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Aucubin, a natural compound isolated from herbal medicine, has been reported to possess multiple beneficial properties. In this study, we aimed to verify the anticancer effect of aucubin on breast cancer and investigate the effect of cancer on the intestinal flora and whether aucubin has a therapeutic effect on intestinal problems caused by cancer. We established the breast cancer model with mouse 4T1 cell line and BALB/c mice. Aucubin was given once a day by gavage for 14 days. The results showed that aucubin suppress the growth of tumor in vivo by inducing tumor cell apoptosis. The tumor suppression rate of aucubin could reach 51.31 ± 4.07%. Organ histopathology was evaluated by tissue staining, which demonstrated that aucubin could alleviate the organ inflammatory damage caused by breast cancer without visible side effects. Moreover, aucubin could increase the expression of colonic tight junction protein occluding and adjust the gut microbiome to normal level according to 16S rDNA high-throughput sequencing. Herein, our results provide evidence for developing aucubin as an alternative and safe therapeutic for breast cancer treatment.

Introduction Alzheimer’s disease (AD) is a progressive brain disorder, and one of the most common causes of dementia and amnesia. Due to the complex pathogenesis of AD, the underlying mechanisms remain unclear. Although scientists have made increasing efforts to develop drugs for AD, no effective therapeutic agents have been found. Objectives Natural products and their constituents have shown promise for treating neurodegenerative diseases, including AD. Thus, in-depth study of medical plants, and the main active ingredients thereof against AD, is necessary to devise therapeutic agents. Methods In this study, N2a/APP cells and SAMP8 mice were employed as in vitro and in vivo models of AD. Multiple molecular biological methods were used to investigate the potential therapeutic actions of oxyphylla A, and the underlying mechanisms. Results Results showed that oxyphylla A, a novel compound extracted from Alpinia oxyphylla, could reduce the expression levels of amyloid precursor protein (APP) and amyloid beta (Aβ) proteins, and attenuate cognitive decline in SAMP8 mice. Further investigation of the underlying mechanisms showed that oxyphylla A exerted an antioxidative effect through the Akt-GSK3β and Nrf2-Keap1-HO-1 pathways. Conclusions. Taken together, our results suggest a new horizon for the discovery of therapeutic agents for AD.

Background Ziziphi Spinosae Semen (ZSS), which is widely consumed as a medicine and food dual-use plant in some regions of Asian countries, has various health benefits. γ-aminobutyric acid (GABA), a non-proteinaceous amino acid, is one of the major neurotransmitter inhibitors that has a relaxant function. In this study, a system pharmacology approach was proposed to evaluate the effects of a mixture composed by ZSS and GABA (ZSSG) on sleep improvement. Methods Mice were divided into 5 groups (n = 10) and received either no treatment or sodium pentobarbital or sodium barbital with Diaz or ZSSG. The effects of ZSSG on improving sleep quality were evaluated in mice. The major ingredients of ZSSG were analyzed by UPLC-Q/TOF-MS. Network-based ingredient-insomnia proximity was applied to explore its major ingredients. Results The results showed that ZSSG displayed significant effects on decreasing sleep latency and prolonging sleep duration in sodium pentobarbital-induced sleeping mouse model (P P

We have previously designed and synthesized a series of novel memantine nitrates, and some of them have shown neuroprotective effects; however, the detailed mechanisms remain unknown. In this study, we demonstrated that MN-12, one of the memantine nitrates, concentration-dependently protected against glutamate-induced neurotoxicity in rat primary cultured cerebellar granule neurons (CGNs). Western blotting assays revealed that MN-12 might possess neuroprotective effects through the inhibition of ERK pathway and activation of PI3K/Akt pathway concurrently. Moreover, MN-12 concentration-dependently dilated precontracted rat middle cerebral artery through activation of NO-cGMP pathway ex vivo. In the 2-vessel occlusion (2VO) rat model, MN-12 alleviated the impairments of spatial memory and motor dysfunction possibly via neuroprotection and improvement of the cerebral blood flow. Furthermore, the results of preliminary pharmacokinetic studies showed that MN-12 might quickly distribute to the major organs including the brain, indicating that MN-12 could penetrate the blood-brain barrier. Taken together, MN-12 might provide multifunctional therapeutic benefits for dementia associated with Alzheimer's disease, vascular dementia, and ischemic stroke, via neuroprotection and vessel dilation to improve the cerebral blood flow.

