How incubation temperature affects hatchling performance in reptiles: an integrative insight based on plasticity in metabolic enzyme.

Evaluating the effects of temperature variations on animals plays an important role in understanding the threat of climate warming. The effects of developmental temperature on offspring performance are critical in evaluating the effects of warming temperatures on the fitness of oviparous species, but the physiological and biochemical basis of this developmental plasticity is largely unknown. In this study, we incubated eggs of the turtle Pelodiscus sinensis at low (24 °C), medium (28 °C), and high (32 °C) temperatures, and evaluated the effects of developmental temperature on offspring fitness, and metabolic enzymes in the neck and limb muscles of hatchlings. The hatchlings from eggs incubated at the medium temperature showed better fitness-related performance (righting response and swimming capacity) and higher activities of metabolic enzymes (hexokinase, HK; lactate dehydrogenase, LDH) than hatchlings from the eggs incubated at high or low temperatures. In addition, the swimming speed and righting response were significantly correlated with the HK activities in limb (swimming speed) and neck (righting response) muscles, suggesting that the developmental plasticity of energy metabolic pathway might play a role in determining the way incubation temperature affects offspring phenotypes. Integrating the fitness-related performance and the activities of metabolic enzymes, we predict that the P. sinensis from high latitude would not face the detrimental effects of climate warming until the average nest temperatures reach 32 °C.

Ano1 regulates embryo transport by modulating intracellular calcium levels in oviduct smooth muscle.

Oviductal smooth muscle exhibits spontaneous rhythmic contraction (SRC) and controls the passage of the ova at the exact time, but its mechanistic regulation remains to be determined. In this study, female mice with Ano1SMKO (smooth muscle-specific deletion of Ano1) had reduced fertility. Deficiency of Ano1 in mice resulted in impaired oviductal SRC function and reduced calcium signaling in individual smooth muscle cells in the oviduct. The Ano1 antagonist T16Ainh-A01 dose-dependently inhibited SRCs and [Ca2+]i in the oviducts of humans and mice. A similar inhibitory effect of SRCs and [Ca2+]i was observed after treatment with nifedipine. In our study, ANO1 acted primarily as an activator or amplifier in [Ca2+]i and contraction of tubal smooth muscle cells. We found that tubal SRC was markedly attenuated in patients with ectopic pregnancy. Then, our study was designed to determine whether chloride channel Ano1-mediated smooth muscle motility is associated with tubal SRC. Our findings reveal a new mechanism for the regulation of tubal motility that may be associated with abnormal pregnancies such as ectopic pregnancies.

Azoarene activation for Schmidt-type reaction and mechanistic insights.

The Schmidt rearrangement, a reaction that enables C-C or C-H σ bond cleavage and nitrogen insertion across an aldehyde or ketone substrate, is one of the most important and widely used synthetic tools for the installation of amides and nitriles. However, such a reaction frequently requires volatile, potentially explosive, and highly toxic azide reagents as the nitrogen donor, thus limiting its application to some extent. Here, we show a Schmidt-type reaction where aryldiazonium salts act as the nitrogen precursor and in-situ-generated cyclopenta-1,4-dien-1-yl acetates serve as pronucleophiles from gold-catalyzed Nazarov cyclization of 1,3-enyne acetates. Noteworthy is that cycloketone-derived 1,3-enyne acetates enabled ring-expansion relay to access a series of 2-pyridone-containing fused heterocycles, in which nonsymmetric cycloketone-derived counterparts demonstrated high regioselectivity. Aside from investigating the scope of this Schmidt-type reaction, mechanistic details of this transformation are provided by performing systematic theoretical calculations.

Coeloglossum viride Var. Bracteatum Extract Attenuates MPTP-Induced Neurotoxicity in vivo by Restoring BDNF-TrkB and FGF2-Akt Signaling Axis and Inhibiting RIP1-Driven Inflammation.

