Luteolin Alleviates Cadmium-Induced Kidney Injury by Inhibiting Oxidative DNA Damage and Repairing Autophagic Flux Blockade in Chickens.

Chickens are a major source of meat and eggs in human food and have significant economic value. Cadmium (Cd) is a common environmental pollutant that can contaminate feed and drinking water, leading to kidney injury in livestock and poultry, primarily by inducing the generation of free radicals. It is necessary to develop potential medicines to prevent and treat Cd-induced nephrotoxicity in poultry. Luteolin (Lut) is a natural flavonoid compound mainly extracted from peanut shells and has a variety of biological functions to defend against oxidative damage. In this study, we aimed to demonstrate whether Lut can alleviate kidney injury under Cd exposure and elucidate the underlying molecular mechanisms. Renal histopathology and cell morphology were observed. The indicators of renal function, oxidative stress, DNA damage and repair, NAD+ content, SIRT1 activity, and autophagy were analyzed. In vitro data showed that Cd exposure increased ROS levels and induced oxidative DNA damage and repair, as indicated by increased 8-OHdG content, increased γ-H2AX protein expression, and the over-activation of the DNA repair enzyme PARP-1. Cd exposure decreased NAD+ content and SIRT1 activity and increased LC3 II, ATG5, and particularly p62 protein expression. In addition, Cd-induced oxidative DNA damage resulted in PARP-1 over-activation, reduced SIRT1 activity, and autophagic flux blockade, as evidenced by reactive oxygen species scavenger NAC application. The inhibition of PARP-1 activation with the pharmacological inhibitor PJ34 restored NAD+ content and SIRT1 activity. The activation of SIRT1 with the pharmacological activator RSV reversed Cd-induced autophagic flux blockade and cell injury. In vivo data demonstrated that Cd treatment caused the microstructural disruption of renal tissues, reduced creatinine, and urea nitrogen clearance, raised MDA content, and decreased the activities or contents of antioxidants (GSH, T-SOD, CAT, and T-AOC). Cd treatment caused oxidative DNA damage and PARP-1 activation, decreased NAD+ content, decreased SIRT1 activity, and impaired autophagic flux. Notably, the dietary Lut supplement observably alleviated these alterations in chicken kidney tissues induced by Cd. In conclusion, the dietary Lut supplement alleviated Cd-induced chicken kidney injury through its potent antioxidant properties by relieving the oxidative DNA damage-activated PARP-1-mediated reduction in SIRT1 activity and repairing autophagic flux blockade.

Luteolin alleviates cadmium-induced metabolism disorder through antioxidant and anti-inflammatory mechanisms in chicken kidney.

Cadmium (Cd) is a common environmental pollutant associated with an increased incidence of renal metabolic diseases. Luteolin (Lut), a natural flavonoid, is widely used for its multifaceted therapeutic properties in inflammatory diseases. However, whether Lut protects against Cd-induced nephrotoxicity is still equivocal. The present study investigated the effects of Lut supplementation on renal oxidative stress, inflammation and metabolism and their related mechanisms. Therefore, 40 chickens were treated with Cd and/or Lut with automatic water and free food intake for 1 mo and then the kidney tissues were collected to explore this issue. In this study, Cd exposure induced renal glycolipid metabolism disorders and resultant kidney damage by periodic acid Schiff (PAS) staining, Oil Red O staining, total cholesterol (TC), triglyceride (TG), and glucose (Glu) levels in kidney, which were significantly ameliorated by Lut. Moreover, Lut also normalized the expression levels of factors related to Cd-disturbed glycolipid metabolism, improving metabolic homeostasis, and contributing to alleviating kidney damage. Furthermore, Lut demonstrated therapeutic potential against Cd-induced renal oxidative stress and inflammation by enhancing antioxidant capacity and inhibiting cytokine production in the kidney tissues. Mechanistically, Lut activated the AMPK/SIRT1/FOXO1 signaling pathway, attenuating oxidative stress and inflammatory responses, ameliorating the metabolic disturbance. In conclusion, these observations demonstrate that Lut treatment activates AMPK/SIRT1/FOXO1 signaling pathway, decreases oxidative stress and inflammation response, which may contribute to prevent Cd-induced metabolism disorder and consequent kidney damage.

Ferroptosis: First evidence in premature duck ovary induced by polyvinyl chloride microplastics.

