Triptonide induces apoptosis and inhibits the proliferation of ovarian cancer cells by activating the p38/p53 pathway and autophagy.

Ovarian cancer is a common malignant tumor in women, and 70 % of ovarian cancer patients are diagnosed at an advanced stage. Drug chemotherapy is an important method for treating ovarian cancer, but recurrence and chemotherapy resistance often lead to treatment failure. In this study, we screened 10 extracts of Tripterygium wilfordii, a traditional Chinese herb, and found that triptonide had potent anti-ovarian cancer activity and an IC50 of only 3.803 nM against A2780 cell lines. In addition, we determined that triptonide had a better antitumor effect on A2780 cell lines than platinum chemotherapeutic agents in vitro and that triptonide had no significant side effects in vivo. We found that triptonide induced apoptosis in ovarian cancer cells through activation of the p38/p53 pathway and it also induced cell cycle arrest at the S phase. In addition, we demonstrated that triptonide could activate lethal autophagy, which led to growth inhibition and cell death in ovarian cancer cells, resulting in an anti-ovarian cancer effect. Triptonide exerts its anti-ovarian cancer effect through activation of the p38/p53 pathway and induction of autophagy to promote apoptosis, which provides a new candidate drug and strategy for the treatment of ovarian cancer.

Astaxanthin Improved the Cognitive Deficits in APP/PS1 Transgenic Mice Via Selective Activation of mTOR.

Astaxanthin (Ast) is an effective neuroprotective and antioxidant compound used to treat Alzheimer's disease (AD); however, the underlying in vivo molecular mechanisms remain unknown. In this study, we report that Ast can activate the mammalian target of rapamycin (mTOR) pathway in the 8-month-old APP/PS1 transgenic mouse model of AD. Our results suggest that Ast could ameliorate the cognitive defects in APP/PS1 mice by activating the mTOR pathway. Moreover, mTOR activation perturbed the mitochondrial dynamics, increased the synaptic plasticity after 21 days of treatment with Ast (10 mg/kg/day), and increased the expression of Aß-degrading enzymes, mitochondrial fusion, and synapse-associated proteins and decreased the expression of mitochondrial fission proteins. Intraperitoneal injection of the mTOR inhibitor, rapamycin, abolished the effects of Ast. In conclusion, Ast activates the mTOR pathway, which is necessary for mitochondrial dynamics and synaptic plasticity, leading to improved learning and memory. Our results support the use of Ast for the treatment of cognitive deficits. Graphical abstract In summary, Ast ameliorates cognitive deficits via facilitating the mTOR-dependent mitochondrial dynamics and synaptic damage, and reducing Aß accumulation. This model supports the use of Ast for the treatment of cognitive deficits.

The Secretion from Bone Marrow Mesenchymal Stem Cells Pretreated with Berberine Rescues Neurons with Oxidative Damage Through Activation of the Keap1-Nrf2-HO-1 Signaling Pathway.

Oxidative stress is a potential pathological mechanism of Alzheimer's disease (AD). Berberine (BBR) can improve antioxidative capacity and inhibit Aß protein aggregation and tau protein hyperphosphorylation in AD, and stem cell therapy is also increasingly recognized as a therapy for AD. Bone marrow mesenchymal stem cells (BMSCs) have many advantages, as they exhibit antioxidant and anti-inflammatory activity and secrete a variety of neurotrophic factors, and play important roles in neurodegenerative disease treatment. In this study, we investigated the antioxidant effects of secretions from BMSCs pretreated with BBR on tert-butyl hydroperoxide (t-BHP)-damaged neurons. We demonstrated that BBR can enhance BMSC viability and the secretion of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), both of which are vital neurotrophic factors that maintain neuronal growth. Moreover, conditioned medium from BBR-treated BMSCs (BBR-BMSC-CM) reduced reactive oxygen species (ROS) production, attenuated a decrease in the mitochondrial membrane potential, and ameliorated neuronal apoptosis by decreasing levels of the apoptotic proteins Bax/Bcl-2, cytochrome c, and cleaved caspase-3/caspase-3. In addition, increased synaptophysin (SYP) and postsynaptic density protein 95 (PSD95) levels indicated that neuronal synaptic function was restored. Further study revealed that BBR-BMSC-CM activated the antioxidant proteins Keap1, Nrf2, and HO-1. In conclusion, our results showed that BBR-BMSC-CM attenuated apoptosis and oxidative damage in neurons by activating the Keap1-Nrf2-HO-1 signaling pathway. Taken together, these results also suggest BBR as a drug to stimulate the secretion of nutritional cytokines with the potential to treat AD.