The tuber of Coeloglossum viride var. bracteatum is a Tibetan medicine that has been used for generations as a tonic for Yang and Qi, tranquilizing, to enhance intelligence and to promote longevity. We have previously characterized the constituents of Coeloglossum viride var. bracteatum extract (CE) and investigated its anti-Alzheimer's disease (AD) effect in mice models. However, the exact role of CE in Parkinson's disease (PD), especially the neurotrophic and inflammatory pathways regulated by CE, remains unknown. In this study, we investigated the anti-PD effects of CE in an MPTP-induced acute mouse model and its underlying mechanisms, focusing on BDNF, FGF2 and their mediated signaling pathways and RIP1-driven inflammatory signaling axis. Pole test and traction test were performed for behavioral analysis. RT-PCR, IHC and Western blotting were performed to assay the mRNA, tissues, and protein, respectively. We found that CE improved dyskinesia in MPTP-intoxicated mice, which was confirmed by the pole test and traction test. Also, oxidative stress and astrocyte activation and inflammation were alleviated. MPTP-intoxication disrupted the levels of BDNF, FGF2 and their mediated signaling pathways, triggered elevation of pro-inflammatory factors such as TNF-α, IL-1ß, and IL-6, and activated RIP1-driven inflammatory axis. However, CE restored the levels of BDNF, FGF2 and TrkB/Akt signaling pathways while inhibiting the RIP1-driven inflammatory signaling axis, thereby inhibiting apoptosis, preventing loss of nigrostriatal neurons, and maintaining cellular homeostasis. Thus, CE is a promising agent for the treatment of PD.

DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis.

The small molecule DAPT inhibits the Notch signaling pathway by blocking γ-secretase mediated Notch cleavage. Given the critical role of the Notch signaling axis in inflammation, we asked whether DAPT could block Notch-mediated inflammation and thus exert neuronal protection. We established a mouse model of chronic exposure to cadmium (Cd)-induced toxicity and treated it with DAPT. DAPT was effective in ameliorating Cd-induced multi-organ damage and cognitive impairment in mice, as DAPT restored abnormal performance in the Y-maze, forced swimming and Morris water maze (MWM) tests. DAPT also reversed Cd-induced neuronal loss and glial cell activation to normal as observed by immunofluorescence and immunohistochemistry of brain tissue sections. In addition, Cd-intoxicated mice showed significantly increased levels of the Notch/HES-1 signaling axis and NF-κB, as well as decreased levels of the inflammatory inhibitors C/EBPß and COP1. However, DAPT down regulated the elevated Notch/HES-1 signaling axis to normal, eliminating inflammation and thus protecting the nervous system. Thus, DAPT effectively eliminated the neurotoxicity of Cd, and blocking γ-secretase as well as Notch signaling axis may be a potential target for the development of neuronal protective drugs.

Astragalin attenuates AlCl3/D-galactose-induced aging-like disorders by inhibiting oxidative stress and neuroinflammation.

Astragalin (AST) is a natural flavonoid with excellent antioxidant and anti-inflammatory activities. However, whether AST is an effective chemical for neuronal protection and its underlying mechanisms remain to be elucidated. In this study, we established a mouse model of cognitive impairment and aging-like phenotype induced by sequential administration of AlCl3 and D-galactose (Gal). We found that AST effectively ameliorated cognitive impairment in the model mice and improved their learning and memory performance in the Morris water maze (MWM) test. AlCl3/Gal-induced activation of astrocytes and microglia and inflammation were observed by immunohistochemistry and immunofluorescence, but could be attenuated by AST. In addition, alterations in oxidative stress-regulating enzymes or markers, including T-SOD, T-AOC, CAT, GSH-Px, and MDA, as well as the pro-inflammatory factors TNF-α, IL-1ß, and IL-6, were restored. At the mechanistic level, AlCl3/Gal-intoxicated mice showed a significant elevation of Notch/HES-1 and NF-κB signaling axis corresponding to microglia activation and inflammation. AST attenuated the activation of Notch/HES-1 and NF-κB signaling axis, thus reducing the inflammation. In summary, AST is a promising natural product to protect neurons from toxin-induced injury, indicating its therapeutic potential for neurological disorders.

Salidroside alleviates cadmium-induced toxicity in mice by restoring the notch/HES-1 and RIP1-driven inflammatory signaling axis.