Ferroptosis is frequently observed in fibrosis and diseases related to iron metabolism disorders in various mammalian organs. However, research regarding the damage mechanism of ferroptosis in the female reproductive system of avian species remains unclear. In this study, Muscovy female ducks were divided into three groups which were given purified water, 1 mg/L polyvinyl chloride microplastics (PVC-MPs) and 10 mg/L PVC-MPs for two months respectively, to investigate the ferroptosis induced by PVC-MPs caused ovarian tissue fibrosis that lead to premature ovarian failure. The results showed that the high accumulation of PVC-MPs in ovarian tissue affected the morphology and functional activity of ovarian granulosa cells (GCs) and subsequently caused the follicular development disorders and down-regulated the immunosignaling of ovarian steroidogenesis proteins 3ß-hydroxysteroid dehydrogenase (3ß-HSD), 17ß-hydroxysteroid dehydrogenase (17ß-HSD), CYP11A1 cytochrome (P450-11A1) and CYP17A1 cytochrome (P450-17A1) suggested impaired ovarian function. In addition, PVC-MPs significantly up-regulated positive expression of collagen fibers, significantly increased lipid peroxidation and malondialdehyde (MDA) level, along with encouraged overload of iron contents in the ovarian tissue were the characteristics of ferroptosis. Further, immunohistochemistry results confirmed that immunosignaling of ferroptosis related proteins Acyl-CoA synthetase (ACSL4), Cyclooxygenase 2 (COX2) and ferritin heavy chain 1 (FTH1) were significantly increased, but solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase (GPX4) were decreased by PVC-MPs in the ovarian tissue. In conclusion, our study demonstrates that PVC-MPs induced ferroptosis in the ovarian GCs, leading to follicle development disorders and ovarian tissue fibrosis, and ultimately contributing to various female reproductive disorders through regulating the proteins expression of ferroptosis.

Oligomeric proanthocyanidins ameliorates osteoclastogenesis through reducing OPG/RANKL ratio in chicken's embryos.

Skeletal disorders can seriously threaten the health and the performance of poultry, such as tibial dyschondroplasia (TD) and osteoporosis (OP). Oligomeric proanthocyanidins (OPC) are naturally occurring polyphenolic flavonoid compounds that can be used as potential substances to improve the bone health and the growth performance of poultry. Eighty 7-day-old green-eggshell yellow feather layer chickens were randomly divided into 4 groups: basal diet and basal diet supplementation with 25, 50, and 100 mg/kg OPC. The results have indicated that the growth performance and bone parameters of chickens were significantly improved supplementation with OPC in vivo, including the bone volume (BV), the bone mineral density (BMD) and the activities of antioxidative enzymes, but ratio of osteoprotegerin (OPG)/receptor activator of NF-κB (RANK) ligand (RANKL) was decreased. Furthermore, primary bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes/macrophages (BMMs) were successfully isolated from femur and tibia of chickens, and co-cultured to differentiate into osteoclasts in vitro. The osteogenic differentiation derived from BMSCs was promoted treatment with high concentrations of OPC (10, 20, and 40 µmol/L) groups in vitro, but emerging the inhibition of osteoclastogenesis by increasing the ratio of OPG/RANKL. In contrary, the osteogenic differentiation was also promoted treatment with low concentrations of OPC (2.5, 5, and 10 µmol/L) groups, but osteoclastogenesis was enhanced by decreasing the ratio of OPG/RANKL in vitro. In addition, OPG inhibits the differentiation and activity of osteoclasts by increasing the autophagy in vitro. Dietary supplementation of OPC can improve the growth performance of bone and alter the balance of osteoblasts and osteoclasts, thereby improving the bone health of chickens.

Co-exposure to PVC microplastics and cadmium induces oxidative stress and fibrosis in duck pancreas.

PVC microplastics (PVC-MPs) are environmental pollutants that interact with cadmium (Cd) to exert various biological effects. Ducks belong to the waterfowl family of birds and therefore are at a higher risk of exposure to PVC-MPs and Cd than other animals. However, the effects of co-exposure of ducks to Cd and PVC-MPs are poorly understood. Here, we used Muscovy ducks to establish an in vivo model to explore the effects of co-exposure to 1 mg/L PVC-MPs and 50 mg/kg Cd on duck pancreas. After 2 months of treatment with 50 mg/kg Cd, pancreas weight decreased by 21 %, and the content of amylase and lipase increased by 25 % and 233 %. However, exposure to PVC-MPs did not significantly affect the pancreas. Moreover, co-exposure to PVC-MPs and Cd worsened the reduction of pancreas weight and disruption of pancreas function compared to exposure to either substance alone. Furthermore, our research has revealed that exposure to PVC-MPs or Cd disrupted mitochondrial structure, reduced ATP levels by 10 % and 18 %, inhibited antioxidant enzyme activity, and increased malondialdehyde levels by 153.8 % and 232.5 %. It was found that exposure to either PVC-MPs or Cd can induce inflammation and fibrosis in the duck pancreas. Notably, co-exposure to PVC-MPs and Cd exacerbated inflammation and fibrosis, with the content of IL-1, IL-6, and TNF-α increasing by 169 %, 199 %, and 98 %, compared to Cd exposure alone. The study emphasizes the significance of comprehending the potential hazards linked to exposure to these substances. In conclusion, it presents promising preliminary evidence that PVC-MPs accumulate in duck pancreas, and increase the accumulation of Cd. Co-exposure to PVC-MPs and Cd disrupts the structure and function of mitochondria and promotes the development of pancreas inflammation and fibrosis.

