Persistent activation of Nrf2 in a p62-dependent non-canonical manner aggravates lead-induced kidney injury by promoting apoptosis and inhibiting autophagy.

INTRODUCTION: Lead (Pb) is an environmental toxicant that poses severe health risks to humans and animals, especially renal disorders. Pb-induced nephrotoxicity has been attributed to oxidative stress, in which apoptosis and autophagy are core events. OBJECTIVES: Nuclear factor erythroid 2-related factor 2 (Nrf2) acts as a major contributor to counteract oxidative damage, while hyperactivation or depletion of Nrf2 pathway can cause the redox imbalance to induce tissue injury. This study was performed to clarify the function and mechanism of Nrf2 in Pb-triggered kidney injury. METHODS AND RESULTS: First, data showed that Pb exposure activates Nrf2 pathway in primary rat proximal tubular cells. Next, Pb-induced Nrf2 activation was effectively regulated by pharmacological modulation or siRNA-mediated knockdown in vitro and in vivo assays. Notably, Pb-triggered cytotoxicity, renal injury and concomitant apoptosis were improved by Nrf2 downregulation, confirming that Pb-induced persistent Nrf2 activation contributes to nephrotoxicity. Additionally, Pb-triggered autophagy blockage was relieved by Nrf2 downregulation. Mechanistically, we found that Pb-induced persistent Nrf2 activation is attributed to reduced Nrf2 ubiquitination and nuclear-cytoplasmic loss of Keap1 in a p62-dependent manner. CONCLUSIONS: In conclusion, these findings highlight the dark side of persistent Nrf2 activation and potential crosstalk among Pb-induced persistent Nrf2 activation, apoptosis and autophagy blockage in Pb-triggered nephrotoxicity.

Effects of Inorganic and Organic Manganese Supplementation on Growth Performance, Tibia Development, and Oxidative Stress in Broiler Chickens.

Manganese (Mn) is an essential trace element for broiler chickens; its deficiency causes tibial dyschondroplasia (TD) characterized by lameness and growth retardation. Inorganic and organic manganese sources are used in global poultry production, but there is a lack of systematic investigations to compare the bioavailability among them. In this study, 120 1-day-old Arbor Acres (AA) broilers were randomly divided into four groups (n = 30), i.e., control group (Mn sulfate, 60 mg/kg), Mn-D group (Mn deficiency, 22 mg/kg), Mn-Gly group (Mn glycinate, 60 mg/kg), and Mn-Pro group (Mn proteinate, 60 mg/kg). During the 42-day experiment, growth performance, tibial bone parameters, pathological index changes, serum biochemical changes, and oxidative stress indicators were evaluated. These results not only suggested that Mn plays a crucial role in the normal development of tibia and the maintenance of redox homeostasis in broilers, but also proved that organic Mn supplementation, especially Mn proteinate, improved the tibia development and the absorption efficiency, as well as overall oxidative stress status of broilers, suggesting that it had greater bioavailability than inorganic Mn. Thus, application of organic Mn source may be an effective way to reduce economic losses and resolve animal welfare concerns due to TD in commercial poultry farming.

Manganese deficiency induces avian tibial dyschondroplasia by inhibiting chondrocyte proliferation and differentiation.

