneal injection with CEONC (30 mg/kg); Group 3 received oral CdCl2 (5 mg/kg); and Group 4 received CdCl2 (5 mg/kg) followed by CEONC (30 mg/kg) for 4 weeks. After 50 days, we terminated the experiment and assessed male reproductive hormones, sperm motility, viability and morphology, and testes histopathology and conducted a comet assay. The results revealed that co-administration of CEONC with CdCl2 exposure increased reproductive hormone levels, improved sperm motility and viability, prevented sperm morphological changes, recovered the testicular histology, and decreased DNA damage in the testicular tissue compared to rats exposed to CdCl2 alone. CEONC administration produced no adverse effects and enhanced all sperm parameters. Our findings demonstrate that CEONC is a potential treatment for preventing reproductive damage induced by cadmium exposure.

Silymarin modulates cadmium-induced oxidative stress in human spermatozoa.

Environmental pollutants such as cadmium can negatively affect sperm parameters and decrease male fertility by inducing oxidative stress. Antioxidants are considered a useful strategy for oxidative stress conditions to neutralize free radicals and strengthen the antioxidant defence system. In this study, the effects of the common application of silymarin, as a natural antioxidant, with cadmium were assessed on human sperm. The washed human sperm samples were divided into five groups: (1) spermatozoa at 0- hour; (2) spermatozoa at 3 h; (3) spermatozoa treated with cadmium (20 µM) for 3 h; (4) spermatozoa treated with silymarin (2 µM) + cadmium (20 µM) for 3 h and (5) spermatozoa treated with silymarin (2 µM) for 3 h. Our results displayed that cadmium reduced sperm motility, viability, plasma membrane integrity and acrosome integrity by increasing malondialdehyde levels and decreasing the total antioxidant capacity and antioxidant enzymes activity. While silymarin attenuated oxidative stress biomarkers in human sperm treated with cadmium, and consequently improved the sperm quality. In summary, cadmium-induced oxidative stress impaired human sperm structures and silymarin with its antioxidant properties compensated for the adverse effects of oxidative stress on human spermatozoa.

The Antioxidant, Cytotoxic and Antimicrobial Potential of Phenolic Acids-Enriched Extract of Elicited Hairy Roots of Salvia bulleyana.

Hairy root cultures are valuable sources of a range of phytochemicals. Among them, Salvia bulleyana root culture is a promising source of polyphenols, especially rosmarinic acid (RA), a phenolic acid depside with pleiotropic activity and a wide application in medicine and cosmetology. The aim of the study was to enhance the culture productivity by finding suitable elicitation protocol and to determine its biological potential in terms of antioxidant, anticancer and antimicrobial properties. The total content of phenols and the levels of particular constituents in root extracts were analyzed using HPLC-PDA. Among four elicitors tested (yeast extract; methyl jasmonate, MJA; trans-anethol; and cadmium chloride), MJA was found to be the most effective. The greatest boost in phenolic production (up to 124.4 mg/g dry weight) was observed after three-day treatment with MJA at 100 µM, with an almost 100% improvement compared to the controls (non-treated root culture). The hydromethanolic extract from the elicited culture exhibited strong antioxidant activity with IC50 values of 11.1 µg/mL, 6.5 µg/mL and 69.5 µg/mL for DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid)) and superoxide anion radical, respectively. Moreover, in concentrations of 0.5-5 mg/mL the extract inhibited the growth of LoVo, AGS and HeLa cell lines, but was safe for the L929 cells up to the concentration of 5 mg/mL. The extract also exhibited moderate antimicrobial activity. Thus, the results confirmed that elicitation can be a beneficial strategy for increase the phenolic acid biosynthesis in hairy roots of S. bulleyana, and that such a highly productive culture can show significant biological potential.

Histopathological evaluation of IBA-1, GFAP activity in the brain cortex of rats administered cadmium chloride.