Resveratrol Alleviates Zearalenone-Induced Intestinal Dysfunction in Mice through the NF-κB/Nrf2/HO-1 Signalling Pathway.

Zearalenone (ZEA), a mycotoxin widely present in crops and food, poses a major threat to animal and human health. The consumption of ZEA-contaminated food or feed causes intestinal damage. Therefore, exploring how to mitigate the intestinal damage caused by its ZEA is becoming increasingly important. Resveratrol (RSV), a polyphenol compound, mainly exists in Vitis vinifera, Polygonum cuspidatum, Arachis hypogaea, and other plants. It has potent anti-inflammatory and antioxidant activity. The primary objective of this study was to assess the defensive effects of RSV and its molecular mechanism on the intestinal mucosal injury induced by ZEA exposure in mice. The results showed that RSV pretreatment significantly reduced serum DAO and that D-lactate levels altered intestinal morphology and markedly restored TJ protein levels, intestinal goblet cell number, and MUC-2 gene expression after ZEA challenge. In addition, RSV significantly reversed serum pro-inflammatory factor levels and abnormal changes in intestinal MDA, CAT, and T-SOD. Additional research demonstrated that RSV decreased inflammation by blocking the translocation of nuclear factor-kappaB (NF-κB) p65 and decreased oxidative stress by activating the nuclear factor E2-related factor 2 (Nrf2) pathway and its associated antioxidant genes, including NQO1, γ-GCS, and GSH-PX. In summary, RSV supplementation attenuates intestinal oxidative stress, inflammation, and intestinal barrier dysfunction induced by ZEA exposure by mediating the NF-κB and Nrf2/HO-1 pathways.

Mitigating effect of pomegranate peel extract against the furan induced testicular injury by apoptosis, steroidogenic enzymes and oxidative stress.

Furan is generated in a wide array of heat-treated foods through thermal degradation, leading to severe impairments in the male reproductive system. The main objective of this study was to investigate the potential of pomegranate peel extract (PGPE) in mitigating testicular dysfunctions induced by furan. Male rats were categorized into four groups: control/untreated, PGPE, furan, and PGPE + furan group. The study results revealed that furan-treated rats exhibited significantly elevated aminotransferase and phosphatase activity, and also generated increased oxidative stress, and reduced antioxidative stress protein activity. Additionally, protein content levels (ALT, AST, ALP, and ACP) and activities of steroidogenic Leydig cell hydroxysteroid dehydrogenase (3ß-HSD and 17ß-HSD) enzymes were significantly decreased. Significant variations in testicular parameters, apoptotic genes (Bcl-2, P53, and Caspase3), inflammatory and anti-inflammatory cytokines (IL1ß, IL10), male sex hormones follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, and sperm quality were also observed. Furthermore, testicular histological abnormalities were confirmed by biochemical and molecular modifications. Notably, PGPE pre-treated furan-intoxicated animals exhibited significant improvements in most of the assessed parameters compared to furan-treated groups. In conclusion, PGPE presents essential preventive measures and a novel pharmacological potential therapy against furan-induced testicular injury.

SIRT1 alleviates Cd nephrotoxicity through NF-κB/p65 deacetylation-mediated pyroptosis in rat renal tubular epithelial cells.

