Perillaldehyde ameliorates lipopolysaccharide-induced acute lung injury via suppressing the cGAS/STING signaling pathway.

Acute lung injury (ALI) is a common life-threatening illness characterized by a lung inflammatory response and oxidative stress, and effective agent therapies are currently lacking. mtDNA can be recognized by cGAS/STING, the dysregulation of which leads to inflammatory diseases, such as ALI. Perillaldehyde(PAH), one of the major active components of traditional Chinese medicine made from Perilla frutescens, has antioxidant and antiinflammatory effects. The aim of this study was to explore whether PAH can protect against lipopolysaccharide (LPS)-induced ALI and whether its protective effect is exerted through the regulation of cGAS/STING signaling. We found that PAH significantly inhibited lung histological changes, inflammatory cell infiltration, and the overproduction of inflammatory cytokines induced by LPS. Moreover, PAH inhibited LPS-induced oxidative stress, as shown by the deceases in superoxide dismutase (SOD) and glutathione(GSH) levels and increased in malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels. In addition, PAH markedly downregulated the expression of cGAS, STING, p-TBK, p-IRF3, p-P65, and p-IκB, and pharmacological inhibition of cGAS/STING inhibited ALI- induced by LPS. Furthermore, the levels of mitochondrial ROS (mROS) and mtDNA were increased, and cGAS/STING-mediated IRF3/NF-κB signaling was activated during the inflammatory response- induced by LPS in RAW264.7 cells. In addition, pretreatment with the STING activator partially abolished the inhibitory effect of PAH on the inflammation and activation of STING-mediated IRF3/NF-κB signaling induced by LPS. Overall, the results revealed that PAH can effectively alleviate ALI by inhibiting cGAS/STING-mediated IRF3/NF-κB signaling, and that PAH may be a potential candidate agent for the treatment of ALI.

Hypothalamic warm-sensitive neurons require TRPC4 channel for detecting internal warmth and regulating body temperature in mice.

Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were thought to sense internal warmth, using this information as feedback to regulate body temperature (Tcore). However, the cellular and molecular mechanisms by which WSNs measure temperature remain largely undefined. Via a pilot genetic screen, we found that silencing the TRPC4 channel in mice substantially attenuated hypothermia induced by light-mediated heating of the POA. Loss-of-function studies of TRPC4 confirmed its role in warm sensing in GABAergic WSNs, causing additional defects in basal temperature setting, warm defense, and fever responses. Furthermore, TRPC4 antagonists and agonists bidirectionally regulated Tcore. Thus, our data indicate that TRPC4 is essential for sensing internal warmth and that TRPC4-expressing GABAergic WSNs function as a novel cellular sensor for preventing Tcore from exceeding set-point temperatures. TRPC4 may represent a potential therapeutic target for managing Tcore.

Hernandezine, a natural herbal alkaloid, ameliorates type 2 diabetes by activating AMPK in two mouse models.

BACKGROUND: AMP-activated protein kinase (AMPK) is an effective target for treating diabetes. However, successful drug development is delayed due to issues including toxicity. Plant-derived natural product AMPK activators have emerged as a new way to treat diabetes due to its potential low safety risks. Here, we studied the effect of hernandezine (HER), a natural product derived from Thalictrum, in activating AMPK and treating T2D in mouse models. METHOD: We tested HER in various cells and tissues, including primary hepatocytes, skeletal myotubes cell lines, as well as major metabolic tissues from diabetic (db/db) and diet-induced obesity (DIO) model mice. The effect of HER on glucose uptake via AMPK in vitro and in vivo was confirmed utilizing cell transfection and adenovirus interference analysis. Tissue staining assessed the effect of HER on adipogenesis. Real-time quantitative polymerase chain reaction (real-time PCR) was applied to verify the effect of HER on transcription factors. Western blot analysis was used to determine the activation of phosphorylated AMPK and ACC pathways. RESULTS: Biochemically, we found that HER prevented pAMPK from dephosphorylation to prolong its activity, disproving previous direct activation model and providing a new model to explain HER-mediated AMPK activation. HER could be orally delivered to animals and has a 3-fold long half-life in vivo as compared to metformin. Importantly, long-term oral HER treatment potently reduced body weight and blood glucose in both type 2 diabetes mullitus (T2DM) mouse models by increasing glucose disposal and reducing lipogenesis, and appeared not to induce cardiac hypertrophy. CONCLUSION: Natural product HER indirectly activates AMPK by suppressing its dephosphorylation. Oral HER effectively alleviated hyperglycemia and reduced body weight in T2D mouse models, appeared to have a low risk of causing cardiac hypertrophy, and might be a potential therapeutic option for T2DM.