Purpose: This study aims to evaluate the changes in brain tissue and blood-brain barrier due to oxidative stress during cadmium (Cd) poisoning by biochemical, histopathological, and immunohistochemical methods. Methods: 170-190 g weighing eight-week-old female Wistar albino rats were divided into two groups (control and experimental), with 7 animals in each group. Experimental group rats were given 2 mg/kg/day powdered cadmium chloride dissolved in water intraperitoneally every day for two weeks. Biochemical, histopathological and immunohistochemical examination was performed. Results: It was seen that brain malondialdehyde (MDA) levels increased significantly, and glutathione (GSH) and catalase (CAT) activity levels decreased. In addition to degeneration in some pyramidal cells and glial cells, deformity, and picnosis in the nucleus, dilation of the meninges and cortex vessels, and inflammation around the blood vessels were observed. An increase was found in ionized calcium binding adaptor molecule 1 (IBA-1) expression in microglia cells and degenerative endothelial cells, and increased glial fibrillary acidic protein (GFAP) expression was observed in astrocytes and degenerate neurons. Conclusions: It has been shown that cadmium toxicity may cause microgliosis and astrogliogenesis by inducing cytokine production due to cell degeneration, vascularity, and inflammation in the brain cortex and by affecting microglia, astrocytes cells.

[Renal injury induced by cadmium chloride and the protective effect of vitamin C in mice].

OBJECTIVE: To investigate the renal injury induced by cadmium chloride(CdCl_2) and the protective effect of vitamin C(VC) in mice. METHODS: Forty healthy clean grade male Kunming mice were randomly divided into 4 groups: control group(double distilled water gavage and intraperitoneal injection), VC group(200 mg/kg VC gavage and double distilled water intraperitoneal injection), CdCl_2 group(double distilled water gavage and 2 mg/kg CdCl_2 intraperitoneal injection), VC+CdCl_(2 )group(200 mg/kg VC gavage and 2 mg/kg CdCl_2 intraperitoneal injection). Exposure for 30 days.24 hours after the last exposure, the eyeballs were taken out for blood, and the renal tissue was immediately taken out to calculate kidney coefficient and then separate renal cells. The levels of reactive oxygen species(ROS) were detected by DCFH-DA kit and flow cytometry. Blood urea nitrogen(BUN), serum creatinine(Scr)and ß2 microglobulin(ß2-MG), cystatin C(Cys C), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), malondialdehyde(MDA), Caspase3 and Caspase9 kits were used to detect the corresponding indicators respectively. The contents of Cd~(2+) and Zn~(2+) in serum and kidney were detected by graphite furnace atomic absorption spectrometry. RESULTS: The levels of kidney coefficient and BUN, Scr, ß2-MG were 1.36±0.10, (19.34±0.63)mmol/L, (61.30±2.04)mmol/L and(1.02±0.10)g/mL respectively in CdCl_(2 )group, which were higher than those in the control group and VC group(P<0.05). The levels of the above four indexes in VC+CdCl_(2 )group were 1.09±0.10, (9.65±0.50)mmol/L, (41.85±1.27)mmol/L and(0.61±0.01)g/mL respectively, which were lower than those in CdCl_2 group(P<0.05). CdCl_2 exposure resulted in unclear glomerular contour, swelling of renal tubules, interstitial hyperemia, and exfoliated epithelial cells in the lumen. VC pretreatment could improve the above changes. The levels of Cd~(2+) in serum and renal tissue of mice in CdCl_2 group were(4.36±0.07)µg/L, (18.6±1.95)µg/g respectively, which were higher than that of control group and VC group(P<0.05), in VC+CdCl_2 group, the level were(2.12±0.06)µg/L and(2.18±0.09)µg/g, they were lower than that of CdCl_2 group(P<0.05). The level of serum Zn~(2+ )in CdCl_2 group was(11.35±1.03)µg/L, that was lower than control group(P<0.05). The level of serum Zn~(2+) in VC+CdCl_2 group was(26.98±3.13)µg/L, which was higher than that of CdCl_2 group(P<0.05). The levels of ROS, MDA, Caspase3 and Caspase9 in kidney tissue of mice in CdCl_2 group were(1.86±0.13), (4.78±0.15)nmol/mg, 1.50±0.24 and 1.69±0.17 respectively, which were higher than those in control group(P<0.05). And the level of GSH-Px was(261.3±23.36)U/mg, it was lower than that in control group(P<0.05). Compared with the CdCl_2 group, the levels of ROS, MDA, Caspase3 and Caspase9 in VC+CdCl_2 group decreased, and the level of GSH-Px increased, the difference was statistically significant(P<0.05). CONCLUSION: CdCl_2 exposure can lead to oxidative stress, damage of glomerulus and renal tubules, imbalance of zinc ion homeostasis, and damage of renal function. VC pretreatment can reduce the damage caused by CdCl_2 to a certain extent.