Cadmium (Cd) is a widely distributed environmental pollutant, primarily causing nephrotoxicity through renal proximal tubular cell impairment. Pyroptosis is an inflammation-related nucleotide-binding oligomerization segment-like receptor family 3 (NLRP3)-dependent pathway for programmed cell death. We previously reported that inappropriate inflammation caused by Cd is a major contributor to kidney injury. Therefore, research on Cd-induced inflammatory response and pyroptosis may clarify the mechanisms underlying Cd-induced nephrotoxicity. In this study, we observed that Cd-induced nephrotoxicity is associated with NLRP3 inflammasome activation, leading to an increase in proinflammatory cytokine expression and secretion, as well as pyroptosis-related gene upregulation, both in primary rat proximal tubular (rPT) cells and kidney tissue from Cd-treated rats. In vitro, these effects were significantly abrogated through siRNA-based Nlrp3 silencing; thus, Cd may trigger pyroptosis through an NLRP3 inflammasome-dependent pathway. Moreover, Cd exposure considerably elevated reactive oxygen species (ROS) content. N-acetyl-l-cysteine, an ROS scavenger, mitigated Cd-induced NLRP3 inflammasome activation and subsequent pyroptosis. Mechanistically, Cd hindered the expression and deacetylase activity of SIRT1, eventually leading to a decline in SIRT1-p65 interactions, followed by an elevation in acetylated p65 levels. The administration of resveratrol (a SIRT1 agonist) or overexpression of Sirt1 counteracted Cd-induced RELA/p65/NLRP3 pathway activation considerably, leading to pyroptosis. This is the first study to reveal significant contributions of SIRT1-triggered p65 deacetylation to pyroptosis and its protective effects against Cd-induced chronic kidney injury. Our results may aid in developing potential therapeutic strategies for preventing Cd-induced pyroptosis through SIRT1-mediated p65 deacetylation.

A critical review on male-female reproductive and developmental toxicity induced by micro-plastics and nano-plastics through different signaling pathways.

It is widely accepted that humans are constantly exposed to micro-plastics and nano-plastics through various routes, including inhalation of airborne particles, exposure to dust, and consumption of food and water. It is estimated that humans may consume thousand to millions of micro-plastic particles, equating to several milligrams per day. Prolonged exposure to micro-plastics and nano-plastics has been linked to negative effects on different living organisms, including neurotoxicity, gastrointestinal toxicity, nephrotoxicity, and hepatotoxicity, and developmental toxicities. The main purpose of this review is to explore the effect of micro-plastics and nano-plastics on the male and female reproductive system, as well as their offspring, and the associated mechanism implicated in the reproductive and developmental toxicities. Micro-plastics and nano-plastics have been shown to exert negative effects on the reproductive system of both male and female mammals and aquatic animals, including developmental impacts on gonads, gametes, embryo, and their subsequent generation. In addition, micro-plastics and nano-plastics impact the hypothalamic-pituitary axes, leading to oxidative stress, reproductive toxicity, neurotoxicity, cytotoxicity, developmental abnormalities, poor sperm quality, diminishes ovarian ovulation and immune toxicity. This study discusses the so many different signaling pathways associated in the male and female reproductive and developmental toxicity induced by micro-plastics and nano-plastics.

Inefficient Sox9 upregulation and absence of Rspo1 repression lead to sex reversal in the B6.XYTIR mouse gonad†.

Sry on the Y-chromosome upregulates Sox9, which in turn upregulates a set of genes such as Fgf9 to initiate testicular differentiation in the XY gonad. In the absence of Sry expression, genes such as Rspo1, Foxl2, and Runx1 support ovarian differentiation in the XX gonad. These two pathways antagonize each other to ensure the development of only one gonadal sex in normal development. In the B6.YTIR mouse, carrying the YTIR-chromosome on the B6 genetic background, Sry is expressed in a comparable manner with that in the B6.XY mouse, yet, only ovaries or ovotestes develop. We asked how testicular and ovarian differentiation pathways interact to determine the gonadal sex in the B6.YTIR mouse. Our results showed that (1) transcript levels of Sox9 were much lower than in B6.XY gonads while those of Rspo1 and Runx1 were as high as B6.XX gonads at 11.5 and 12.5 days postcoitum. (2) FOXL2-positive cells appeared in mosaic with SOX9-positive cells at 12.5 days postcoitum. (3) SOX9-positive cells formed testis cords in the central area while those disappeared to leave only FOXL2-positive cells in the poles or the entire area at 13.5 days postcoitum. (4) No difference was found at transcript levels of all genes between the left and right gonads up to 12.5 days postcoitum, although ovotestes developed much more frequently on the left than the right at 13.5 days postcoitum. These results suggest that inefficient Sox9 upregulation and the absence of Rspo1 repression prevent testicular differentiation in the B6.YTIR gonad.

Role of Mitochondrial Reactive Oxygen Species-Mediated Chaperone-Mediated Autophagy and Lipophagy in Baicalin and N-Acetylcysteine Mitigation of Cadmium-Induced Lipid Accumulation in Liver.