OBJECTIVE: Salidroside (SAL) is a marker glycoside of Rhodiola rosea with significant antioxidant, anti-inflammatory, and other health benefits. In this study, we determined its neuroprotective effects against Cd-induced toxicity in cultured cells and mice. MATERIALS AND METHODS: GL261 cell and Cd-intoxicated mouse model were used. ICP-MS and MWM were performed to measure Cd content and Cd-induced cognitive impairment in mice, respectively. RESULTS: SAL attenuated Cd toxicity in GL261 cells as well as protected mice from substantial organic damage and cognitive deficits. SAL treatment alleviated Cd-induced oxidative stress, glial cell activation, and elevation of pro-inflammatory factors including TNF-α, IL-1ß, and IL-6. Cd-induced cognitive deficits observed in the Morris water maze in mice were rescued by SAL. At the mechanistic level, SAL maintained the activity of antioxidant enzymes such as SOD and GSH-Px in the serum and brain, and scavenged the peroxidation product MDA, thereby restoring redox homeostasis in vivo, attenuating neuronal damage, and ultimately antagonized Cd-induced toxicity. Furthermore, Cd activated the RIP1-driven inflammatory signaling pathway and Notch/HES-1 signaling axis in the brain, leading to inflammation and neuronal loss, which could be attenuated by SAL. CONCLUSION: SAL is a natural product with good anti-Cd effects, indicating that Rhodiola rosea is promising plant that is worthy of cultivation for health and economic benefits.

Coeloglossum viride var. bracteatum extract attenuates Aß-induced toxicity by inhibiting RIP1-driven inflammation and necroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Tibetan ginseng named Wangla (tuber of Coeloglossum viride var. bracteatum) is a traditional tonic that has Yang-strengthening and qi-enhancing, tranquilizing, intelligence-enhancing and longevity-enhancing properties. It has been used to treat impotence, spermatorrhea, anemia and insomnia. Therefore, its characteristic components and neuronal modulating effects were studied. AIM OF THE STUDY: To investigate the elimination of Aß-induced toxicity by CE and to elucidate the molecular mechanisms involving BDNF, FGF2, and their related signaling axis, and the RIP1-driven inflammatory pathway. MATERIALS AND METHODS: We established Aß-induced toxicity models in cultured neurons and ICR mice, respectively. MWM and fear conditioning tests were performed for behavioral analysis of cognitive functions in mice. Western blot was used to investigate the levels of BDNF, FGF2, and their downstream effector TrkB/Akt/Bcl-2, as well as the RIP1-driven RIP1/RIP3/MLKL pathway. Immunofluorescence assay is used to examine the status of glial cells. RESULTS: CE abrogated Aß toxicity and inhibited apoptosis in cultured neurons, mainly by regulating the BDNF, FGF2, and TrkB/Akt signaling pathways as well as RIP1-driven inflammation and necroptosis. Similarly, mice injected intracerebrally with Aß exhibited cognitive deficits and had elevated oxidative stress and inflammatory factors detected in their serum and brain. However, CE-treated mice showed recovery of cognitive abilities and quelled levels of oxidative stress and inflammatory factors. Moreover, Aß toxicity led to a reduction in BDNF, FGF2, and related signaling regulators in the hippocampus and prefrontal cortex, accompanied by activation of RIP1-driven inflammatory signaling pathways, and a reduction in TBK1 and Bcl-2. However, CE restored the levels of BDNF, FGF2, and TrkB/Akt signaling pathway, while inhibiting RIP1-induced RIP1/RIP3/MLKL pathway, thereby antagonizing apoptosis and maintaining neuronal activity. CONCLUSIONS: CE effectively eliminated the toxicity of Aß in cultured neurons and mouse models, which holds promise for drug development.

Anti-osteoporosis effect of Semen Cuscutae in ovariectomized mice through inhibition of bone resorption by osteoclasts.