Immunity and inflammatory responses in gilthead sea bream (Sparus aurata L.) exposed to sub-lethal mixture of carbamazepine, cadmium chloride and polybrominated diphenyl ether.

Chemical contaminants such as industrial and urban by-products, pharmaceuticals, drugs metabolites and, plastics, are continuously found in the oceans, affecting its quality and organism's welfare. Although these compounds are found at concentrations ranged ng L-1, there is an increasing concern about the potential adverse effects of the interactions among those substances present, simultaneously, in a mixture. In the present study, specimens of sea bream (Sparus aurata) were exposed, by food, to rising concentrations of a mixture of carbamazepine, polybrominated diphenyl ether-47 and cadmium chloride, for 15 days and then, maintained, with the same control diet, without contaminants, for other 15 days. Samples of skin mucus, serum, head-kidney, liver and intestine were sampled at 0, 15 and 30 days. Cellular immune parameters were evaluated on head-kidney, as well as humoral parameters were determined on skin mucus and serum. In addition, the expression of some genes, related to immunity, was analysed on liver and intestine. Both cellular and humoral response were affected at 15 days, showing slightly signs of recovery at 30 days. Besides, the expression of immune-related genes was highly affected, suggesting the development of inflammatory processes, as well as a reduction of immune parameters. Overall, the mixture of compounds severally affected the immune system of sea bream, suggesting a lower degree of recovery. The prolonged exposure to a mixture of these compounds could entail serious change on population immunity and, eventually, promote changes on marine biota.

Protective effect of Feijoa sellowianan fruit on testicular toxicity-induced by cadmium chloride.

The purpose of the present study was to investigate the protective potential of Feijoa fruit extract on cadmium chloride (CdCl2 )-induced testicular injury and pituitary-gonadal axis. Adult male Wistar rats were randomly divided into four groups: (a) control (normal saline, orally), (b) cadmium chloride (0.1 mg/kg, single dose, intraperitoneally), (c) Feijoa fruit extract (400 mg/kg, orally for 30 consecutive days) and (d) CdCl2  + Feijoa fruit extract. One day after receiving the last medicine, the LH, FSH, prolactin and testosterone concentration were assayed. Also, sperm parameters and tissue structure of the testis were evaluated. Administration of Feijoa fruit extract after CdCl2 injection in rats ameliorated sperm parameters such as sperm count, morphology, motility and sperm viability, increased levels of LH, FSH, prolactin and testosterone and improved testicular histology. According to the results of this study, it was shown that Feijoa can reduce the destructive side effects of CdCl2 on testicular tissue and sex hormones of the pituitary-gonadal pathway.

Resistance to benzalkonium chloride and cadmium chloride in Listeria monocytogenes isolates from food and food-processing environments in southern Brazil.

