Activation of α7nAChR by PNU282987 improves cognitive impairment through inhibiting oxidative stress and neuroinflammation in D-galactose induced aging via regulating α7nAChR/Nrf2/HO-1 signaling pathway.

Aging is an important risk factor for neurodegenerative diseases. The activation of α7 nicotinic acetylcholine receptor (α7nAChR) is involved in inflammation and cognition, but the specific role it plays in aging remains unknown. This study aimed to investigate the anti-aging effect of the activation of α7nAChR on aging rats and BV2 cells induced by D-galactose, as well as its potential mechanism. D-galactose induced an increase in the SA-ß-Gal positive cells, expression of p16 and p21 in vivo and in vitro. α7nAChR selective agonist PNU282987 decreased levels of pro-inflammatory factors, MDA, and Aß, enhanced SOD activity and levels of anti-inflammatory factor (IL10) in vivo. PNU282987 enhanced the expression of Arg1, decreased the expression of iNOS, IL1ß and TNFα in vitro. PNU282987 upregulated the levels of α7nAChR, Nrf2 and HO-1 in vivo and in vitro. The results of Morris water maze and novel object recognition tests showed that PNU282987 improved cognitive impairment in aging rats. Furthermore, α7nAChR selective inhibitor methyllycaconitine (MLA) results were opposite with PNU282987. PNU282987 improves cognitive impairment through inhibiting oxidative stress and neuroinflammation in D-galactose induced aging via regulating the α7nAChR/Nrf2/HO-1 signaling pathway. Therefore, targeting the α7nAChR may be a viable therapeutic approach for anti-inflammaging and neurodegenerative diseases.

S-adenosylmethionine improves cognitive impairment in D-galactose-induced brain aging by inhibiting oxidative stress and neuroinflammation.

Oxidative stress and neuroinflammation play crucial roles in aging. S-adenosylmethionine (SAM), a popular supplement, is a potential antioxidant and candidate therapy for depression. This study aimed to evaluate the neuroprotective effects of SAM on D-galactose-induced brain aging and explore its underlying mechanisms. Brain aging model was established with D-galactose (180 mg/kg/day) for 8 weeks. During the last 4 weeks, SAM (16 mg/kg) was co-administrated with D-galactose. Behavior tests were used to assess cognitive function and depression-like behaviors of rats. Results showed that cognitive impairment and depression-like behaviors were reversed by SAM. SAM reduced neuronal cell loss, increased brain-derived neurotrophic factor level in the hippocampus, inhibited amyloid-ß level and microglia activation, as well as pro-inflammatory factors levels in the hippocampus and serum. Further, SAM enhanced antioxidant capacity and attenuated cholinergic damage by reducing malondialdehyde levels, increasing acetylcholine levels, expression levels of α7 nicotinic acetylcholine receptor (α7nAChR), nuclear factor erythrocyte 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) in the hippocampus. Above all, SAM has a potential neuroprotective effect on ameliorating cognitive impairment in brain aging, which is related to inhibition of oxidative stress and neuroinflammation, as well as α7nAChR signals. DATA AVAILABILITY: Data will be made available on request.

SAM targeting methylation by the methyl donor, a novel therapeutic strategy for antagonize PFOS transgenerational fertilitty toxicity.

DNA methylation have been suggested as possible mediators of long-term health effects of environmental stressors. This study aimed to evaluate the potential therapy of methylation of S-adenosyl-l-methionine (SAM) on PFOS induced trangeneral reproductive toxicity. In this study, postnatal 5d Sprague Dawley rats were randomly divided into four groups: control, PFOS, PFOS + SAM, and PFOS + Decitabine (DAC). The F0 rats were exposed to 5 mg/kg PFOS and SAM or DAC until PND60. The development of the offsprings were monitored without PFOS exposure. The fertility in F0, F1 rats, and change in F1 testes were observed. The results were as follows. The significant increase in F0 pregnancy rate, and survival rate in F1 offspring in PFOS + SAM relative to PFOS group were observed. Changes of birth weights and physical development in F1 offspring with SAM were approached as a corresponding variation of the control after the deparation period. No pregnant in F1 maternal rats in the PFOS and DAC groups were found, but pregnant in the SAM group. Significantly decrease in the percentage of abnormal seminiferous tubules and increase in expression of promyelocytic leukemia zinc finger (PLZF+) spermatogonial stem cells in F1 testis compared with the PFOS group. Taken together, Methyl donor SAM improve PLZF + spermatogonia stem cell proliferation, attenuate damage in testicular tissue structure, which subsequently improve the transgenerational growth retard and infertility induced by PFOS chronic stress.