Effects of magnesium valproate adjuvant therapy on patients with dementia: A systematic review and meta-analysis.

BACKGROUND: Current research has found contradictory results on the treatment of magnesium valproate (VPM) in patients with dementia (PwD). OBJECTIVES: Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD. PURPOSE: Current research has found contradictory results on the treatment of VPM in PwD. Here, we conducted a meta-analysis to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD. METHODS: MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI), and Wan Fang databases were researched to gather relevant data on magnesium valproate assistant therapy for patients with dementia (PwD) by using medical subject headings and term words. RESULTS: After the final screening, 22 RCT studies (a total of 1899 participants) were included in this meta-analysis, which compared VPM adjuvant treatment with antidementia or psychotropic drug monotherapy. Significant differences were found in the scores on mini-mental state examination (P = .028), Alzheimer disease assessment scale cognitive subscale (P < .05), Bech-Rafaelsen Mania Rating Scale (P < .05), behavioral pathology in Alzheimer disease rating scale (P = .001), activities of daily living (P < .05), and Pittsburgh Sleep Quality Index (P < .05). Besides, the levels of inflammatory factors including IL-1ß, IL-6, and TNF-α were significantly lower than those in the monotherapy group (P < .05). While there was no increase in the incidence of adverse events (P = .383), VPM as an assistant therapy is generally well tolerated in PwD. CONCLUSION: By meta-analysis, evidence was found to support VPM additional used for the treatment of cognitive function, psychiatric symptoms, or disease improvement in PwD. VPM may be a potential drug to aid in the treatment of dementia patients. However, there was lack of enough evidence to classification of dementia severity in our inclusion study. More research is still needed, including clinical trials evaluating VPM as a complementary therapy.

Cooling-activated dorsomedial hypothalamic BDNF neurons control cold defense in mice.

BDNF and its expressing neurons in the brain critically control feeding and energy expenditure (EE) in both rodents and humans. However, whether BDNF neurons would function in thermoregulation during temperature challenges is unclear. Here, we show that BDNF neurons in the dorsomedial hypothalamus (DMHBDNF ) of mice are activated by afferent cooling signals. These cooling-activated BDNF neurons are mainly GABAergic. Activation of DMHBDNF neurons or the GABAergic subpopulations is sufficient to increase body temperature, EE, and physical activity. Conversely, blocking DMHBDNF neurons substantially impairs cold defense and reduces energy expenditure, physical activity, and UCP1 expression in BAT, which eventually results in bodyweight gain and glucose/insulin intolerance. Therefore, we identify a subset of DMHBDNF neurons as a novel type of cooling-activated neurons to promote cold defense. Thus, we reveal a critical role of BDNF circuitry in thermoregulation, which deepens our understanding of BDNF in controlling energy homeostasis and obesity.

Qi-Tai-Suan, an oleanolic acid derivative, ameliorates ischemic heart failure via suppression of cardiac apoptosis, inflammation and fibrosis.