Cadmium (Cd) is a major health concern globally and can accumulate and cause damage in the liver for which there is no approved treatment. Baicalin and N-acetylcysteine (NAC) have been found to have protective effects against a variety of liver injuries, but it is not clear whether their combined use is effective in preventing and treating Cd-induced lipid accumulation. The study found that Cd increased the production of mitochondrial reactive oxygen species (mROS) and elevated the level of chaperone-mediated autophagy (CMA). Interestingly, mROS-mediated CMA exacerbates the Cd-induced inhibition of lipophagy. Baicalin and NAC counteracted inhibition of lipophagy by attenuating Cd-induced CMA, suggesting an interplay between CMA elevation, mitochondrial destruction, and mROS formation. Maintaining the stability of mitochondrial structure and function is essential for alleviating Cd-induced lipid accumulation in the liver. Choline is an essential component of the mitochondrial membrane and is responsible for maintaining its structure and function. Mitochondrial transcriptional factor A (TFAM) is involved in mitochondrial DNA transcriptional activation and replication. Our study revealed that the combination of baicalin and NAC can regulate choline metabolism through TFAM and thereby maintain mitochondrial structure and functionality. In summary, the combination of baicalin and NAC plays a more beneficial role in alleviating Cd-induced lipid accumulation than the drug alone, and the combination of baicalin and NAC can stabilize mitochondrial structure and function and inhibit mROS-mediated CMA through TFAM-choline, thereby promoting lipophagy to alleviate Cd-induced lipid accumulation.

Cadmium Induces Kidney Iron Deficiency and Chronic Kidney Injury by Interfering with the Iron Metabolism in Rats.

Cadmium (Cd) is a common environmental pollutant and occupational toxicant that seriously affects various mammalian organs, especially the kidney. Iron ion is an essential trace element in the body, and the disorder of iron metabolism is involved in the development of multiple pathological processes. An iron overload can induce a new type of cell death, defined as ferroptosis. However, whether iron metabolism is abnormal in Cd-induced nephrotoxicity and the role of ferroptosis in Cd-induced nephrotoxicity need to be further elucidated. Sprague Dawley male rats were randomly assigned into three groups: a control group, a 50 mg/L CdCl2-treated group, and a 75 mg/L CdCl2-treated group by drinking water for 1 month and 6 months, respectively. The results showed that Cd could induce renal histopathological abnormalities and dysfunction, disrupt the mitochondria's ultrastructure, and increase the ROS and MDA content. Next, Cd exposure caused GSH/GPX4 axis blockade, increased FTH1 and COX2 expression, decreased ACSL4 expression, and significantly decreased the iron content in proximal tubular cells or kidney tissues. Further study showed that the expression of iron absorption-related genes SLC11A2, CUBN, LRP2, SLC39A14, and SLC39A8 decreased in proximal tubular cells or kidneys after Cd exposure, while TFRC and iron export-related gene SLC40A1 did not change significantly. Moreover, Cd exposure increased SLC11A2 gene expression and decreased SLC40A1 gene expression in the duodenum. Finally, NAC or Fer-1 partially alleviated Cd-induced proximal tubular cell damage, while DFO and Erastin further aggravated Cd-induced cell damage. In conclusion, our results indicated that Cd could cause iron deficiency and chronic kidney injury by interfering with the iron metabolism rather than typical ferroptosis. Our findings suggest that an abnormal iron metabolism may contribute to Cd-induced nephrotoxicity, providing a novel approach to preventing kidney disease in clinical practice.

Baicalin and N-acetylcysteine regulate choline metabolism via TFAM to attenuate cadmium-induced liver fibrosis.

(Background): Cadmium is an environmental pollutant associated with several liver diseases. Baicalin and N-Acetylcysteine have antioxidant and hepatoprotective effects. (Purpose): However, it is unclear whether baicalin and N-Acetylcysteine can alleviate Cadmium -induced liver fibrosis by regulating metabolism, or whether they exert a synergistic effect. (Study design): We treated Cadmium-poisoned mice with baicalin, N-Acetylcysteine, or baicalin+ N-Acetylcysteine. We studied the effects of baicalin and N-Acetylcysteine on Cadmium-induced liver fibers and their specific mechanisms. (Methods): We used C57BL/6 J mice, and AML12, and HSC-6T cells to establish in vitro assays and in vivo models. (Results): Metabolomics was used to detect the effect of baicalin and N-Acetylcysteine on liver metabolism, which showed that compared with the control group, the Cadmium group had increased fatty acid and amino acid levels, with significantly reduced choline and acetylcholine contents. Baicalin and N-Acetylcysteine alleviated these Cadmium-induced metabolic changes. We further showed that choline alleviated Cadmium -induced liver inflammation and fibrosis. In addition, cadmium significantly promoted extracellular leakage of lactic acid, while choline alleviated the cadmium -induced destruction of the cell membrane structure and lactic acid leakage. Western blotting showed that cadmium significantly reduced mitochondrial transcription factor A (TFAM) and Choline Kinase α(CHKα2) levels, and baicalin and N-Acetylcysteine reversed this effect. Overexpression of Tfam in mouse liver and AML12 cells increased the expression of CHKα2 and the choline content, alleviating and cadmium-induced lactic acid leakage, liver inflammation, and fibrosis. (Conclusion): Overall, baicalin and N-Acetylcysteine alleviated cadmium-induced liver damage, inflammation, and fibrosis to a greater extent than either drug alone. TFAM represents a target for baicalin and N-Acetylcysteine, and alleviated cadmium-induced liver inflammation and fibrosis by regulating hepatic choline metabolism.