Cardiotoxicity is a well-known adverse effect of doxorubicin (Dox) administration, but the underlying molecular mechanism of this effect is not fully understood. Over the past two decades, considerable efforts have focused on the potential molecular targets of cardiotoxicity in the hope that novel targeted therapies will be generated to attenuate Dox-induced cardiotoxicity. Here, we provide a comprehensive overview of genetically modified animals that show enhanced or reduced susceptibility to the cardiotoxic effects of Dox. We focused on the process by which the molecules involved in DNA damage, oxidative stress, apoptosis, autophagy and necrosis are affected in the presence of Dox. We also present a protein-protein interaction network and explain the contribution of the components to the process of Dox-induced cardiotoxicity. More importantly, data from the literature have indicated that PI3Kγ and Rac1 are potential targets with therapeutic advantages in cancer therapy; molecules that target these proteins can simultaneously attenuate Dox-induced cardiotoxicity and enhance its anticancer activity. This review highlights the potential molecular targets that are critical regulators involved in Dox-mediated cardiotoxicity, thus providing further insight into the development of potential treatment strategies to prevent the cardiotoxic effects and enhance the anticancer efficiency of Dox in cancer patients.

Oxaliplatin (OXL) is a third-generation chemotherapeutic agent commonly used to treat metastatic digestive tumors, but one of the main limiting complications of OXL is painful peripheral neuropathy. The present study was to examine the inhibitory effects of blocking microRNA-155 (miR-155) in the dorsal horn of the spinal cord on neuropathic pain induced by OXL in rats and the underlying mechanisms. Behavioral test was performed to examine mechanical pain and cold sensitivity in rats. Real-time RT-PCR and ELISA were employed to determine miR-155 and products of oxidative stress 8-isoprostaglandin F2α (8-iso PGF2α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the dorsal horn. Western blot analysis was used to examine expression of Nrf2-antioxidant response element (Nrf2-ARE), NADPH oxidases (NOXs), and transient receptor potential ankyrin 1 (TRPA1). In results, intrathecal administration of miR-155 inhibitor attenuated mechanical allodynia and cold hyperalgesia in rats with OXL therapy and this was accompanied with restoring of impaired Nrf2-ARE in the dorsal horn. A blockade of miR-155 also attenuated expression of NOX subtype 4 (NOX4) and thereby decreased the levels of 8-iso PGF2α/8-OHdG in the dorsal horn of OXL rats. In addition, inhibiting NOX4 decreased products of oxidative stress in the dorsal horn and attenuated upregulation of TRPA1 induced by OXL. In conclusion, data show the critical role of miR-155 in regulating OXL-induced neuropathic pain likely via oxidative stress-TRPA1 signal pathway, indicating that inhibition of miR-155 has potential benefits in preventing neuropathic pain development during intervention of OXL.

Graphical abstract, Introduction Alzheimer’s disease (AD) is a progressive brain disorder, and one of the most common causes of dementia and amnesia. Due to the complex pathogenesis of AD, the underlying mechanisms remain unclear. Although scientists have made increasing efforts to develop drugs for AD, no effective therapeutic agents have been found. Objectives Natural products and their constituents have shown promise for treating neurodegenerative diseases, including AD. Thus, in-depth study of medical plants, and the main active ingredients thereof against AD, is necessary to devise therapeutic agents. Methods In this study, N2a/APP cells and SAMP8 mice were employed as in vitro and in vivo models of AD. Multiple molecular biological methods were used to investigate the potential therapeutic actions of oxyphylla A, and the underlying mechanisms. Results Results showed that oxyphylla A, a novel compound extracted from Alpinia oxyphylla, could reduce the expression levels of amyloid precursor protein (APP) and amyloid beta (Aβ) proteins, and attenuate cognitive decline in SAMP8 mice. Further investigation of the underlying mechanisms showed that oxyphylla A exerted an antioxidative effect through the Akt-GSK3β and Nrf2-Keap1-HO-1 pathways. Conclusions. Taken together, our results suggest a new horizon for the discovery of therapeutic agents for AD.