Although anti-thrombotic therapy has been successful for prevention of deaths from acute myocardial infarction (MI), by far, there are few preventive and therapeutic options for ischemic heart failure (IHF) after MI. Qi-Tai-Suan (QTS) is an oleanolic acid (OA) derivative which once underwent a clinical trial for treating hepatitis. In this study, we investigated the potential cardioprotective effect of QTS on IHF. IHF mouse model was constructed by coronary artery ligation in male C57BL/6J mice, and the protective effects of QTS on IHF were examined by echocardiography measurement, histological and TUNEL analysis, etc. We found that QTS exhibited promising cardioprotective effect on IHF. QTS treatment significantly improved cardiac function of IHF mice and the symptoms of heart failure. Notably, QTS had much better oral bioavailability (F = 41.91%) in mice than its parent drug OA, and took effects mainly as its original form. Mechanistically, QTS ameliorated ischemic heart failure likely through suppression of cardiac apoptosis, inflammation and fibrosis. Taken together, QTS holds great promise as a preventive and therapeutic agent for ischemic heart failure and related diseases.

Magnesium valproate adjuvant therapy on patients with dementia: A protocol for systematic review and meta-analysis.

BACKGROUND: With the aging population, the prevalence and incidence of dementia disease will continue to rise, and the associated economic burden is increasing as well. However, the available anti-dementia therapeutic arsenal is limited. Meanwhile, magnesium valproate (VPM) as an adjuvant therapy had a general positive effect on the cognitive function and psychiatric symptoms of patient with dementia (PwD). At present, there is lack of meta-analysis focusing on cognitive improvement and disease-modifying about VPM-assisted therapy in the present peer-reviewed literature. Thus, we aimed to likely analyze the efficacy and safety of VPM adjuvant therapy of PwD. METHODS: We will research MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI) and Wan fang databases to gather relevant data on VPM assistant therapy on the PwD. Meta-analysis will be performed using Stata16.0 software. RESULTS: We aim to evaluate the efficacy and safety of VPM in the adjuvant treatment of PwD. CONCLUSION: VPM maybe plays an active role in the treatment of dementia patients and this research will provide reliable evidence for clinicians in therapy of PwD. INPLASY REGISTRATION NUMBER: INPLASY2021110038 (DOI: 10.37766/inplasy2021.11.0038).

Effect of DRD4 Receptor -616 C/G Polymorphism on Thalamic GABA Levels in Pediatric Patients With Primary Nocturnal Enuresis.

BACKGROUND: The single nucleotide polymorphism (SNP) of dopamine D4 receptor (DRD4) promoter (-616; rs747302) is associated with abnormalities of the thalamus in children suffering from primary nocturnal enuresis (PNE). PURPOSE: To investigate the effect of DRD4 -616 C/G SNP on thalamic gamma-aminobutyric acid (GABA) levels in PNE children. STUDY TYPE: Prospective, observational. SUBJECTS: One hundred and seventy-six children with PNE and 161 healthy control children. FIELD STRENGTH/SEQUENCE: 3 T, three-dimensional T1-weighted turbo field echo sequence and MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) MRS sequence. ASSESSMENT: The MEGA-PRESS MRS sequence was used to measure thalamic GABA spectra. The thalamic GABA+ level was calculated using the Gannet 3.0 software package for each participant. A questionnaire was used to determine arousal from sleep (AS) scores. STATISTICAL TESTS: Comparisons of the AS scores and thalamic GABA+ levels were performed using the Mann-Whitney U test between C-allele carriers and GG homozygotes in the PNE and control groups. Spearman correlation analysis was performed to determine the association between AS scores and thalamic GABA levels in PNE children. RESULTS: Thalamic GABA levels in the PNE group were significantly higher than those in the healthy control group (0.178 (0.169-0.186) vs. 0.154 (0.146-0.164), Z = 8.526, Pcorrected < 0.001). The GABA levels in C-allele carriers were significantly higher than those in GG homozygotes in both the PNE and control groups (0.184 (0.181-0.193) vs. 0.170 (0.165-0.177), Z = 8.683, Pcorrected < 0.001; 0.166 (0.156-0.170) vs. 0.147 (0.141-0.152), Z = 9.445, Pcorrected < 0.001). GABA levels in the thalamus were also significantly and positively correlated with AS scores in C-allele carriers in the PNE group (r = 0.747, P < 0.05). DATA CONCLUSION: DRD4 -616 C allele may be associated with increased thalamic GABA+ levels, especially in C-allele carrying PNE children. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

High doses of butyrate induce a reversible body temperature drop through transient proton leak in mitochondria of brain neurons.