Roles of Cyt-c/Caspase-9/Caspase-3/Bax/Bcl-2 pathway in Cd-induced testicular injury in rats and the protective effect of quercetin.

Cadmium (Cd) exposure causes oxidative damage to mitochondria, which would adversely affect rat testicular tissue. Quercetin (Que) is a natural antioxidant with anti-inflammatory, antioxidant and anti-apoptotic effects. However, the mechanism by which Que inhibits Cd-induced apoptosis of testicular cells remains unclear. The purpose of this study was to investigate the role of mitochondrial apoptosis pathway (Cyt-c/Caspase-9/Caspase-3/Bax/Bcl-2 pathway) in inhibiting Cd-induced apoptosis of testicular cells by Que. We used SD rats to simulate Cd chloride exposure by treating all sides of the rats with CdCl2 and/or Que. The levels of GSH and MDA in rat testis were detected using reagent kits. The effects of CdCl2 and/or Que on tissue damage, apoptosis, and gene and protein expression of the Cyt-c/Caspase-9/Caspase-3/Bax/Bcl-2 pathway in rat testis were examined by HE, TUNEL, RNA extraction and reverse-transcriptase polymerase chain reaction (RT-PCR), and Western blot (Wb). The results show that Cd significantly increased the contents of GSH and MDA in rat testis (P < 0.01); conversely, Que significantly reduced the contents of GSH and MDA (P < 0.01). Cd inflicted damage to testicular tissue, and Que addition significantly reduced the damage. Cd increased the number of apoptosis of testicle cells, and Que inhibited testicle-cell apoptosis. In addition, the results of reverse transcription PCR and Wb assays confirmed that, as expected, Cd increased the expression levels of Cyt-c, Caspase-9, Caspase-3, and Bax mRNAs as well as proteins. And at the same time decreased the expression of the anti-apoptotic factor Bcl-2 in the cells. Surprisingly, these effects were reversed when Que was added. Therefore, Que can play an antioxidant and anti-apoptotic role in reducing the testicular tissue damage caused by Cd exposure. This provides a conceptual basis for the later development and utilization of Que as well as the prevention and treatment of tissue damage caused by Cd exposure.

Protective effect of quercetin on cadmium-induced kidney apoptosis in rats based on PERK signaling pathway.

BACKGROUND: Cadmium (Cd) is a highly toxic environmental pollutant that can enter the body through bioaccumulation. The kidney is an important target organ for Cd poisoning. Quercetin (Que) is a natural flavonoid compound with free radical scavenging and antioxidant properties. Previous studies showed that Que can alleviate kidney damage caused by Cd poisoning in rats, but the specific mechanism is still unclear. METHODS: Twenty-four male Sprague-Dawley (SD) rats were divided into four groups: normal saline-treated control group, Cd group treated by intraperitoneal injection of 2 mg/kg b.w. CdCl2, Cd + Que group treated by intraperitoneal injection of 2 mg/kg b.w. CdCl2 and 100 mg/kg b.w. Que, and Que group treated by 100 mg/kg b.w. Que. Four weeks later, the rats were anesthetized with diethyl ether, and blood was taken intravenously. The rats were executed with their necks cut off, and the kidneys were removed. Body weight, kidney organ weight, and glutathione (GSH) and malondialdehyde (MDA) levels were measured. The structure of kidney tissue was observed by hematoxylin and eosin staining, kidney cell apoptosis was detected by TUNEL assay, and the mRNA expression levels of genes related to the PERK signaling pathway were analyzed by RT-PCR. RESULTS: Compared with the control group, the Cd-treated group exhibited a significant decrease in body weight (P < 0.01). Their kidneys showed a significant increase in the relative organ weight (P < 0.01). Moreover, the MDA and GSH levels increased. Kidney tissue damage and renal cell apoptosis were observed, and the mRNA expression levels of genes related to the PERK signaling pathway significantly increased (P < 0.01). Compared with the Cd-treated group, the Cd + Que group exhibited a significant increase in body weight (P < 0.01) and significant decreases in the relative organ weight, MDA and GSH levels, and mRNA expression levels of genes related to the PERK signaling pathway (P < 0.01). Furthermore, kidney tissue damage and renal cell apoptosis were observed. CONCLUSION: Cd treatment resulted in rat weight loss, renal edema, and oxidative stress and caused renal tissue damage and cell apoptosis by activating the PERK signaling pathway. Que was able to restore the body weight and renal coefficient of rats. It also alleviated the oxidative stress and kidney tissue damage caused by Cd and the cell apoptosis caused by Cd through inhibiting the PERK signaling pathway. Thus, Que could be considered for the treatment of kidney diseases caused by Cd poisoning.