Delivery of exogenous proteins by mesenchymal stem cells attenuates early memory deficits in a murine model of Alzheimer's disease.

A promising intervention for Alzheimer's disease (AD) would ideally target key pathological factors that are involved in AD pathogenesis. Soluble factors produced by engrafted mesenchymal stem cells (MSCs) mediate potential therapeutic effects in AD. However, these therapeutic benefits are largely hampered by the limited paracrine capacity of MSCs. In this study, we used adenovirus-mediated gene transduction of bone marrow MSCs to deliver exogenous proteins into the brain of APPswe/PSEN1dE9 (APP/PS1) mice in the early stage of impairment. We observed that engrafted MSCs carrying exogenous (C-X3-C motif) ligand 1 (CX3CL1) alone reduced the production of the inflammatory cytokine TNF-ɑ and improved synapse-related protein expression but not cognitive function. Transplantation of MSCs carrying CX3CL1 and Wnt3a (CX3CL1-Wnt3a-MSC) significantly attenuated the learning and memory impairment when compared with a control group. The improvement of neurobehavioral functions in APP/PS1 mice treated with CX3CL1-Wnt3a-MSC was related to the inhibition of microglial neurotoxicity and promotion of hippocampal neurogenesis. Transplantation of CX3CL1-Wnt3a-MSC also regulated phosphoinositide 3-kinase/activated protein kinase B (PI3K/AKT) signaling to inhibit the activity of glycogen synthase kinase 3 beta (GSK3ß). Taken together, these results indicate that the delivery of exogenous proteins via MSCs can modulate microglial function and enhance neurogenesis, thereby providing new insights into AD intervention.

Lycopene protects against t-BHP-induced neuronal oxidative damage and apoptosis via activation of the PI3K/Akt pathway.

Oxidative stress is a key factor of and closely implicated in the pathogenesis of Alzheimer's disease (AD). We herein used tert-butyl hydroperoxide (t-BHP) to induce oxidative stress and mimic oxidative neurotoxicity in vitro. Lycopene is a natural antioxidant that has a strong ability to eliminate free radicals and shows effective protection in some neurodegenerative disease models. However, the effect of lycopene on t-BHP-induced neuronal damage in primary mouse neurons is unknown. This study aimed to investigate the effects of lycopene on t-BHP-induced neuronal damage and the related mechanisms. We found that lycopene pretreatment effectively enhanced the cell viability, improved the neuron morphology, increased the GSH/GSSG level, restored the mitochondrial membrane potential (ΔΨm) and decreased reactive oxygen species generation. Furthermore, lycopene reduced the ratios of Bax:Bcl-2 and cleaved caspase-3:caspase-3 and the level of cytochrome C, increased the levels of synaptophysin (SYP) and postsynaptic density 95 (PSD95) and activated the PI3K/Akt pathway. In conclusion, lycopene attenuated oxidative stress and reduced t-BHP-induced cell apoptosis, and the mechanism is likely related to activation of the PI3K/Akt pathway. Therefore, lycopene is a potential agent for preventing oxidative stress-mediated AD.

The Secretion from Neural Stem Cells Pretreated with Lycopene Protects against tert-Butyl Hydroperoxide-Induced Neuron Oxidative Damage.

Neural stem cells (NSCs) hold great potential for the treatment of Alzheimer's disease (AD) through both cellular replacement and their secretion of trophic factors. Lycopene is a potent ß-carotenoid antioxidant that has been shown to ameliorate oxidative damage in previous studies. However, it is unclear if lycopene can interact with NSCs to induce the secretion of growth factors, and whether pretreatment with lycopene will allow NSCs to secrete enough trophic factors to reduce oxidative damage to neurons. We pretreated cultured NSCs with lycopene, then applied the lycopene-treated-NSC-conditioned media (Ly-NSC-CM) to primary neuronal cultures exposed to tert-butyl hydroperoxide (t-BHP) to induce oxidative damage. We found that lycopene promoted the secretion of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) from NSCs. In addition, Ly-NSC-CM attenuated oxidative stress and reduced t-BHP-induced cell apoptosis. We found an antiapoptotic effect related to inhibited expression of Bax/Bcl-2, cytochrome C, and cleaved caspase-3. Moreover, Ly-NSC-CM increased the levels of synaptic proteins, including synaptophysin (SYP) and postsynaptic density 95 (PSD-95), and activated the PI3K/Akt pathway in cultured neurons. Collectively, these data indicate that Ly-NSC-CM could protect neurons from t-BHP-induced oxidative damage.