Obesity, which is often caused by adipocyte metabolism dysfunction, is rapidly becoming a serious global health issue. Studies in the literature have shown that camellia oil (Camellia oleifera Abel) exerted potential lipid regulation and other multiple biological activities. Here, we aimed to investigate the effects of camellia oil on obese mice induced by a high-fat diet and to explore gut microbiota alterations after camellia oil intervention. The results showed that oral administration of camellia oil dramatically attenuated the fat deposits, serum levels of the total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, fasting plasma glucose, the atherosclerosis index, the hepatic steatosis and inflammation in high-fat diet-induced obese mice. Meanwhile, the high-density lipoprotein cholesterol level in obese mice was enhanced after the camellia oil treatment. Furthermore, 16S rRNA analysis showed that certain aspects of the gut microbiota, especially the gut microbiota diversity and the relative abundance of Actinobacteria, Coriobacteriaceae, Lactobacillus and Anoxybacillus, were significantly increased by camellia oil treatment while the ratio of Firmicutes to Bacteroidetes was decreased. Taken together, our finding suggested that camellia oil was a potential dietary supplement and functional food for ameliorating fat deposits, hyperglycemia and fatty liver, probably by modifying the gut microbiota composition.

Background:NASH is developed from NAFLD and there is no proven pharmaceutical therapy for patients. Traditional Chinese medicine formula of Qushihuayu(QSHY) shows strong advantage because of their various bioactive compounds in curing NAFLD and NASH.Methods:Male Wistar rats with six weeks old received methionine-choline- supplemented diet (MCS) diet for 8 weeks as the blank control. Another 7 rats received MCD diet for 6 weeks first and MCS&MCD (1:1) mixture diet for the last 2 weeks as the model group. QSHY Pre-treatment, low dosage, medium dosage and high dosage groups were received the same diet as the model group. Except for pre-treatment group (1 week in advanced of other groups), all QSHY treatment groups received QSHY formula by gavage every day since the MCD diet started.Results:QSHY formula decreased the serum ALT and AST levels, lipid droplets, inflammation foci, FAS and α-SMA protein expression than MCD diet group. MAPK pathways phospharylation are markedly depressed by QSHY formula. Moreover, QSHY formula enhanced PPAR-γ and p-p65 translocating into nucleus. The administration of QSHY increased hepatic mRNA levels of Transcription Factor 1 alpha (HNF1A), Hepatocyte Nuclear Factor 4 alpha (HNF4A) and Forkhead box protein A3 (FOXA3) which play a pivotal role in Hepatic stellate cell (HSCs) reprogramming.Conclusion:These findings suggest that QSHY formula exerts a hepatoprotective effect against steatosis and fibrosis presumably via depressed MAPK pathways phosphorylation, reinforcement of PPAR-γ and p-p65 translocating into nucleus and enhanced HSCs reprogramming.

Background Non-alcoholic steatohepatitis (NASH) is an advanced form of non-alcoholic fatty liver disease (NAFLD) for which there is yet any standard pharmacotherapy. Traditional Chinese medicine formula such as Qushihuayu (QSHY) composing of multiple bioactive compounds has been used to treat NAFLD and NASH and shows beneficial effects over single compound treatment. This study aimed to investigate the mechanism of hepatoprotective effect of QSHY formula using a rat model. Methods Six-weeks old male Wistar rats were given methionine/choline supplemented (MCS) diet for 8 weeks and used as the blank control. Another 7 rats, which received methionine/choline deficient (MCD) diet in the first 6 weeks and a MCS&MCD (1:1) mixture diet in the last 2 weeks, were used as the model group. The groups of QSHY pre-treatment, low dosage, medium dosage and high dosage were given the same diet as the model group. Except for pre-treatment group (1 week in advanced of other groups), all QSHY treatment groups received QSHY formula by gavage every day since the MCD diet started. Results In the MCD diet group, the QSHY formula decreased the serum ALT and AST levels, lipid droplets, inflammation foci, FAS and α-SMA protein expression than MCD diet group. MAPK pathways phospharylation were markedly depressed by the QSHY formula. Moreover, QSHY formula enhanced PPAR-γ and p-p65 translocating into nucleus. The administration of QSHY increased hepatic mRNA levels of Transcription Factor 1 alpha (HNF1A), Hepatocyte Nuclear Factor 4 alpha (HNF4A) and Forkhead box protein A3 (FOXA3) which play a pivotal role in Hepatic stellate cell (HSCs) reprogramming. Conclusion These findings suggest that QSHY formula exerts a hepatoprotective effect against steatosis and fibrosis presumably via depressed MAPK pathways phosphorylation, reinforcement of PPAR-γ and p-p65 translocating into nucleus and enhanced HSCs reprogramming.