Osmoregulatory and immunological role of new canceled cells: Mitochondrial rich cells and its future perspective: A concise review.

Mitochondrial-rich cells (MRCs) are one of the most significant canceled type of epithelial cells. Morphologically these cells are totally different from other epithelial cells. These cells primarily implicated in sea-water and fresh-water adaptation, and acid-base regulation. However, in this review paper, we explored some of the most intriguing biological and immune-related functional developmental networks of MRCs. The main pinpoint, MRCs perform a dynamic osmoregulatory and immunological functional role in the gut and male reproductive system. The Na+/K+_ATPase (NKA) and Na+/K+/2Cl cotransporter (NKCC) are key acidifying proteins of MRCs for the ion-transporting function for intestinal homeostasis and maintenance of acidifying the luminal microenvironment in the male reproductive system. Further more importantly, MRCs play a novel immunological role through the exocrine secretion of nano-scale exosomes and multivesicular bodies (MVBs) pathway, which is very essential for sperm maturation, motility, acrosome reaction, and male sex hormones, and these an essential events to produce male gametes with optimal fertilizing ability. This effort is expected to promote the novel immunological role of MRCs, which might be essential for nano-scale exosome secretion.

TFAM-mediated intercellular lipid droplet transfer promotes cadmium-induced mice nonalcoholic fatty liver disease.

Cadmium (Cd) is an important environmental pollutant. Herein, we discovered a new way of lipid accumulation, where lipid droplets can be transferred across cells. In this study, mice and AML12 cells were used to establish models of Cd poisoning. After Cd treatment, the level of TFAM was reduced, thereby regulating the reconstitution of the cytosolic actin filament network. MYH9 is a myosin involved in cell polarization, migration, and movement of helper organelles. Rab18 is a member of the Rab GTPase family, which localizes to lipid droplets and regulates lipid drop dynamics. In this study, we found that Cd increases the interaction between MYH9 and Rab18. However, TFAM overexpression alleviated the increase in Cd-induced interaction between MYH9 and Rab18, thereby reducing the transfer of intercellular lipid droplets and the accumulation of intracellular lipids. Through a co-culture system, we found that the transferred lipid droplets can act as a signal to form an inflammatory storm-like effect, and ACSL4 can act as an effector to transfer lipid droplets and promote lipid accumulation in surrounding cells. These results suggest that TFAM can be used as a new therapeutic target for Cd-induced lipid accumulation in the liver.

Quercetin alleviates cadmium-induced BRL-3A cell apoptosis by inhibiting oxidative stress and the PERK/IRE1α/ATF6 signaling pathway.