Manganese (Mn) is an essential trace element for bone growth, and its deficiency has been shown to increase the incidence of leg abnormalities in fast-growing broilers, such as tibial dyschondroplasia (TD). Proliferation and differentiation of growth plate chondrocyte are critical for tibia development, but their roles in Mn deficiency-induced TD remains to be elucidated. Thirty 1-day-old Arbor Acres chicks were randomly divided into two groups and fed with control diet (60 mg Mn/kg diet) and Mn-deficiency diet (22 mg Mn/kg diet) for 42 days, respectively. Mn deficiency-induced TD model was successfully established and samples from proximal tibia metaphysis and growth plate were collected for assays. Pathological observation showed that Mn deficiency induced morphological abnormality and irregular arrangement of chondrocytes in proliferative and hypertrophic zone of tibial growth plate. Also, Mn deficiency decreased mRNA and protein expression levels of type II collagen and type X collagen in tibial growth plate, indicating the impairment of proliferating and hypertrophic chondrocytes. Moreover, down-regulated gene expression levels of Sox9, Tgf-ß, Ihh, Runx2, Mef2c and Bmp-2 were shown in tibial growth plate of Mn-deficiency group, demonstrating that Mn deficiency inhibited the transcription levels of key regulators to disrupt chondrocyte proliferation and differentiation. Collectively, these findings confirmed that Mn deficiency affected the proliferation and differentiation of chondrocytes in tibial growth plate via inhibiting related regulatory factors, leading to TD in broilers.

Supplementation with beta-1,3-glucan improves productivity, immunity and antioxidative status in transition Holstein cows.

Dairy cows undergo dramatic physiological changes during the transition from late pregnancy to early lactation, which make them vulnerable to metabolic stress and immune dysfunction. The objective of this study was to evaluate the effects of a commercial beta-1,3-glucan product (Aleta™, containing 50% beta-1,3-glucan) on productivity, immunity and antioxidative status in transition cows. Fifty-four multiparous Holstein cows received a control diet or a diet supplemented with 5 or 10 g of beta-1,3-glucan per cow per day from 21 days before expected calving to 21 days after parturition. Blood samples were collected at day -21, 1, and 21 relative to calving. Colostrum and milk were collected at day 1 and 21 after calving, respectively. Data showed that supplementation with beta-1,3-glucan had no effect on milk composition, but increased milk production. Beta-1,3-glucan treatment also improved the milk quality, as shown by reduced milk somatic cell count and increased immunoglobulin levels in colostrum. Notably, beta-1,3-glucan markedly reduced serum levels of pro-inflammatory cytokines and C-reactive protein, while elevated serum immunoglobulin levels, indicating its immunity enhancement in transition cows. Moreover, beta-1,3-glucan addition reduced the serum malondialdehyde level and enhanced the activities of serum superoxide dismutase and catalase, which enhanced the antioxidative capacity in transition cows. In summary, supplementation with beta-1,3-glucan improves productivity, immunity and antioxidative status in transition dairy cows.

Effects of beta-1,3-glucan supplementation on concentrations of serum metabolites in transition Holstein cows.

Objectives of this study were to evaluate the alleviating effects of a commercial beta-1,3-glucan product (Aleta, containing 50% beta-1,3-glucan, Kemin Industries) on metabolic stress in transition Holstein cows as reflected by circulating metabolites and enzymes. Fifty-four multiparous Holstein cows were randomly allocated to three groups with 18 cows each. Cows in each group received a commercial basal diet or the basal diet supplemented with Aleta calculated to supply 5 or 10 g of Aleta per cow per day. Blood samples were collected at day -21, 1, and 21 relative to calving for determination of serum triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDLC), very low density lipoprotein (VLDL), glucose, insulin, ß-hydroxybutyric acid (BHBA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamyl transpeptidase (GGT), and non-esterified fatty acid (NEFA). Supplementation with Aleta markedly elevated serum concentrations of TG, TC, HDLC, LDL-C and VLDL, implying its positive effect on lipid metabolism in transition dairy cows. Aleta treatment significantly decreased the serum concentrations of NEFA and BHBA, but markedly elevated the serum concentrations of glucose and insulin. Also, Aleta treatment significantly elevated the dry matter intake and milk production in postpartum cows, indicating the alleviating effect of Aleta on negative energy balance in transition cows. Moreover, Aleta treatment significantly reduced the serum activities of AST, ALT and GGT, indicating its hepatoprotective effect on transition cows. These results suggest that Aleta supplementation may help to improve fat metabolism disorder initiated by negative energy balance in transition dairy cows.