ETHNOPHARMACOLOGICAL RELEVANCE: Semen Cuscutae, called Tu-si-zi in Chinese, is a kind of dried mature seed in the Convolvulaceae family. It mainly distributes in China, Korea, Pakistan, Vietnam, India and Thailand. It is used as a kidney-tonifying drug for treatment of aging related diseases such as osteoporosis in traditional Chinese medicine. However, the exact mechanisms on bone resorption are poorly studied. AIM OF THE STUDY: The aim of this study was to investigate the potential effect of Semen Cuscutae on ovariectomy (OVX)-induced osteoporosis in mice and clarify the exact mechanisms by which Semen Cuscutae exert the anti-osteoporosis effect. MATERIALS AND METHODS: Qualitative and quantitative analyses of Semen Cuscutae were performed by UPLC-Q-TOF-MS and HPLC-MS/MS, respectively. Changes in bone mineral density (BMD) induced by OVX in mice were measured by dual-energy X-ray absorptiometry and micro-computed tomography (µCT). Tartrate-resistant acid phosphatase (TRAP) staining as well as hematoxylin and eosin (HE) staining were used to observe bone microarchitectural changes. ELISA kits were used to assess the therapeutic effects of Semen Cuscutae on the serum levels of osteoprotegerin (OPG), tartrate-resistant acid phosphatase 5b (TRACP-5b), and receptor activator of nuclear factor-κB (RANKL). The effect of Semen Cuscutae on primary cell viability was assessed using CCK-8 and anti-tartrate phosphatase assays. TRAP staining and actin ring staining were used to observe the effect of Semen Cuscutae on osteoclast differentiation. Western blotting was used to measure the effects of Semen Cuscutae on expressions of NFATC1, c-Src kinase, and c-fos. RESULTS: Results from UPLC-Q-TOF-MS showed that the main components of Semen Cuscutae were flavonoid compounds that included quercitrin, quercetin, hyperoside, caffeic acid, rutin, chlorogenic acid, luteolin, apigenin, kaempferol, isoquercetin, cryptochlorogenic acid, isorhamnetin-3-O-glucoside, and astragalin. After the Semen Cuscutae extract was orally administered to OVX mice, bone density increased (P < 0.01) and bone microstructure was significantly improved (P < 0.01 or 0.05). Additionally, Semen Cuscutae exhibited a significant descending effect in the levels of serum TRACP-5b and RANKL, while there was a significant increase in OPG in the Semen Cuscutae group compared with the OVX group, especially at high doses. Moreover, we found that increasing of c-fos, c-Src kinase, and NFATC1 protein expressions were reversed by Semen Cuscutae in vitro and in vivo. CONCLUSIONS: Our results showed that Semen Cuscutae exhibited anti-osteoporosis effects through the c-fos/c-Src kinase/NFATC1 signaling pathway.

Gisenoside Rg1 attenuates cadmium-induced neurotoxicity in vitro and in vivo by attenuating oxidative stress and inflammation.

OBJECTIVE: Gisenoside Rg1 is a potent neuroprotectant in ginseng. The aim of this study was to investigate the elimination effect of Rg1 on cadmium (Cd)-induced neurotoxicity. MATERIALS AND METHODS: A cumulative Cd exposure mouse model was established. Also, the toxicity of Cd and the protective effect of Rg1 were examined in vitro using cultured neurons and microglia. RESULTS: We found that Cd-intoxicated mice exhibited significant injury in the liver, kidney, small intestine, and testis, along with cognitive impairment. Antioxidant enzymes such as SOD, GSH-Px and CAT were reduced in the blood and brain, and correspondingly, the lipid peroxidation product MDA was elevated. In the brain, astrocytes and microglia were activated, characterized by an increase in inflammatory factors such as TNF-α, IL-1ß and IL-6, as well as their protein markers GFAP and IBA1. However, Rg1 eliminated Cd-induced toxicity and restored oxidative stress and inflammatory responses, correspondingly restoring the behavioral performance of the animals. Meanwhile, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the Rg1-mediated elimination of Cd-induced toxicity. CONCLUSION: Rg1 is a promising agent for the elimination of Cd-induced toxicity.

Coeloglossum viride var. bracteatum extract attenuates staurosporine induced neurotoxicity by restoring the FGF2-PI3K/Akt signaling axis and Dnmt3.