We developed a protocol to investigate and optimize the application of contrast-enhanced ultrasound (CEUS) to non-invasive diagnosis of progressing fatty liver disease in mouse models. Eighteen 4-wk-old male C57 L/J mice were randomly assigned to one of the three groups and placed on a control diet, high-fat diet or non-alcoholic steatohepatitis diet for the next 10 wk. After 14 wk, B-mode imaging and CEUS imaging using a VisualSonics Vevo2100 system were performed. CEUS imaging and data analysis using three different parameters-peak enhancement, wash-in rate and wash-in perfusion index-revealed a significant decrease in representative blood flow in the high-fat diet group versus controls and a further significant decrease in the non-alcoholic steatohepatitis group (p0.001; n = 6/group). In conclusion, compared with B-mode imaging, non-targeted CEUS imaging was more sensitive in diagnosing early-stage fatty infiltration-mediated vascularity changes in liver parenchyma and provided a more accurate steatohepatitis diagnosis in mouse models.

A novel highly biocompatible nanosystem made up of a chitosan matrix and filled with magnesium nanoparticles was synthesized using a simple and one-pot strategy, and tested as a promising, well-tolerated tool for photothermal therapy. Moreover, in vivo a proof of concept on hepatocarcinoma-bearing mice is presented.

Nonalcoholic steatohepatitis (NASH) is becoming a huge global health problem. Studies showed that β-glucan displayed potent anti-inflammatory and other multi-beneficial pharmacological properties. Thus, the objective of this study was to investigate the effects of β-glucan on NASH mice induced by the MCD diet. After 8 weeks of β-glucan treatments, results showed that β-glucan effectively decreased the serum ALT and AST levels compared with the MCD model. Besides, histopathological results demonstrated that β-glucan significantly attenuated the fat accumulation, steatosis, and inflammation in the liver compared with that of the MCD group. Furthermore, the ER stress-responsive proteins, including GRP78, p-eiF-2α, and p-JNK, were markedly restrained by β-glucan, while ERp57, p-MAPK, and p-Akt were significantly increased after β-glucan treatment. Collectively, our results suggested that β-glucan beneficially resisted NASH induced by the MCD diet. The ER stress response may be involved in the mechanisms of action of β-glucan. PRACTICAL APPLICATIONS: This study is the first to report the hepatoprotective activity of β-glucan against MCD diet-induced NASH in mice, mainly reflecting its ability to ameliorate hepatic lipid accumulation and inflammation, with the mechanism possibly involving mediating the ER stress signaling pathway. Our results suggest that the β-glucan has good application prospects to be used as a raw material in functional foods for the clinical treatment of NASH.

Danshen (Salvia miltiorrhiza) is a well-known herb in Traditional Chinese Medicine (TCM) for treating cardiovascular diseases, but the underlying mechanism remains to be fully elucidated. Here, we showed that Danshen and its active ingredient rosmarinic acid exhibited antiplatelet effects through the inhibition of ERp57, a member of protein disulfide isomerase (PDI) with potential roles in platelet aggregation. Danshen extract (DSE) exhibited potent inhibitory effects on the platelet aggregation induced by arachidonic acid- (AA-) induced platelet aggregation and the enzymatic activity of ERp57. Rosmarinic acid was identified by virtual screening and molecular docking as one of the hit compounds for ERp57. In line with this, rosmarinic acid displayed significant inhibitory effect on ERp57 activity and inhibited AA-induced platelet aggregation. Taken together, we demonstrated for the first time that DSE and rosmarinic acid displayed inhibitory effects on the catalytic activity of ERp57, providing evidence of the regulatory role of ERp57 underlying the antiplatelet effects of Danshen.

We have previously designed and synthesized a series of novel memantine nitrates, and some of them have shown neuroprotective effects; however, the detailed mechanisms remain unknown. In this study, we demonstrated that MN-12, one of the memantine nitrates, concentration-dependently protected against glutamate-induced neurotoxicity in rat primary cultured cerebellar granule neurons (CGNs). Western blotting assays revealed that MN-12 might possess neuroprotective effects through the inhibition of ERK pathway and activation of PI3K/Akt pathway concurrently. Moreover, MN-12 concentration-dependently dilated precontracted rat middle cerebral artery through activation of NO-cGMP pathway

Ginkgolides are the major active component of Ginkgo biloba for inhibition of platelet activating factor receptor. An azide-alkyne Huisgen cycloaddition reaction was used to introduce a triazole nucleus into the target ginkgolide molecules. A series of ginkgolide-1,2,3-triazole conjugates with varied functional groups including benzyl, phenyl and heterocycle moieties was thus synthesized. Many of the designed derivatives showed potent antiplatelet aggregation activities with IC50 values of 5~21 nM.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer's disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