Resistance to quaternary ammonium compounds such as benzalkonium chloride (BC) has been observed in many Listeria monocytogenes strains worldwide and is associated with cadmium chloride (CC) resistance. Therefore, the aims of this study were to evaluate the susceptibility to BC and CC, detect the presence of resistance genes, and investigate the possible role of efflux pumps in BC and CC resistance in L. monocytogenes isolates from food and food-processing environments in southern Brazil. All 50 L. monocytogenes isolates (100%) were resistant to BC, and 29 isolates (58%) were resistant to CC. According to the resistance genes (mdrL, lde, emrE, bcrABC, radC, qacA, qacC/D, qacH, qacEΔ1, cadA1, cadA2, cadA3, cadA4, and cadC), only the efflux pumps MdrL and Lde were identified in 12 (24%) and 33 (66%) isolates, respectively. The analysis of resistance to BC and CC in the presence of reserpine, an efflux pump inhibitor, showed that the resistance was not influenced by efflux pumps. This study confirmed a high profile of resistance to BC and CC in L. monocytogenes from food sources, and to the knowledge of the authors, this is the first report of the presence of efflux pumps MdrL and Lde in L. monocytogenes from Brazil.

Rutin alleviates cadmium-induced neurotoxicity in Wistar rats: involvement of modulation of nucleotide-degrading enzymes and monoamine oxidase.

Rutin is a flavonoid commonly found in many vegetables, fruits and other plant species. Thus, this study investigated the protective role of rutin on cognitive function and impairment of ectonucleotidase, monoamine oxidase (MAO) and antioxidant enzymes activities in the cortex and hippocampus of cadmium-induced rats. Cognitive impairment was induced by an oral administration of 5 mg/kg Cadmium chloride for 14 consecutive days. Rutin was dissolved in 2% dimethyl sulfoxide (DMSO) and administered orally at the doses of 25 and 50 mg/kg for 14 days. Thereafter, animals were divided into six groups (n = 6) as follows: control, rutin 25 mg/kg, rutin 50 mg/kg, cadmium, cadmium plus rutin 25 mg/kg, cadmium plus rutin 50 mg/kg. After treatment period of 14 days, animals were sacrificed and the brain was dissected into cortex and hippocampus. Results showed that cadmium caused a significant increase in ectonucleotidases, adenosine deaminase (ADA) and MAO activities, with a concomitant decrease in thiol levels and antioxidant enzymes activities. However, treatment with rutin decreased ectonucleotidase, ADA and MAO activities in cadmium-induced rats. In addition, rutin reduced residual level of cadmium ion in the brain of cadmium-induced rats. Conclusively, present findings revealed that rutin could prevent/restored the impairment of the enzymes that regulate the purinergic and monoaminergic extracellular signaling and restore antioxidant status in cognitive impairment caused by prolonged cadmium exposure.

Protective effects of silymarin on testis histopathology, oxidative stress indicators, antioxidant defence enzymes and serum testosterone in cadmium-treated mice.

Cadmium is known as an oxidative stress-inducing factor. Silymarin extracted from Silybum marianum is regarded as a potent antioxidant. The present study investigated the preventing effects of silymarin on cadmium chloride-induced toxicity in terms of testis histopathology and serum testosterone level as well as oxidative stress indicators in mice. In addition, the activities of antioxidant defence enzymes was evaluated. Adult male mice were divided into four groups (n = 6 in each group): (a) control; (b) cadmium chloride; (c) silymarin + cadmium chloride and (d) Silymarin. In this study, cadmium chloride significantly decreased the diameter and wall thickness of the seminiferous tubule, diameter of the spermatogonia nucleus and serum testosterone levels compared to the control group. Furthermore, in mice treated with this pollutant, a significant increase in malondialdehyde was observed while ferric reducing antioxidant power level, and the activity of catalase, superoxide dismutase and glutathione peroxidase were significantly reduced in the testis. In the silymarin + cadmium chloride group, silymarin could significantly reverse the toxic effects of cadmium chloride. The findings of this study showed that silymarin, as a potent antioxidant, can compensate the adverse effects of cadmium chloride on testis histopathology, testosterone level, oxidative stress indicators and antioxidant defence enzymes in mice.

Diallyl disulfide attenuation effect on transcriptome in rat liver cells against cadmium chloride toxicity.