AIMS: Sodium butyrate (SB) is a major product of gut microbiota with signaling activity in the human body. It has become a dietary supplement in the treatment of intestinal disorders. However, the toxic effect of overdosed SB and treatment strategy remain unknown. The two issues are addressed in current study. MATERIALS AND METHODS: SB (0.3-2.5 g/kg) was administrated through a single peritoneal injection in mice. The core body temperature and mitochondrial function in the brown adipose tissue and brain were monitored. Pharmacodynamics, targeted metabolomics, electron microscope, oxygen consumption rate and gene knockdown were employed to dissect the mechanism for the toxic effect. KEY FINDINGS: The temperature was reduced by SB (1.2-2.5 g/kg) in a dose-dependent manner in mice for 2-4 h. In the brain, the effect was associated with SB elevation and neurotransmitter reduction. Metabolites changes were seen in the glycolysis, TCA cycle and pentose phosphate pathways. Adenine nucleotide translocase (ANT) was activated by butyrate for proton transportation leading to a transient potential collapse through proton leak. The SB activity was attenuated by ANT inhibition from gene knockdown or pharmacological blocker. ROS was elevated by SB for the increased ANT activity in proton leak in Neuro-2a. SIGNIFICANCE: Excessive SB generated an immediate and reversible toxic effect for inhibition of body temperature through transient mitochondrial dysfunction in the brain. The mechanism was quick activation of ANT proteins for potential collapse in mitochondria. ROS may be a factor in the ANT activation by SB.

Synthesis and anti-inflammatory activity of saponin derivatives of δ-oleanolic acid.

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases.

Dietary Melatonin Therapy Alleviates the Lamina Cribrosa Damages in Patients with Mild Cognitive Impairments: A Double-Blinded, Randomized Controlled Study.

BACKGROUND Alzheimer's disease (AD) is a degenerative disease that is characterized by massive neuron devastations in the hippocampus and cortex. Mild cognitive impairment (MCI) is the transitory stage between normality and AD dementia. This study aimed to investigate the melatonin induced effects on the lamina cribrosa thickness (LCT) of patients with MCI. MATERIAL AND METHODS The LCT data of patients with MCI were compared to LCT data of healthy controls. Subsequently, all MCI patients were randomly assigned into an experimental group (with melatonin treatment) or a placebo group (without any melatonin treatment). RESULTS The LCT of MCI patients decreased significantly compared with healthy controls. The univariate analysis showed that the lower the Mini Mental State Examination (MMSE) score (P=0.038; 95% CI: 0.876, -0.209), the smaller hippocampus volume (P=0.001; 95% CI: -1.594, -2.911), and the upregulated level of cerebrospinal fluid (CSF) T-tau (P=0.036; 95% CI: 2.546, -0.271) were associated significantly with the thinner LCT in MCI patients. There were 40 patients in the experimental group and 39 patients in the placebo group. The mean age of the experimental group was not significantly different from the placebo group (66.3±8.8 versus 66.5±8.3; P>0.05). The LCT and hippocampus volume of the melatonin treated group were significantly larger compared with the placebo group (P<0.001). On the other hand, the CSF T-tau level of the melatonin treated group was significantly lower compared with the untreated group (P<0.001). CONCLUSIONS LCT assessment might allow early diagnosis of MCI. Dietary melatonin therapy could provide an effective medication for MCI patients with LCT alterations.

Lipid-lowering effects of oleanolic acid in hyperlipidemic patients.