Salvia miltiorrhiza (Danshen) is a well-known traditional Chinese medicine for treating various diseases, such as breast cancer. However, knowledge regarding its mechanisms is scant. Herein, the active ingredient dihydrotanshinone I (DHT) in Salvia miltiorrhiza extract (SME), which binds ERp57 was identified and verified by an enzymatic solid-phase method combined with LC-MS/MS. DHT potentially inhibited ERp57 activity and suppressed ERp57 expression at both the RNA and protein levels. Molecular docking simulation indicated that DHT could form a hydrogen bond with catalytic site of ERp57. Moreover, ERp57 overexpression decreased DHT-induced cytotoxicity in MDA-MB-231 cells. Thereafter, the signaling pathway downstream of ERp57 was investigated by Western blot analysis. The mechanistic study revealed that DHT treatment resulted in activation of endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and cellular apoptosis. In conclusion, our data implied that DHT targeted ERp57 for inhibition and induced ER stress and UPR activation, which in turn triggered breast cancer cell apoptosis.

Fatty acid synthase (FASN), the key enzyme in de novo lipogenesis, is an attractive therapeutic target for diseases characterized by excessive lipid accumulation. Many FASN inhibitors have failed in the clinical trial phase, largely because of poor solubility and safety. In this study, we generated a novel small-molecule FASN inhibitor by structure-based virtual screening. PFI09, the lead compound, is easy to synthesize, and inhibits the lipid synthesis in OP9 mammalian cell line and Caenorhabditis elegans as well as the proliferation of several cancer cell lines via the blockade of FASN. Mechanistic investigations show that PFI09 induces S-phase arrest, cell division reduction and apoptosis. We also develop a chemically stable analog of PFI09, MFI03, which reduces the proliferation of PC3 tumor cells both in vitro and in vivo, without toxicity to mice. In summary, our data suggest that MFI03 is an effective FASN inhibitor and a promising antineoplastic drug candidate.

Andrographolide is among the most promising anti-tumor and anti-angiogenic components in Andrographis paniculata but its poor bioavailability and limited efficacy pose difficulties for its therapeutic development. Therefore, improving its pharmaceutical features and potency, by modifying its chemical structure, is desirable. In the present study, a new andrographolide derivative (AGP-40) was synthesized and characterized for its anti-angiogenic properties. Human umbilical vein endothelial cells (HUVECs) and zebrafish models were used to identify the anti-angiogenic activity of AGP-40. AGP-40 significantly suppressed the formation of blood vessels in zebrafish and inhibited proliferation, migration and tube formation in vitro. The anti-angiogenic effects of AGP-40 are at least partially mediated via the PI3K/Akt and MEK/Erk(1/2) signaling pathways. Furthermore, AGP-40 exhibited stronger anti-proliferative effects than andrographolide against A549, HepG2, Hela cancer cell lines. This study is the first to demonstrate the promising anti-angiogenic activity of the new andrographolide derivative AGP-40. Our results indicate that AGP-40 could serve as a potential therapeutic agent for the treatment and prevention of diseases associated with excessive angiogenesis.

Curcumin and fenretinide are 2 well-known and promising chemotherapeutic compounds via various molecular mechanisms. However, the anticancer capacity of either curcumin or fenretinide is limited. This prompted us to examine the combined anticancer effects of curcumin and fenretinide. Our results demonstrate for the first time that there is synergistic anticancer effect of combined treatment with these 2 agents, leading to enhanced cytotoxicity and enhanced expression level of pro-apoptotic protein cleaved PARP in non-small cell lung cancer (NSCLC) cells while showed little toxicity to rat cardiomyoblast normal cells. The combination treatment was also demonstrated to inhibit lung carcinoma growth in vivo. Furthermore, we show that fenretinide or the ER stress inhibitor 4-PBA decreased curcumin-induced Glucose-regulated protein 78 (GRP78) upregulation, and produced a similar enhanced cytotoxic effect. In addition, GRP78 knockdown by siRNA also enhanced the cytotoxic effect of curcumin in A549 and H1299 cells. Our findings suggest that the 2 small molecules, when used in combination, can potentially be effective therapeutic agents for treating NSCLC, at least in part, by regulating endoplasmic reticulum (ER) chaperone protein GRP78.