We previously demonstrated the antioxidant activity of Coeloglossum viride var. bracteatum extract (CE) in rat cortical neurons and in mice with chemically induced cognitive impairment. In this work, we established a staurosporine (STS)-induced toxicity model to decipher the neuroprotective mechanisms of CE. We found that CE protected cell viability and neurite integrity in STS-induced toxicity by restoring the levels of FGF2 and its associated PI3K/Akt signaling axis. LY294002, a pan-inhibitor of PI3K, antagonized the activity of CE, although its-mediated restoration of FGF2 was unaffected. In addition, CE restored levels of Bcl-2/Caspase-3, PKCα/CaM pathway, and Dnmt3a and Dnmt3b, two methyltransferases that contribute to de novo DNA methylation. The Dnmts inhibitor 5-azacytidine impaired CE-mediated restoration of Dnmt3 or CaM, as well as the transition of DNA methylation status on the Dnmt3 promoter. These results reveal potential mechanisms that could facilitate the study and application of CE as a neuroprotective agent.

Edaravone attenuates cadmium-induced toxicity by inhibiting oxidative stress and inflammation in ICR mice.

The neurotoxicity caused by cadmium (Cd) is well known in humans and experimental animals. However, there is no effective treatment for its toxicity. In this study, we established Cd toxicity models in cultured cells or mice to investigate the detoxification effect of edaravone (Eda). We found that Eda protected GL261 cells from Cd toxicity and prevented the loss of cell viability. In Cd-exposed mice, liver, kidney and testicular damage, as well as cognitive dysfunction were observed. Oxidative stress and inflammatory responses, such as decreased SOD and CAT, increased LDH and MDA, and abnormal changes in the inflammatory factors TNF-α, IL-1ß, IL-6 and IL-10 were detected in serum and brain tissue. Eda protected mice from Cd-induced toxicity and abrogated oxidative stress and inflammatory responses. Also, Eda prevented inflammatory activation of microglia and astrocytes and was accompanied by restoration of the neuronal marker protein MAP2, indicating restoration of neuronal function. In addition, the BDNF-TrkB/Akt and Notch/HES-1 signaling axes were involved in the response of Eda to the elimination of Cd toxicity. In conclusion, Eda does contribute to the clearance of Cd-induced toxicity.

Engaging yne-allenones in tunable catalytic silane-mediated conjugate transfer reductions.

New tunable catalytic [2+2] cycloaddition/silane-mediated conjugate transfer reductions of yne-allenones have been developed, by which substituent-diverse cyclobutarenes with generally good yields were selectively synthesized by adjusting Fe-H and Cu-H catalytic systems. Use of the Fe-H system triggers 1,6-conjugate reduction to dihydrocyclobuta[a]naphthalen-4-ols whereas the Cu-H complex enables 1,4-conjugate reduction to cyclobuta[a]naphthalen-4(2H)-ones.

Edaravone attenuates H2O2 or glutamate-induced toxicity in hippocampal neurons and improves AlCl3/D-galactose induced cognitive impairment in mice.

Edaravone (Eda) is a free radical scavenger used in clinical trials for the treatment of ischemic stroke and amyotrophic lateral sclerosis. However, how Eda exerts its neuroprotective effects remains to be elucidated. We investigated the neuroprotective effects of Eda in cultured hippocampal neurons and in a mouse model of AlCl3/D-galactose-induced cognitive impairment. Eda protected hippocampal neurons by eliminating H2O2 or glutamate-induced toxicity, leading to decreased cell viability and neurite shortening. Consistently, Eda restored impaired levels of BDNF, FGF2 and their associated signaling axes (including TrkB, p-Akt and Bcl-2) to attenuate neuronal death. In a mouse model of chemically-induced cognitive impairment, Eda restored the levels of BDNF, FGF2 and TrkB/Akt signaling axis to attenuate neuronal apoptosis, thereby ameliorating cognitive impairment. Meanwhile, the pro-inflammation was eliminated due to the restoration of pro-inflammatory factors such as TNF-α, IL-6, IL-1ß, and NOS2. In summary, Eda is an effective drug for protecting neurons from neurotoxic injury. BDNF, FGF2, and their regulated pathways may be potential therapeutic targets for neuroprotection.

Anti-perimenopausal osteoporosis effects of Erzhi formula via regulation of bone resorption through osteoclast differentiation: A network pharmacology-integrated experimental study.

