Rational Design of Gd-DOTA-Type Contrast Agents for Hepatobiliary Magnetic Resonance Imaging.

The safety risks of gadolinium (Gd3+)-based contrast agents (GBCAs) arise from their inevitable leakage of Gd3+, and the pursuit of more stable GBCAs for magnetic resonance imaging (MRI) has drawn increasing attention. Yet, Gd-EOB-DTPA and Gd-BOPTA are the only two authorized GBCAs for liver diagnosis in spite of their weak stability. In this study, one of the pendent arms of the most inert commercial Gd-DOTA was decorated with phenyl moieties, in which obvious enhancements of both kinetic and thermodynamic stability were achieved. Gd-L4 with a para-substituted OBn group was observed with ready hepatocellular uptake, with significant contrast provided in diagnosing orthotopic hepatocellular carcinoma, and its hepatobiliary secretion accounted for more than 50% of the injection dose in mice. In this study, Gd-L4 was found with comparable performance in liver MRI diagnosis to that of commercial Gd-EOB-DTPA and was thus deemed as an ideal candidate for further clinical applications.

Phosphorylation of 17ß-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice.

17ß-hydroxysteroid dehydrogenase-13 is a hepatocyte-specific, lipid droplet-associated protein. A common loss-of-function variant of HSD17B13 (rs72613567: TA) protects patients against non-alcoholic fatty liver disease with underlying mechanism incompletely understood. In the present study, we identify the serine 33 of 17ß-HSD13 as an evolutionally conserved PKA target site and its phosphorylation facilitates lipolysis by promoting its interaction with ATGL on lipid droplets. Targeted mutation of Ser33 to Ala (S33A) decreases ATGL-dependent lipolysis in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Importantly, a transgenic knock-in mouse strain carrying the HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops hepatic steatosis with reduced lipolysis and increased inflammation. Moreover, Hsd17B1333A/A mice are more susceptible to high-fat diet-induced nonalcoholic steatohepatitis. Finally, we find reproterol, a potential 17ß-HSD13 modulator and FDA-approved drug, confers a protection against nonalcoholic steatohepatitis via PKA-mediated Ser33 phosphorylation of 17ß-HSD13. Therefore, targeting the Ser33 phosphorylation site could represent a potential approach to treat NASH.

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.

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.

A responsive fluorescent probe for detecting and imaging pyruvate kinase M2 in live cells.

In this study, we designed and tested fluorescent probe zy-2 for specific and responsive imaging of pyruvate kinase M2 (PKM2), which can be excited by 419 nm light. A 17-fold enhancement in the responsive emission upon zy-2's binding to PKM2 was observed, imaging of which was successfully recorded in a time- and concentration-dependent manner in PKM2-positive cells. Thus, we obtained a responsive fluorescent probe for the specific and sensitive detection of PKM2, which is innovative in design and applicable to the detection of cancer cells.

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.

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.

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.

ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins.

Zinc transporter 8 (ZnT8) is an important zinc transporter highly expressed in pancreatic islets. Deficiency of ZnT8 leads to a marked decrease in islet zinc, which is thought to prevent liver diseases associated with oxidative stress. Herein, we aimed to investigate whether loss of islet zinc affects the antioxidant capacity of the liver and acute drug-induced liver injury. To address this question, we treated ZnT8 knockout (KO) or wild-type control mice with 300 mg/ kg acetaminophen (APAP) or phosphate-buffered saline (PBS). Unexpectedly, we found that loss of ZnT8 in mice ameliorated APAP-induced injury and was accompanied by inhibition of c-Jun N-terminal kinase (JNK) activation, reduced hepatocyte death, and decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). An increase in hepatic glutathione (GSH) was observed, corresponding to a decrease in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. APAP-induced inflammation and glycogen depletion were alleviated. In contrast, no significant changes were observed in cytochrome P450 family 2 subfamily E member 1 (CYP2E1), the main enzyme responsible for drug metabolism. Elevated levels of hepatic zinc and metallothionein (MT) were also observed, which may contribute to the hepatoprotective effect in ZnT8 KO mice. Taken together, these results suggest that ZnT8 deficiency protects the liver from APAP toxicity by attenuating oxidative stress and promoting hepatocyte proliferation. This study provides new insights into the functions of ZnT8 and zinc as key mediators linking pancreatic and hepatic functions.

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.

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.