Different doses of partial liver irradiation promotes hepatic regeneration in rat.

The aim of this study is to investigate whether partial liver irradiation promotes hepatic regeneration in rat. Left-half liver of rat was irradiated to 10 Gy, and the Right-half to 0, 5, 10 and 15 Gy, respectively. Then, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels were evaluated on 0 day, 15-day, 30-day, 45-day and 60-day after liver irradiation. Next, the serum HGF, NF-κB and TGF-ß1 levels were also analyzed on 60-day after liver irradiation. Lastly, the cyclinD1 protein expression was appraised by western blots on 60-day after liver irradiation. ALT, AST and ALP levels were reduced compared with that of controls. The serum HGF, NF-κB and TGF-ß1 levels, and the cyclinD1 protein expression in liver irradiation group were increased compared with that of controls group. However, hepatic regeneration of higher dose-irradiated cirrhotic liver was triggered a more enhanced regeneration, compared with that of higher doses group. In summary, these results suggest that different doses of partial liver irradiation promotes hepatic regeneration in rat.

Tetra-sulfonate phthalocyanine zinc-bovine serum albumin conjugate-mediated photodynamic therapy of human glioma.

BACKGROUND: Glioma is the most common brain malignancy with poor prognosis. The current treatments for gliomas are mainly based on surgery, chemotherapy, and radiotherapy, which exhibit limited efficacy. Photodynamic therapy (PDT) using photosensitizers has been applied to glioma therapy. However, different photosensitizers usually lead to different therapeutic effects and adverse reactions. OBJECTIVE: This study investigates the anti-tumor effect of photosensitizer ZnPcS4-BSA in xenograft glioma tumors. METHODS: The xenograft glioma tumor model was established by inoculating nude mice with U251 cells. Tumor growth was evaluated by tumor volume, weight, and inhibition rate. Cell apoptosis was evaluated using TUNEL staining. Vascular endothelial growth factor (VEGF) expression and microvessel density were measured by immunohistochemistry. RESULTS: Significant decreases in tumor volume and weight as well as significant increases in tumor inhibition rate, cell apoptosis, VEGF expression, and microvessel density were observed in mice in the low- and high-dose PDT groups compared to the control, irradiation alone, and photosensitizer alone groups. No significant difference in cytotoxicity was observed between control group and photosensitizer alone group. Photosensitizer ZnPcS4-BSA significantly inhibited xenograft glioma tumor growth through induction of apoptosis. CONCLUSION: PDT using ZnPcS4-BSA may be effective for the therapy of gliomas.

Salvianolic acid B promotes survival of transplanted mesenchymal stem cells in spinal cord-injured rats.

AIM: Stem cells hold great promise for brain and spinal cord injuries (SCI), but cell survival following transplantation to adult central nervous system has been poor. Salvianolic acid B (Sal B) has been shown to improve functional recovery in brain-injured rats. The present study was designed to determine whether Sal B could improve transplanted mesenchymal stem cell (MSC) survival in SCI rats. METHODS: SCI rats were treated with Sal B. The Basso-Beatie-Bresnahan (BBB) scale was used to test the functional recovery. Sal B was used to protect MSC from being damaged by TNF-alpha in vitro. Bromodeoxyuridine-labeled MSC were transplanted into SCI rats with Sal B intraperitoneal injection, simultaneously. MSC were examined, and the functional recovery of the SCI rats was tested. RESULTS: Sal B treatment significantly reduced the lesion area from 0.26+/-0.05 mm2 to 0.15+/-0.03 mm2 (P<0.01) and remarkably raised the BBB scores on d 28, post-injury, from 7.3+/-0.9 to 10.5+/-1.3 (P<0.05), compared with the phosphate-buffered saline (PBS) control group. MSC were protected from the damage of TNF-alpha by Sal B. The number of surviving MSC in the MSC plus Sal B groups were 1143.3+/-195.6 and 764.0+/-81.3 on d 7 and 28, post-transplantation, more than those in the MSC group, which was 569.3+/-72.3 and 237.0+/-61.3, respectively (P<0.05). Rats with MSC transplanted and Sal B injected obtained higher BBB scores than those with MSC transplanted alone (P<0.05) and PBS (P<0.01). CONCLUSION: Sal B provides neuroprotection to SCI and promotes the survival of MSC in vitro and after cell transplantation to the injured spinal cord in vivo.