Oleanolic acid (OA) is a pentacyclic triterpenoid compound extracted from olea europaeal, a traditional Chinese medicine herb. OA has been used in the clinic as a hepatoprotective medicine in China since 1970s. In our previous study, we observed that OA could ameliorate hyperlipidemia in animal models. In the present study, we conducted a small-scale clinical trial to evaluate the hypolipidemia effect of OA in hyperlipidemic patients. Hyperlipidemic patients were administrated with OA for four weeks (4 tablets once, three times a day). The blood samples of the patients were collected before and after OA treatment. The biological parameters were measured. Furthermore, three patients' blood samples were studied with DNA microarray. After OA administration, the TC, TG, and HDLC levels in serum decreased significantly. DNA microarray analysis results showed that the expressions of 21 mRNAs were significantly changed after OA treatment. Bioinformatics analysis showed 17 mRNAs were up-regulated and 4 mRNAs were down-regulated significantly after OA treatment. Five mRNAs (CACNA1B, FCN, STEAP3, AMPH, and NR6A1) were selected to validate the expression levels by qRT-PCR. Therefore, OA administration differentially regulated the expression of genes involved in lipid metabolism. The data showed a clinical evidence that OA could improve hyperlipidemia and also unveiled a new insight into the molecular mechanisms underlying the pharmacological effect of OA on hyperlipidemia.

Glycyrrhetinic Acid Functionalized Graphene Oxide for Mitochondria Targeting and Cancer Treatment In Vivo.

Mitochondria-mediated apoptosis (MMA) is a preferential option for cancer therapy due to the presence of cell-suicide factors in mitochondria, however, low permeability of mitochondria is a bottleneck for targeting drug delivery. In this paper, glycyrrhetinic acid (GA), a natural product from Glycyrrhiza glabra, is found to be a novel mitochondria targeting ligand, which can improve mitochondrial permeability and enhance the drug uptake of mitochondria. GA-functionalized graphene oxide (GO) is prepared and used as an effective carrier for targeted delivery of doxorubicin into mitochondria. The detailed in vitro and in vivo mechanism study shows that GA-functionalized GO causes a decrease in mitochondrial membrane potential and activates the MMA pathway. The GA-functionalized drug delivery system demonstrates highly improved apoptosis induction ability and anticancer efficacy compared to the non-GA-functionalized nanocarrier delivery system. The GA-functionalized nanocarrier also shows low toxicity, suggesting that it can be a useful tool for drug delivery.

Nigegladines A-C, Three Thymoquinone Dimers from Nigella glandulifera.

Nigegladines A-C (1-3), three thymoquinone dimers, were isolated from the seeds of Nigella glandulifera. Racemic 1 possesses a unique tricyclo[5.4.0.12,6]dodecane carbon skeleton, and compounds 2 and 3 are two unusual diterpenoid alkaloids with indole cores. Their structures were determined by extensive spectroscopic analyses, and that of 1 was confirmed by single-crystal X-ray diffraction. Both (+)-1 and (-)-1 exhibited significant protective effects against hypoxia/reoxygenation-induced H9c2 myocardial cell injury.

Asiatic acid mitigates hyperglycemia and reduces islet fibrosis in Goto-Kakizaki rat, a spontaneous type 2 diabetic animal model.

The Goto-Kakizaki (GK) rat is a spontaneous type 2 diabetic animal model, which is characterized by a progressive loss of beta islet cells with fibrosis. In the present study, the hypoglycemic effect of asiatic acid (AA) in GK rats was examined. GK rats receiving AA at a daily dose of 25 mg·kg(-1) for four weeks showed a significant reduction in blood glucose levels. Age-matched normal Wistar rats were given 0.5% sodium carboxymethyl cellulose (CMC-Na) solution for the same periods and used as control. Compared to the normal Wistar rats, GK rats treated with AA showed improvement in insulin resistance partially through decreasing glucose level (P < 0.01) and insulin level (P < 0.05). Furthermore, the results of immunohistochemistry indicate that AA treatment reduced islet fibrosis in GK rats. Fibronectin, a key protein related to islet fibrosis, was over-expressed in GK rats, which was reversed significantly by AA treatment (P < 0.05). These findings suggest that AA has a beneficial effect on lowering blood glucose levels in GK rats and improves fibrosis of islets in diabetes, which may play a role in the prevention of islets dysfunction.