Liver cancer is the fifth commonly occurring cancer worldwide with the annual death rate of 9.1%. Hepatocellular carcinoma is the most frequent kind of primary liver cancer and occurs mostly in patients with chronic liver disease and cirrhosis. Because the cancer is generally detected only in the later stages, it is often treated with therapies such as radiation, ablation, and chemotherapy, which produces serious side effects and has a low recovery rate. Therefore, researchers are now focused on herbal-based drugs with increased efficacy and with no side effects to treat cancer. One such drug is mangiferin, a xanthanoid possessing augmented antioxidant, anti-inflammatory, and antidiabetic properties. The present study investigated the anticarcinogenic property of mangiferin against DEN-induced hepatocellular carcinoma. Hepatocellular carcinoma was induced in healthy Sprague-Dawley rats by treating them with 0.01% diethylnitrosamine (DEN) in the drinking water for 12 weeks, followed by 50 mg of mangiferin for a period of 8 weeks. Biochemical, oxidative stress markers, antioxidant status, and tumor marker level in the DEN- and DEN + mangiferin-treated rats liver were assessed to detect the efficacy of mangiferin in inhibiting cancer induction. The anticarcinogenic property of mangiferin was confirmed by evaluating the apoptotic protein expression and histological analysis of liver tissue from DEN- and DEN + mangiferin-treated rats. Our results show that mangiferin possesess anticarcinogenic properties against DEN-induced hepatocellular carcinoma. We predict that further investigation will reveal mangiferin as a potent drug to treat liver cancer.

Overactivation of N-methyl-D-aspartate (NMDA) receptors has been associated with neurodegenerative disorders such as Alzheimer's disease (AD), cerebral vascular disorders and amyotrophic lateral sclerosis (ALS). We have previously designed and synthesized a series of memantine nitrate and some of them have shown vessel dilatory effects and neuroprotective effects; however, the detailed mechanisms have not been elucidated. In this study, we further demonstrated that memantine nitrate-06 (MN-06), one of the novel compounds derived from memantine, possessed significant neuroprotective effects against glutamate-induced excitotoxicity in rat primary cerebellar granule neurons (CGNs). Pretreatment of MN-06 reversed the activation of GSK3b and the suppression of phosphorylated Akt induced by glutamate. In addition, the neuroprotective effects of MN-06 could be abolished by LY294002, the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor. Ca2+ imaging shown that pretreatment of MN-06 prevented Ca2+ influx induced by glutamate. Moreover, MN-06 might inhibit the NMDA-mediated current by antagonizing NDMA receptors, which was further confirmed by molecular docking simulation. Taken together, MN-06 protected against glutamate-induced excitotoxicity by blocking calcium influx and attenuating PI3-K/Akt/GSK-3b pathway, indicating that MN-06 might be a potential drug for treating neurodegenerative disorders.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), and there is no cure for it at present. We have previously reported that the tetramethylpyrazine (TMP) derivative T-006 exhibited beneficial effects in Alzheimer’s disease (AD) models. However, its effect on PD remains unclear. In the present study, we investigated the neuroprotective effects and underlying mechanisms of T-006 against 6-hydroxydopamine- (6-OHDA-) induced lesions in in vivo and in vitro PD models. Our results demonstrated that T-006 alleviated mitochondrial membrane potential loss and restored the energy metabolism and mitochondrial biogenesis that were induced by 6-OHDA in PC12 cells. In addition, animal experiments showed that administration of T-006 significantly attenuated the 6-OHDA-induced loss of tyrosine hydroxylase- (TH-) positive neurons in the SNpc, as well as dopaminergic nerve fibers in the striatum, and also increased the concentration of dopamine and its metabolites (DOPAC, HVA) in the striatum. Functional deficits were restored following T-006 treatment in 6-OHDA-lesioned mice, as demonstrated by improved motor coordination and rotational behavior. In addition, we found that the neuroprotective effects of T-006 were mediated, at least in part, by the activation of both the PKA/Akt/GSK-3β and CREB/PGC-1α/NRF-1/TFAM pathways. In summary, our findings demonstrate that T-006 could be developed as a novel neuroprotective agent for PD, and the two pathways might be promising therapeutic targets for PD.