Targeting Mitochondrial Metabolism and RNA Polymerase POLRMT to Overcome Multidrug Resistance in Cancer.

Clinically, the prognosis of tumor therapy is fundamentally affected by multidrug resistance (MDR), which is primarily a result of enhanced drug efflux mediated by channels in the membrane that reduce drug accumulation in tumor cells. How to restore the sensitivity of tumor cells to chemotherapy is an ongoing and pressing clinical issue. There is a prevailing view that tumor cells turn to glycolysis for energy supply due to hypoxia. However, studies have shown that mitochondria also play crucial roles, such as providing intermediates for biosynthesis through the tricarboxylic acid (TCA) cycle and a plenty of ATP to fuel cells through the complete breakdown of organic matter by oxidative phosphorylation (OXPHOS). High OXPHOS have been found in some tumors, particularly in cancer stem cells (CSCs), which possess increased mitochondria mass and may be depends on OXPHOS for energy supply. Therefore, they are sensitive to inhibitors of mitochondrial metabolism. In view of this, we should consider mitochondrial metabolism when developing drugs to overcome MDR, where mitochondrial RNA polymerase (POLRMT) would be the focus, as it is responsible for mitochondrial gene expression. Inhibition of POLRMT could disrupt mitochondrial metabolism at its source, causing an energy crisis and ultimately eradicating tumor cells. In addition, it may restore the energy supply of MDR cells to glycolysis and re-sensitize them to conventional chemotherapy. Furthermore, we discuss the rationale and strategies for designing new therapeutic molecules for MDR cancers by targeting POLRMT.

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.

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.

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.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside Restores BDNF-TrkB and FGF2-Akt Signaling Axis to Attenuate Stress-induced Depression.

Depression is a long term inhibitory mood that heavily disabled human beings. We have previously demonstrated anti-depression effect of 2,3,5,4'-tetrahydroxystilbene-2-O-ß-d-glucoside (THSG) in chronic-restraint stress (CRS) induced depressive-like mice by restoring the oxidative pathway and neuroinflammation. In this study, we examine the conditions of neurotrophins in CRS-induced depressive-like mice and whether THSG could be an antidepressant by ameliorating the neurotrophins and their associated signaling axis. CRS produced downregulation of antioxidants, the decline of brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and associated signaling regulators in the hippocampus and prefrontal cortex, corresponding to the behavioral inability and anhedonia. Administration of THSG restored the expression of antioxidants and neurotrophins BDNF, FGF2. Besides, THSG recovered the Akt signaling pathway and antagonistically restored the expression of Bcl-2 and cleaved-caspase-3 to inhibit apoptosis. Consistently, behavioral performances were recovered from CRS-induced motor inability and anhedonia. In summary, THSG is effective to attenuate stress-induced depression by ameliorating the biochemistry of neurotrophins and their related signaling pathways. These results may provide an avenue to take BDNF as a target to explore folk medicine for anti-depression.

Deciphering structure, function and mechanism of lysine acetyltransferase HBO1 in protein acetylation, transcription regulation, DNA replication and its oncogenic properties in cancer.

HBO1 complexes are major acetyltransferase responsible for histone H4 acetylation in vivo, which belongs to the MYST family. As the core catalytic subunit, HBO1 consists of an N-terminal domain and a C-terminal MYST domain that are in charge of acetyl-CoA binding and acetylation reaction. HBO1 complexes are multimeric and normally consist of two native subunits MEAF6, ING4 or ING5 and two kinds of cofactors as chromatin reader: Jade-1/2/3 and BRPF1/2/3. The choices of subunits to form the HBO1 complexes provide a regulatory switch to potentiate its activity between histone H4 and H3 tails. Thus, HBO1 complexes present multiple functions in histone acetylation, gene transcription, DNA replication, protein ubiquitination, and immune regulation, etc. HBO1 is a co-activator for CDT1 to facilitate chromatin loading of MCM complexes and promotes DNA replication licensing. This process is regulated by mitotic kinases such as CDK1 and PLK1 by phosphorylating HBO1 and modulating its acetyltransferase activity, therefore, connecting histone acetylation to regulations of cell cycle and DNA replication. In addition, both gene amplification and protein overexpression of HBO1 confirmed its oncogenic role in cancers. In this paper, we review the recent advances and discuss our understanding of the multiple functions, activity regulation, and disease relationship of HBO1.