Roles of lncRNA UCA1-miR-18a-SOX6 axis in preventing hypoxia injury following cerebral ischemia.

The present study aimed to elucidate the roles and possible molecular mechanisms of long noncoding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) in neuronal pheochromocytoma (PC)-12 cells under hypoxic conditions. The neuronal PC-12 cells were exposed to hypoxic and normoxic conditions followed by the measurement of the expression of lncRNA UCA1. In addition, the cells were transfected with short hairpin RNAs (sh-RNAs) against UCA1 (sh-UCA1), SOX6 (sh-SOX6), negative control (sh-NC), pEX-SOX6, pEX, miR-18a mimic, mimic NC, miR-18a inhibitor, and inhibitor NC. Under different treatments of transfection, cell viability and migration and invasion potential were analyzed. In addition, the induction of apoptosis was investigated by studying the expression profiles of apoptosis-related proteins. Hypoxia treatment significantly enhanced the expression of UCA1, which in turn induced injury in PC-12 cells characterized by the inhibition of cell viability, the reduction in migration and invasion potential, and the promotion of cell apoptosis. Moreover, the suppression of UCA1 alleviated the hypoxia injury. In addition, the relationship between UCA1 and miR-18a and between miR-18a and SRY-box containing gene 6 (SOX6) were explored. MiR-18a was found to be a direct target of UCA1, an upregulation of which mediated the effects of suppression of UCA1 (alleviated hypoxic injury). Besides, SOX6 was found to be a target of miR-18a whose expression could be negatively regulated by miR-18a. An overexpression of SOX6 could also aggravate hypoxia injury in PC-12 cells, whereas a knockdown of SOX6 exhibited contrary results. Our findings indicated that the down-regulation of UCA1 promoted the expression of miR-18a that led to a reduction in the expression of its target protein, SOX6, thereby contributing to the hypoxia injury following cerebral ischemia.

Effect of Lycium bararum polysaccharides on methylmercury-induced abnormal differentiation of hippocampal stem cells.

The aim of the present study was to observe the effects of a general extract of Lycium bararum polysaccharides (LBPs) on methylmercury (MeHg)-induced damage in hippocampus neural stem cells (hNSCs). The hippocampal tissues of embryonic day 16 Sprague-Dawley rats were extracted for the isolation, purification and cloning of hNSCs. Following passage and proliferation for 10 days, the cells were allocated at random into the following groups: Control, LBPs, MeHg and MeHg + LBPs. MTT and microtubule-associated protein 2 (MAP-2)/glial fibrillary acidic protein/Hoechst immunofluorescence tests were performed to detect the differentiation and growth of hNSCs in the various groups. The differentiation rate of MeHg-treated hNSCs and the perimeter of MAP-2-positive neurons were 3.632±0.63% and 62.36±5.58 µm, respectively, significantly lower compared with the control group values of 6.500±0.81% and 166±8.16 µm (P<0.05). Furthermore, the differentiation rate and the perimeter of MAP-2-positive neurons in LBPs groups cells was 7.75±0.59% and 253.3±11.21 µm, respectively, significantly higher compared with the control group (P<0.05). The same parameters in the MeHg + LBPs group were 5.92±0.98% and 111.9±6.07 µm, respectively, significantly higher than the MeHg group (P<0.05). The astrocyte differentiation rates in the MeHg and MeHg + LBPs group were 41.19±2.14 and 34.58±1.70, respectively (P<0.05). These results suggest that LBPs may promote the generation and development of new neurons and inhibit the MeHg-induced abnormal differentiation of astrocytes. Thus, LBPs may be considered to be a potential new treatment for MeHg-induced neurotoxicity in hNSCs.

MeHg Suppressed Neuronal Potency of Hippocampal NSCs Contributing to the Puberal Spatial Memory Deficits.