In parallel with the prevalence metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in most countries. It features a constellation of simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma. There are no approved drugs for effective management of NAFLD and NASH. Jianpi Huoxue formula (JPHX) mainly consists of Atractylodes macrocephal(Baizhu), Salvia miltiorrhiza (Danshen), Rasux Paeonia Alba (Baishao), Rhizoma Alismatis (Zexie), and Fructus Schisandrae Chinensis (Wuweizi), which may have beneficial effects on NAFLD. The aim of the study was to identify the effect of JPHX on NAFLD.A NAFLD model was induced by methionine-choline-deficient food (MCD) in Wistar rats and orally administered with simultaneous JPHX, once a day for 8 weeks. Hepatocellular injury, lipid profile, inflammation, fibrosis, and apoptosis were evaluated. The results showed that JPHX significantly decreased the abnormal serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared with the MCD model (Pαlevels and reduced collagen and matrix metalloproteinases in MCD diet-fed rats. In addition, JPHX prevented rats from MCD-induced cellular apoptosis, as suggested by TUNEL staining, and suppressed the activation of caspase 3 and 7 proteins. JPHX also inhibited the phosphorylation of JNK. In conclusion, JPHX exhibited a hepatoprotective effect against NAFLD in an MCD experimental model.

Doxorubicin (Dox) is a well-known chemotherapeutic agent used in the treatment of various cancers. However, Dox-induced cardiotoxicity limits its further clinical use. We have previously reported a small molecular named biotin-conjugated ADTM analog (BAA) that exhibits cytoprotective effects against oxidative stress-induced cell injury in cardiomyoblast H9c2 cells. Here, the protective effects of BAA, indexed by attenuation of the cardiotoxicity induced by Dox as well as synergistic antitumor activity that increases the chemotherapeutic efficacy of Dox were investigated. Our results demonstrated that BAA significantly ameliorated Dox-induced toxicity in the H9c2 cells and zebrafish models. In addition, BAA attenuated Dox-induced endoplasmic reticulum (ER) stress in H9c2 cells. An ER stress inhibitor, 4-phenylbutyric acid, reversed the protective effect of BAA in H9c2 cells. In contrast, in human breast tumor MDA-MB-231 cells, BAA significantly enhanced Dox-induced cytotoxicity through upregulating Dox-induced ER stress response. Taken together, our findings indicate that Dox combined with BAA can significantly enhance its antitumor activity in breast cancer cells and reduce its cardiotoxicity, at least in part, by mediating ER stress activation.

Background Upregulated fibroblast growth factor 19 (FGF19) expression in human hepatocellular carcinoma (HCC) specimens is associated with tumor progression and poor prognosis. Nonalcoholic steatohepatitis (NASH) patients are at high risk for malignant transformation into HCC. Methods A steatohepatitis-HCC model was established in male C57L/J mice treated with N-nitrosodiethylamine (DEN) and high-fat diet (HFD). A mouse HCC cell line (Hepa1–6) and a mouse hepatocyte line (FL83B) were used to elucidate the mechanism by free fatty acids (FFA) treatment. FGF15, the mouse orthologue of FGF19, and it receptor fibroblast growth factor receptor4 (FGFR4) as well as co-receptor β-klotho were studied. FGF19 signaling was also studied in human samples of HCC with steatohepatitis. Results HCC incidence and tumor volume were significantly increased in the DEN+HFD group compared to that in the DEN+control diet (CD) group. Increased levels of FGF15/FGFR4/β-klotho, aberrant epithelial–mesenchymal transition (EMT) and Wnt/β-catenin signaling were detected in DEN+HFD mice. Blockage of the FGF15 signal can attenuate cell migration ability and aberrant EMT and Wnt/β-catenin signaling. Conclusions Up-regulated FGF15/FGFR4 signaling promoted the development of HCC by activation of EMT and Wnt/β-catenin signaling in the lipid metabolic disorder microenvironment. Further investigation of FGF19/FGFR4 signaling is important for potential early diagnosis and therapeutic targeting in HCC patients. Electronic supplementary material The online version of this article (10.1186/s13046-018-0781-8) contains supplementary material, which is available to authorized users.

Doxorubicin (Dox) is a chemotherapeutic agent widely used for the treatment of numerous cancers. However, the clinical use of Dox is limited by its unwanted cardiotoxicity. Mitochondrial dysfunction has been associated with Dox-induced cardiotoxicity. To mitigate Dox-related cardiotoxicity, considerable successful examples of a variety of small molecules that target mitochondria to modulate Dox-induced cardiotoxicity have appeared in recent years. Here, we review the related literatures and discuss the evidence showing that mitochondria-targeting small molecules are promising cardioprotective agents against Dox-induced cardiac events.