ETHNOPHARMACOLOGICAL RELEVANCE: Erzhi formula (EZF) consists of Ecliptae herba (EH) and Fructus Ligustri Lucidi (FLL) at a ratio 1:1, and constitutes a well-known formula in China that is commonly used for treating menopausal diseases. AIM OF THE STUDY: In this study, we explored the pharmacologic actions and potential molecular mechanisms underlying EZF's action in preventing and treating osteoporosis. MATERIALS AND METHODS: The active components and related targets of EZF's anti-osteoporotic effects were predicted by network pharmacology, and functional enrichment analysis was also performed. We then used an osteoporosis model of ovariectomized (OVX) mice to detect the effects of EZF on osteoporosis. RESULTS: The results from network pharmacology identified a total of 10 active ingredients from EH and 13 active ingredients from FLL that might affect 65 potential therapeutic targets. GO enrichment analysis revealed that EZF affected bone tissue primarily via hormone (particularly estradiol)-related pathways and bone resorption by osteoclast differentiation. KEGG analysis demonstrated that bone-related factors such as Runt-related transcription factor 2 (Runx2), Ca2, estrogen receptor1 (ESR1), androgen receptors (AR), and TNFα served as the primary targets during osteoclastic differentiation. In vivo experiments showed that the formula significantly improved the diminution in estrogen and the subsequent uterine atrophy induced by ovariectomy (P < 0.01 or 0.05), implying that the EZF exerted its actions via regulation of estradiol and the nourishing effects of the uterus in OVX mice. Dual-energy X-ray absorptiometry and micro-CT showed that EZF significantly inhibited bone loss and improved bone micro-architecture by statistically increasing the number of bone trabeculae and decreasing the separation of bone trabeculae in OVX mice (P < 0.01 or 0.05); EZF also inhibited bone loss and enhanced bone-fracture load. Furthermore, we confirmed that EZF reduced the calcium concentrations, augmented protein and mRNA levels for Runx2 in the bone marrow, and reduced PPARγ levels. RANKL-a key downstream regulatory protein of many targets that was referred to in our results of network pharmacology as being involved in the regulation of osteoclastogenesis-was significantly diminished by EZF; it also elevated OPG content. In addition, we used monocytes of bone-marrow origin to detect the effects of the potential components of EZF on osteoclast differentiation and found that wedelolactone, oleanolic acid, echinocystic acid, luteolin, and luteolin-7-o-glucoside significantly inhibited osteoclast differentiation from monocytes induced by 25 ng/mL MCSF and 50 ng/mL RANKL (P < 0.01 or 0.05). CONCLUSIONS: Our present study indicated that EZF significantly inhibited the bone loss induced by OVX in mice by its regulation of estradiol combined with the nourishing effect of the uterus, and that it also attenuated bone resorption by decreasing the RANKL/OPG ratio so as to inhibit osteoclast maturation.

2,3,5,4'-tetrahydoxystilbene-2-O-ß-D-glucoside eliminates staurosporine-induced cytotoxicity by restoring BDNF-TrkB/Akt signaling axis.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside (THSG) is the major active ingredient in Plygonum multiflorum that displays a great deal of health-benefits including anti-oxidation, anti-hyperlipidemia, anti-cancer, anti-inflammation and neuroprotection. However, it is unclear whether THSG exerts neuroprotective functions by regulating neurotrophic factors and their associated signaling pathways. In this study, hippocampal neurons were challenged with staurosporine (STS) to establish a neural damage model. We found that STS-induced cytotoxicity introduced significant morphological collapse and initiating cell apoptosis, along with the down regulation of BDNF and TrkB/Akt signaling axis. In contrast, neurons pretreated with THSG showed resistance to STS-induced toxicity and maintained cell survival. THSG rescued STS induced dysfunctions of BDNF and its associated TrkB/Akt signaling, and restored the expression of Bcl-2 and Caspase-3. However, inhibition of TrkB activity by K252a or Akt signaling by LY294002 abolished the neuroprotective effects of THSG. Therefore, BDNF and TrkB/Akt signaling axis is a promise target for THSG mediated neuroprotective functions.

Edaravone protects rat astrocytes from oxidative or neurotoxic inflammatory insults by restoring Akt/Bcl-2/Caspase-3 signaling axis.

