β-amyloid (Aβ) peptides play an important role in cognition deficits, neuroinflammation, and apoptosis observed in Alzheimer's disease (AD). Activation of cyclic AMP (cAMP) signalling enhances memory and inhibits inflammatory and apoptotic responses. However, it is not known whether inhibition of phosphodiesterase-4 (PDE4), a critical controller of intracellular cAMP concentrations, affects AD-associated neuroinflammatory and apoptotic responses and whether these responses contribute to deficits of memory mediated by cAMP signalling. We addressed these issues using memory tests and neurochemical measures. Specifically, rats microinfused with aggregated Aβ25-35 (10 μg/side) into bilateral CA1 subregions displayed deficits in learning ability and memory, as evidenced by decreases in escape latency during acquisition trials and exploratory activities in the probe trial in the water-maze task and 24-h retention in the passive avoidance test. These effects were reversed by rolipram (0.1, 0.25 and 0.5 mg/kg.d i.p.), a prototypic PDE4 inhibitor, in a dose-dependent manner. Interestingly, Aβ25-35-treated rats also displayed decreases in expression of phosphorylated cAMP response-element binding protein (pCREB) and Bcl-2, but increases in expression of NF-κB p65 and Bax in the hippocampus; these effects were also reversed by rolipram in a dose-dependent manner. Similar neurochemical results were observed by replacing Aβ25-35 with Aβ1-42, a full-length amyloid peptide that quickly forms toxic oligomers. These results suggest that PDE4 inhibitors such as rolipram may reverse Aβ-induced memory deficits at least in part via the attenuation of neuronal inflammation and apoptosis mediated by cAMP/CREB signalling. PDE4 could be a target for treatment of memory loss associated with AD.

Ferroptosis plays a role in several diseases such as iron overload-induced liver diseases. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. Numerous antioxidants have been identified to control ferroptosis but the cell-autonomous mechanisms responsible for regulating ferroptosis remain elusive. In the present study, we found that iron overload promoted ferroptosis in hepatocytes by excessively inducing HO-1 expression, which contributed to the progression of liver injury and fibrosis, accompanied by the upregulation of the FGF21 protein level in vitro and in vivo. Interestingly, both recombinant FGF21 and Fgf21 overexpression significantly protected against iron overload-induced hepatocytes mitochondria damage, liver injury and fibrosis by inhibiting ferroptosis. In contrast, the loss of FGF21 aggravated iron overload-induced ferroptosis. Notably, FGF21-induced HO-1 inhibition (via the promotion of HO-1 ubiquitination and degradation) and NRF2 activation provide a mechanistic explanation for this phenomenon. Taken together, we identified FGF21 as a novel ferroptosis suppressor. Thus, FGF21 activation may provide an effective strategy for the potential treatment of iron overload-induced ferroptosis-related diseases, such as hereditary haemochromatosis (HH).

We investigated the effects of dietary supplementation with Bacillus subtilis PB6 ( B. subtilis PB6) during late gestation and lactation on sow reproductive performance, antioxidant indices, and gut microbiota. A total of 32 healthy Landrace × Yorkshire sows on d 90 of gestation were randomly assigned to 2 groups, with 16 replicates per group, receiving basal diet (CON) or the basal diet + 0.2% B. subtilis PB6, containing 4.0 × 10 8 CFU/kg of feed (BS). The litter sizes (total born) and numbers of piglets born alive were larger in the BS group ( P < 0.01), whereas the weights of piglets born alive and the piglet birth intervals were lower in the BS group ( P < 0.05). Although the litter weights and piglet bodyweights (after cross-fostering) were lower after BS treatment ( P < 0.05), the litter sizes, litter weights, lactation survival rate, and litter weight gains at weaning were higher in BS group ( P < 0.05). The concentrations of malondialdehyde (MDA) in the sow sera at parturition were lower in the BS group ( P < 0.01). The serum total antioxidant capacity (T-AOC) at parturition and the serum catalase (CAT) concentrations on d 21 of lactation were higher in the BS group ( P < 0.05). Dietary supplementation with B. subtilis PB6 ( P < 0.05) reduced the serum endotoxin concentrations in the sows and the serum cortisol concentrations of the piglets at d 14 of lactation. The α-diversity indices of microbial were higher in the CON group ( P < 0.05). At the phylum level, B. subtilis PB6 supplementation increased the relative abundances of Gemmatimonadete and Acidobacteria (both P < 0.01) and reduced those of Proteobacteria, and Actinobacteria (both P < 0.05). At the genus level, B. subtilis PB6 supplementation increased the relative abundance of Ruminococcaceae_UCG-013 cc ( P < 0.05) and reduced that of Streptococcus ( P < 0.05). This study demonstrated that adding 4.0 × 10 8 CFU/kg B. subtilis PB6 to sows’ feed during late gestation and lactation could shorten piglet birth intervals, enhance the growth performance of suckling piglets, and improve the gut health of sows during late gestation.

Background Global consumption of protein per capita is rising, while rates of infertility are increasing. However, a clear relationship between protein intake and reproductive health has not been demonstrated. The activation of the quiescent primordial follicles is the first step of folliculogenesis, and their activation must be tightly controlled to prevent premature exhaustion of the ovarian follicular reserve. Methods The primordial follicle reserve of wild-type or liver-specific ablation of fibroblast growth factor 21 (FGF21) in mice, subjected to limited or excessive protein diets or oral gavage test, were detected in vivo. Mouse ovary organ cultures were used to examine the direct role of metabolites or metabolic hormones on primordial follicle activation. Findings Mouse primordial follicle activation, was reduced by restricted protein intake and was accelerated by excessive protein intake, in an ovarian mTORC1 signaling-dependent manner. Furthermore, restricted or excessive protein intake resulted in an augmentation or decline of oocyte number and fertility at older age, respectively. Liver-specific ablation of FGF21, which resulted in a reduction of 87% in circulating FGF21, abrogated the preserving effect of low-protein intake on primordial follicle pool. Interestingly, FGF21 had no direct effect on the activation of primordial follicles, but instead required an adipokine adiponectin. Moreover, AdipoRon, an oral adiponectin receptor agonist, prevented the over-activation effect of excessive protein intake on primordial follicle activation. Interpretation Dietary protein consumption controlled ovarian primordial follicle reserve and fertility, which required coordination between FGF21 and adiponectin. Fund (Grant 31772616).