In this report, liver cells were treated with cadmium chloride (CdCl2 ) and diallyl disulfide (DADS), a major compound from garlic to attenuate the toxic effect of Cd on transcriptome. The viability of Cd treated cells was reduced to 19.9% ± 2.4% in comparison to the untreated cells, whereas the viability of DADS pretreated cells was increased to 48.6% ± 2%. The attenuation effect of DADS was studied at shorter period (6 hours). Transcriptome analysis of CdCl2 alone treated cells resulted in 2119 and 982 (up and down) regulated genes (≥ 2 or ≤ 2-fold), whereas pretreated cells with DADS resulted in 2597 and 1784 genes. These genes were known to function in many important biological processes. Affymetrix array analysis was validated by the pathway specific PCR array that exhibited the same trend of expression. The current study clearly shows the DADS attenuation effect on transcriptome in CdCl2 -treated rat liver cells.

Resveratrol protects against cadmium chloride-induced hippocampal neurotoxicity by inhibiting ER stress and GAAD 153 and activating sirtuin 1/AMPK/Akt.

This study investigated whether the apoptotic effect induced by cadmium chloride (CdCl2 ) in rat's hippocampi and neuroprotection afforded by resveratrol (RES) are mediated by modulation of ER stress and involve sirtuin 1 (SIRT1)/AMPK/Akt axis. Adult male Wistar rats were divided into four groups (n = 24/group) as control, control + RES (300 mg/kg), CdCl2 (5 mg/kg), and CdCl2 + RES. All treatments were conducted orally for 45 days. Also, cultured hippocampal cells were treated with CdCl2 in the presence or absence of RES and with or without preincubation with SIRT1, AMPK, or PI3K inhibitors. CdCl2 impaired retention and spatial memories of rats and reduced levels and activities of SIRT1 and inhibited AMPK/Akt axis in their hippocamapi where SIRT1 was the upstream regulator. It also enahnced hippocampal levels of reactive oxygen species (ROS) and expression of caspase-12 and caspase-3, depleted glutathione (GSH) levels, and activated GRP78, activating transcription factor-6, GAAD 153, X-box binding protein-1 arms of ER stress. On the contrary, RES coadminsitration completley abolished all these events. Interstingly and in control rats, RES not only increased levels of GSH, but also enhenced protein levels of B-cell lymphoma 2 (Bcl-2) and dwonregulated GAAD 153. In both control and CdCl2 -treated rats, pharmacological inhibtion of SIRT1, AMPK, and Akt compleltely abolished all effects afforded by RES. In conclusion, CdCl2 -induced hippocampal apopotis is associated with reduction of SIRT1/AMPK/Akt activity levels, ROS generation, downregulation of Bcl-2, and activities, activation of ER stress, and GAAD 153, whereas RES is able to reverse these effects through activation of SIRT1/AMPK/Akt.

Carnosic Acid Attenuates Cadmium Induced Nephrotoxicity by Inhibiting Oxidative Stress, Promoting Nrf2/HO-1 Signalling and Impairing TGF-ß1/Smad/Collagen IV Signalling.

Cadmium (Cd) imparts nephrotoxicity via triggering oxidative stress and pathological signal transductions in renal cells. The present study was performed to explore the protective mechanism of carnosic acid (CA), a naturally occurring antioxidant compound, against cadmium chloride (CdCl2)-provoked nephrotoxicity employing suitable in vitro and in vivo assays. CA (5 µM) exhibited an anti-apoptotic effect against CdCl2 (40 µM) in normal kidney epithelial (NKE) cells evidenced from cell viability, image, and flow cytometry assays. In this study, CdCl2 treatment enhanced oxidative stress by triggering free radical production, suppressing the endogenous redox defence system, and inhibiting nuclear factor erythroid 2-related factor 2 (Nrf2) activation in NKE cells and mouse kidneys. Moreover, CdCl2 treatment significantly endorsed apoptosis and fibrosis via activation of apoptotic and transforming growth factor (TGF)-ß1/mothers against decapentaplegic homolog (Smad)/collagen IV signalling pathways, respectively. In contrast, CA treatment significantly attenuated Cd-provoked nephrotoxicity via inhibiting free radicals, endorsing redox defence, suppressing apoptosis, and inhibiting fibrosis in renal cells in both in vitro and in vivo systems. In addition, CA treatment significantly (p < 0.05-0.01) restored blood and urine parameters to near-normal levels in mice. Histological findings further confirmed the protective role of CA against Cd-mediated nephrotoxicity. Molecular docking predicted possible interactions between CA and Nrf2/TGF-ß1/Smad/collagen IV. Hence, CA was found to be a potential therapeutic agent to treat Cd-mediated nephrotoxicity.