Cadmium (Cd) is a highly toxic environmental pollutant. The liver is an important metabolic organ in the body and is susceptible to Cd toxicity attacks. Quercetin (Que) is a flavonoid compound with pharmacological activities of scavenging free radicals and antioxidant activity. Previous studies have shown that Que can alleviate Cd caused hepatocyte apoptosis in rats, but the specific mechanism remains unclear. To explore the specific mechanism, we established a model of Cd toxicity and Que rescue in BRL-3A cells and used 4-phenylbutyrate (4-PBA), an endoplasmic reticulum stress (ERS) inhibitor, as positive control. Set up a control group, Cd treatment group, Cd and Que co treatment group, Que treatment group, Cd and 4-PBA co treatment group, and 4-PBA treatment group. Cell Counting Kit-8 (CCK-8) method was employed to measure cell viability. Fluorescence staining was applied to observe cell apoptosis. Flow cytometry was performed to detect reactive oxygen species levels. Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot method was adopted to detect the mRNA and protein expression levels of ERS and apoptosis-related genes. The results showed that compared with the control group, the Cd treated group showed a significant decrease in cell viability (P < 0.01), an increase in intracellular ROS levels, and apoptosis. The mRNA and protein expression levels of ERS and apoptosis related factors such as GRP78, IRE1α, XBP1, ATF6, Caspase-12, Caspase-3 and Bax in the cells were significantly increased (P < 0.01), while the mRNA and protein expression levels of Bcl-2 were significantly reduced (P < 0.01). Compared with the Cd treatment group, the Cd and Que co treatment group and the Cd and 4-PBA co treatment group showed a significant increase in cell viability (P < 0.01), a decrease in intracellular ROS levels, a decrease in cell apoptosis, and a significant decrease in the expression levels of ERS and apoptosis related factors mRNA and protein (P < 0.01), as well as a significant increase in Bcl-2 mRNA and protein expression (P < 0.01). We confirmed that Que could alleviate the apoptosis caused by Cd in BRL-3A cells, and the effects of Que were similar to those of ERS inhibitor.

Cadmium exposure exacerbates kidney damage by inhibiting autophagy in diabetic rats.

The incidence of diabetes mellitus (DM) is gradually increasing, making it a widespread global health concern. Cadmium (Cd) is a common toxic heavy metal in the environment, and cadmium exposure may be associated with diabetic nephropathy (DN). However, the mechanism of Cd-induced DN remains unclear. In this study, we aimed to determine the effect of cadmium on diabetic kidney injury and the underlying mechanism in diabetic rats and a renal tubular epithelial cell line (NRK-52E cells). Our results could provide novel insights on the nephrotoxic mechanism of cadmium. HE, PAS, and Masson staining were used to observe pathological renal injury. COL-I, COL-IV, CTSB, and CTSD protein levels were detected by immunohistochemistry and western blotting. Immunofluorescence was used to detect the fluorescence intensity of p62 and LC3 proteins in kidney tissue. TEM was used to observe the ultrastructure of mitochondria and number of autophagosomes. After cadmium exposure, DM rats showed a dramatic decrease in body weight compared to the unexposed DM group. Relative kidney weight showed a contrasting trend after cadmium exposure. Urinary microalbumin/creatinine significantly increased in normal and DM rats after cadmium exposure. However, the trend was clearer in the DM groups than in the control groups. Endogenous creatinine clearance exhibited a contrasting trend. After cadmium exposure in DM rats, MDA content significantly increased and GSH, CAT, SOD, and GSH-PX activation reduced compared to normal controls. Pathological damage was more pronounced, and the expression of autophagy related proteins and apoptosis and fibrosis proteins was significantly higher in vivo and vitro in the cadmium-exposed groups than in unexposed controls. Further, lysosomal protein levels were lower, and ROS content and autophagosome count significantly higher in the cadmium exposed groups compared to the unexposed controls. Therefore, Cadmium exposure aggravates diabetic kidney injury via autophagy inhibition.

Interactive mechanism between connexin43 and Cd-induced autophagic flux blockage and gap junctional intercellular communication dysfunction in rat hepatocytes.

Cadmium (Cd) is a significant environmental contaminant known for its potential hepatotoxic effects. However, the precise mechanisms underlying Cd-induced hepatotoxicity have yet to be fully understood. Therefore, the purpose of this study was to investigate the dynamic role of connexin 43 (Cx43) in response to Cd exposure, particularly its impact on gap junctional intercellular communication (GJIC) and autophagy in hepatocytes. To establish an in vitro model of Cd-induced hepatocyte injury, the Buffalo rat liver 3A cell line (BRL3A) was utilized.In order to elucidate the mechanism by which Cx43 influences Cd-induced hepatocyte toxic injury, inhibitors of Cx43 (Dynasore) and P-Cx43 (Ro318220) were employed in the model. The findings revealed that inhibiting Cx43 and its phosphorylation further compromised GJIC function, exacerbating the impairment, while also intensifying the blockage of autophagic flux. To gain further insight into the role of Cx43, siRNA was utilized to knock down Cx43 expression, yielding similar results. The down-regulation of Cx43 expression was found to worsen the morphological damage induced by cadmium exposure, diminish the cell proliferation capacity of BRL3A cells, and exacerbate the disruption of GJIC and autophagic flow caused by Cd.These findings suggest that Cx43 may serve as a potential therapeutic target for the treatment of liver damage resulting from Cd exposure. By targeting Cx43, it may be possible to mitigate the adverse effects of Cd on hepatocytes.