Doxorubicin (Dox) is an anthracycline antibiotic widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. We have previously shown that a Danshensu (DSS) derivative, ADTM, displayed strong cardioprotective effects. With improved chemical stability and activity, a novel DSS derivative, D006, based on the structure of ADTM, was synthesized. In the present study, the protective effects of D006, indexed by attenuation of the cardiotoxicity induced by Dox as well as chemosensitizing effects that increase the antitumor activity of Dox, were investigated. Our results showed that D006 was more potent than either parental compound, or their use in combination, in ameliorating Dox-induced toxicity in H9c2 cells. In our zebrafish model, D006, but not DSS, alone significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, D006 upregulated mitochondrial biogenesis and increased mtDNA copy number after Dox treatment of H9c2 cells. D006 promoted the expression of HO-1 protein in a time-dependent manner while the HO-1 inhibitor, Znpp, reversed the protective effects of D006. In human breast tumor MCF-7 cells, D006 enhanced Dox-induced cytotoxicity by increasing apoptosis. In conclusion, our results indicate that a new DSS derivative exhibits promising protective effects against Dox-induced cardiotoxicity both in vivo and in vitro, an effect at least partially mediated by induction of HO-1 expression and the activation of mitochondrial biogenesis. Meanwhile, D006 also potentiated the anti-cancer effects of Dox in breast tumor cells.

Icaritin, a prenylflavonoid isolated from Herbal Epimedii, is well known for its osteoplastic and anti-tumour activities. Here, we examined the cardioprotective actions of icaritin on cardiac H9c2 cells under oxidative stress conditions induced by treatment with tert-butylhydroperoxide (t-BHP). Icaritin at a concentration range between 1 and 4 µM effectively increased cell viability and decreased lactate dehydrogenase (LDH) leakage and reactive oxygen species (ROS) release in t-BHP treated cells, reflecting its ability to reduce t-BHP-induced cell injury. Icaritin also protected cell membrane integrity by preventing the collapse of the mitochondrial membrane potential. In addition, pretreatment of NF-E2-related factor 2 (Nrf2) siRNA and Akt inhibitor abolished the cardioprotective effect of icaritin. Furthermore, Nrf2 siRNA transfection interfered with the effect of icaritin on the inhibition of Ca2+ overload, whereas Akt inhibitor reduced icaritin-induced haemo-oxygenase-1 (HO-1) expression. Collectively, these results suggest that icaritin exerted its cardioprotective effect through the Akt/Nrf2/HO-1 and calcium signalling pathways.

C19 -diterpenoid alkaloids are the main components of Aconitum duclouxii Levl. The process of separation and purification of these compounds in previous studies was tedious and time consuming, requiring multiple chromatographic steps, thus resulted in low recovery and high cost. In the present work, five C19 -diterpenoid alkaloids, namely, benzoylaconine (1), N-deethylaconitine (2), aconitine (3), deoxyaconitine (4), and ducloudine A (5), were efficiently prepared from A. duclouxii Levl (Aconitum L.) by ethyl acetate extraction followed with counter-current chromatography. In the process of separation, the critical conditions of counter-current chromatography were optimized. The two-phase solvent system composed of n-hexane/ethyl acetate/methanol/water/NH3 ·H2 O (25%) (1:1:1:1:0.1, v/v) was selected and 148.2 mg of 1, 24.1 mg of 2, 250.6 mg of 3, 73.9 mg of 4, and 31.4 mg of 5 were obtained from 1 g total Aconitum alkaloids extract, respectively, in a single run within 4 h. Their purities were found to be 98.4, 97.2, 98.2, 96.8, and 96.6%, respectively, by ultra-high performance liquid chromatography analysis. The presented separation and purification method was simple, fast, and efficient, and the obtained highly pure alkaloids are suitable for biochemical and toxicological investigation.

In the present study, a high-speed counter-current chromatography (HSCCC) was investigated for separation and purification of gardecin on a preparative scale. Hexane–ethyl acetate–methanol–water (0.3:1:0.3:1, v/v) was selected as the optimum solvent system to purify gardecin from a fraction obtained from HPD100 column chromatography fractionation of gardenia. After HSCCC isolation, 20.1 mg of gardecin with purity of 97.4% was obtained from 322 g of dry gardenia fruits. Chemical structure identification of this pigment was carried out by MS, 1H NMR, and 13C NMR. Additionally, antioxidant activity of gardecin in comparison with crocin-1 was investigated. The present results demonstrated that gardecin could be efficiently obtained using HSCCC from this herb and this compound features strong antioxidant activity.

Tables S1-S3, list of antibodies, promers and siRNAs. Method for ultrasound image acquisition. Figure legends for Figures S1-S4. (DOCX 18 kb)