Astrocytes are the major glia cells in the central nervous system (CNS). Increasing evidence indicates that more than to be safe-guard and supporting cells for neurons, astrocytes play a broad spectrum of neuroprotective and pathological functions. Thus, they are compelling models to decipher mechanistic insights of glia cells to CNS insults and for the development of drugs. Edaravone is a free radical scavenger with the capacity to eliminate hydroxyl radicals and lipid peroxides. In this study, we examined the neuroprotective effects of edaravone in rat astrocytes challenged by hydrogen peroxide (H2O2) or bacterial lipopolysaccharides (LPS), respectively. We discovered that edaravone attenuated H2O2-induced oxidative stress by reactivating the Akt signaling axis and antagonistically restoring the expression of apoptosis associated regulators such as Bcl-2 and Caspase-3. Consistently, inhibition of Akt signaling by LY294002 attenuated the anti-oxidative activity of edaravone. In addition, edaravone mitigated LPS-induced morphological changes in astrocytes and alleviated the inflammatory activation and expression of TNF-α, IL-1ß, IL-6 and NOS2. In summary, our data suggested that edavarone effectively protects astrocytes from oxidative stress or infectious insults, which may pave a new avenue for its application in preclinical research and human disease therapeutics.

Tea polyphenols attenuate staurosporine-induced cytotoxicity and apoptosis by modulating BDNF-TrkB/Akt and Erk1/2 signaling axis in hippocampal neurons.

Tea polyphenols (TP) are the major ingredients in tea beverages that display health-benefits including anti-oxidation, anti-inflammation, anti-aging, attenuating blood pressure and deflating. In this study, we investigated the neuroprotective effects of TP to attenuate staurosporine (STS)-induced cytotoxicity. Rat hippocampal neurons were isolated, cultured and incubated with STS to induce neurite collapse and apoptosis, however, the medication of TP eliminated these adverse effects and maintained the morphology of neurons. STS decreased the expression of pro-BDNF, downregulated the TrkB/Akt/Bcl-2 signaling axis and promoted the activation of Erk1/2 and caspase-3. In contrast, TP rescued the expression of pro-BDNF and antagonistically restored the biochemistry of aforementioned signaling effectors. Consistently, the activity of TP can be attenuated by the inhibition of TrkB or Akt by small chemicals K252a and LY294002. Therefore, BDNF-TrkB and Akt signaling axis is essential for TP-mediated neuroprotective effects. In summary, TP showed beneficial effects to protect neurons from exogenous insults such as STS-induced neural cytotoxicity and cell death.

Ginsenoside Rg1 ameliorates the cognitive deficits in D-galactose and AlCl3-induced aging mice by restoring FGF2-Akt and BDNF-TrkB signaling axis to inhibit apoptosis.

Ginsenoside Rg1 is the main active ingredient of Panax ginseng with the activity of neuroprotective, antioxidant and strengthening the immune system. Therefore, we hypothesized that Rg1 may afford anti-aging effects although the mechanism remains to be elucidated. In this study, chemically induced aging mice were established by consecutive administration of D-galactose and AlCl3. We found that Rg1 effectively ameliorates spatial learning and memory deficits in aging mice demonstrated by their improved performance in step down avoidance tests and Morris water maze experiments. Rg1 restored aging-induced decline of FGF2 and BDNF, reactivated TrkB/Akt signaling pathways in the hippocampus and prefrontal cortex to inhibit apoptosis, for the expression of anti-apoptotic protein Bcl-2 and apoptosis promoting enzyme cleaved-Caspase3 were antagonistically restored. Therefore, these results established the anti-aging effects of Rg1, and FGF2, BDNF and associated signaling pathways might be promising targets. Our data may provide a new avenue to the pharmacological research and diet therapeutic role of ethnic products such as Rg1 in anti-aging and aging associated diseases.

Synthesis of Diastereoenriched α-Aminomethyl Enaminones via a Brønsted Acid-Catalyzed Asymmetric aza-Baylis-Hillman Reaction of Chiral N-Phosphonyl Imines.

An effective chiral GAP methodology for preparing α-aminomethyl enaminones through a (R)-CSA-catalyzed asymmetric aza-Baylis-Hillman reaction is reported. Excellent yields and high diastereoselectivity could be obtained under mild conditions and convenient GAP techniques. The confirmations of the absolute configuration of N-phosphonyl imine and chiral enaminone by X-ray diffraction provides an explicit explanation of the chirality mechanism for GAP chemistry.