Hippocampal neurogenesis-related structural damage, particularly that leading to defective adult cognitive function, is considered an important risk factor for neurodegenerative and psychiatric diseases. Normal differentiation of neurons and glial cells during development is crucial in neurogenesis, which is particularly sensitive to the environmental toxicant methylmercury (MeHg). However, the exact effects of MeHg on hippocampal neural stem cell (hNSC) differentiation during puberty remain unknown. This study investigates whether MeHg exposure induces changes in hippocampal neurogenesis and whether these changes underlie cognitive defects in puberty. A rat model of methylmercury chloride (MeHgCl) exposure (0.4 mg/kg/day, PND 5-PND 33, 28 days) was established, and the Morris water maze was used to assess cognitive function. Primary hNSCs from hippocampal tissues of E16-day Sprague-Dawley rats were purified, identified, and cloned. hNSC proliferation and differentiation and the growth and morphology of newly generated neurons were observed by MTT and immunofluorescence assays. MeHg exposure induced defects in spatial learning and memory accompanied by a decrease in number of doublecortin (DCX)-positive cells in the dentate gyrus (DG). DCX is a surrogate marker for newly generated neurons. Proliferation and differentiation of hNSCs significantly decreased in the MeHg-treated groups. MeHg attenuated microtubule-associated protein-2 (MAP-2) expression in neurons and enhanced the glial fibrillary acidic protein (GFAP)-positive cell differentiation of hNSCs, thereby inducing degenerative changes in a dose-dependent manner. Moreover, MeHg induced deficits in hippocampus-dependent spatial learning and memory during adolescence as a consequence of decreased generation of DG neurons. Our findings suggested that MeHg exposure could be a potential risk factor for psychiatric and neurodegenerative diseases.

Effects of Methyl Mercury Chloride on Rat Hippocampus Structure.

The objective of this study is to investigate the impacts of Methyl Mercury Chloride (MMC) on cognitive functions and ultrastructural changes of hippocampus in Sprague Dawley (SD) rats. Thirty healthy 20-day-old male SD rats weighing 30-40 g were randomly divided into three groups to receive daily injections. Two different dose levels were used: 4 mg/kg as high dose (H-MMC) and 2 mg/kg as low dose (L-MMC).The control group received 4 mg/kg saline solution (N-NaCl). After daily subcutaneous injection for 50 days, 6-day Morris water maze tests were used to assess the learning and memory functions of the rats. After a 5-day continuous training, spatial probe tests were conducted of times and paths crossing to the target quadrant on the 6th day. After the rats were euthanized, their hippocampus sections were stained with hematoxylin and eosin and analyzed under bothoptical microscope and electron microscope. The time H-MMC group spent in finding platform was significantly longer as compared toN-NaCl group on day 2 to day 5 and L-MMC group on day 4 to day 5. The number of crossing times of H-MMC group to the target quadrant was 0.63 ± 0.74, which is much lower than C-NaCl group (3.13 ± 1.56) with P value <0.05. No statistically significant difference in crossing times was found between L-MMC and C-NaCl groups. For H-MMC group, decreasing number of neurons and disorganized nerve cells were examined under light microscope. Swelling and dissolution of Golgi complex were examined under electron microscope, along with endoplasmic reticulum expansion and cytoplasmic edema. Mild cytoplasmic edema was found in L-MMC group. MMC can cause cognitive impairment in terms of learning and memory in SD rats. Additionally, it can also cause changes in the ultrastructure of neurons and morphological changes in the hippocampus, causing significant damage.

Methylmercury chloride damage to the adult rat hippocampus cannot be detected by proton magnetic resonance spectroscopy.

Previous studies have found that methylmercury can damage hippocampal neurons and accordingly cause cognitive dysfunction. However, a non-invasive, safe and accurate detection method for detecting hippocampal injury has yet to be developed. This study aimed to detect methylmercury-induced damage on hippocampal tissue using proton magnetic resonance spectroscopy. Rats were given a subcutaneous injection of 4 and 2 mg/kg methylmercury into the neck for 50 consecutive days. Water maze and pathology tests confirmed that cognitive function had been impaired and that the ultrastructure of hippocampal tissue was altered after injection. The results of proton magnetic resonance spectroscopy revealed that the nitrogen-acetyl aspartate/creatine, choline complex/creatine and myoinositol/creatine ratio in rat hippocampal tissue were unchanged. Therefore, proton magnetic resonance spectroscopy can not be used to determine structural damage in the adult rat hippocampus caused by methylmercury chloride.