Mimosa pudica Protects the Testes Against Cadmium-Induced Inflammation and Oligospermia: Potential Benefits in Treatment of Heavy Metal Toxicity.

Cadmium is a known environmental and industrial pollutant with an enormous tissue disrupting potential. Mimosa pudica (M. pudica) is a creeping annual or perennial herb known to possess anti asthmatic, anti-epileptic, anti-tumour, anti-fertility, aphrodisiac, analgesic, anti-depressant, sedative, emetic properties and a strong radical scavenging activity. This research was aimed at investigating the ameliorative effects of M. pudica on cadmium-induced testicular damage in adult male Sprague Dawley rats. Twenty adult Sprague Dawley rats were employed in the study. They were divided into 4 groups (A-D) of 5 rats each, and toxicity was induced by administering 0.4 mg/ml cadmium chloride through drinking water to groups B-D for 21days. M. pudica extract was administered orally at 250 and 500 mg/kg to groups C and D. Animals in Groups C and D showed remarkable histological improvements in testicular tissue and markedly reduced damages when compared with group B.The active sperm motility of group B (6.00 ±â€¯1.00%) was significantly (p = 0.0001) decreased compared to that of the groups A (15.00 ±â€¯0.00%)) and C (13.00 ±â€¯1.22%). Sperm count analysis of group B (1.36 ±â€¯0.28 × 106/cc), C (4.18 ±â€¯0.81 × 106/cc) and D (2.54 ±â€¯1.13 × 106/cc) were significantly lower (p = <0.05) when compared with group A (12.78 ±â€¯0.92 × 106/cc), respectively. Sperm morphology of group A (70.00 ±â€¯3.16%), B (66.00 ±â€¯2.50), C (74.00 ±â€¯2.45%) and D (64.00 ±â€¯2.45%) recorded no significant difference. This study demonstrates that M. pudica has potential protective and restorative properties on the histoarchitecture of the testes of cadmium-treated rats.

Quantitative assessment of heavy metal effects on sperm function using computer-aided sperm analysis and cytotoxicity assays.

One known environmental risk factor impacting on human reproduction is heavy metal pollution. Although some metals (e.g., Cu, Se and Zn) have protective effects on the male reproductive system in low doses, heavy metals can accumulate to toxic levels and result in poor semen quality and decreased sperm function. We investigated the effect of CuSO4 and CdCl2 (10, 50, 100 and 250 µg/ml or 500 µg/ml) on human sperm motility and vitality by using computer-aided sperm analysis (CASA) and two cytotoxicity assays (WST-1 and XTT). Several sperm motility parameters were significantly reduced after 5 hr of exposure to the highest concentrations of CuSO4 (250 µg/ml) and CdCl2 (500 µg/ml). The WST-1 assay also revealed significantly lower absorbance values for 50, 100 and 250 µg/ml CuSO4 and for 500 µg/ml CdCl2 ; however, no significant effect was seen with XTT. The calculated average IC50 value was 50.31±  4.34 µg/ml for CuSO4 and 392.32  ±76.79 µg/ml for CdCl2 . The effects of these metals were confirmed with MgCl2 , a positive control. This study provides threshold concentrations for the harmful effect of CuSO4 and CdCl2 on human spermatozoa and recommends the use of WST-1 as vitality assay in future in vitro studies.