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer's disease.

Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aß) species of AD have been reported, none of these probes has been used to monitor changes of Aßs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aß species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aß-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aßs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aß cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aß plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.

Efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy: a meta-analysis.

BACKGROUND AND PURPOSE: Despite the successful use of a ketogenic diet in pediatric epilepsy, its application in adults has been limited. The aim of this meta-analysis was to summarize the findings of relevant published studies in order to identify the efficacy of and compliance with a ketogenic diet and its main subtypes (i.e., classic ketogenic diet and modified Atkins diet) in adults with intractable epilepsy, and to provide useful information for clinical practice. METHODS: Electronic searches of PubMed, EMBASE, Google Scholar, and the ISI Web of Science were conducted to identify studies of the efficacy of and patient compliance with a ketogenic diet in adults with intractable epilepsy; the included studies were reviewed. Meta-analyses were performed using STATA to determine combined efficacy rates and combined rates of compliance with the ketogenic diet and its main subtypes. RESULTS: In total, 12 studies qualified for inclusion, and data from 270 patients were evaluated.The results of the meta-analysis revealed combined efficacy rates of all types of ketogenic diet, a classical ketogenic diet, and a modified Atkins diet were 42%, 52%, and 34%, respectively; the corresponding combined compliance rates were 45%, 38%, and 56%. CONCLUSIONS: The results indicate that a ketogenic diet is a promising complementary therapy in adult intractable epilepsy, and that while a classical ketogenic diet may be more effective, adult patients are likely to be less compliant with it than with a modified Atkins diet.

Maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.

AIM: To investigate the molecular signaling mechanism by which the plant-derived, pentacyclic triterpene maslinic acid (MA) exerts anti-diabetic effects. METHOD: HepG2 cells were stimulated with various concentrations of MA. The effects of MA on glycogen phosphorylase a (GPa) activity and the cellular glycogen content were measured. Western blot analyses were performed with anti-insulin receptor ß (IRß), protein kinase B (also known as Akt), and glycogen synthase kinase-3ß (GSK3ß) antibodies. Activation status of the insulin pathway was investigated using phospho-IRß, as well as phospho-Akt, and phospho-GSK3ß antibodies. The specific PI3-kinase inhibitor wortmannin was added to the cells to analyze the Akt expression. Enzyme-linked immunosorbent assay (ELISA) was used to measure the effect of MA on IRß auto-phosphorylation. Furthermore, the effect of MA on glycogen metabolism was investigated in C57BL/6J mice fed with a high-fat diet (HFD). RESULTS: The results showed that MA exerts anti-diabetic effects by increasing glycogen content and inhibiting glycogen phosphorylase activity in HepG2 cells. Furthermore, MA was shown to induce the phosphorylation level of IRß-subunit, Akt, and GSK3ß. The MA-induced activation of Akt appeared to be specific, since it could be blocked by wortmannin. Finally, MA treatment of mice fed with a high-fat diet reduced the model-associated adiposity and insulin resistance, and increased the accumulated hepatic glycogen content. CONCLUSION: The results suggested that maslinic acid modulates glycogen metabolism by enhancing the insulin signaling pathway and inhibiting glycogen phosphorylase.

Synthesis of A B C-ring subunit of C-nor-D-homo-steroidal alkaloids: towards the total synthesis of cyclopamine.

A practical approach to the synthesis of the A, B and C-ring subunit of cyclopamine has been developed. This synthetic tactic highlights the utility of mandelate acetal-mediated resolution of the fused ring ketone (±)-4 and IBX-mediated oxidation cascades from 12 to 9. The availability of advanced intermediates from enantiomerically pure (+)-4 and 2 could provide efficient access to biologically active and structurally diverse C-nor-D-homo-steroidal alkaloids such as cyclopamine.

The discovery and development of prasugrel.

INTRODUCTION: Prasugrel (CS-747, LY640315) is a third-generation thienopyridine, which gained approval by the FDA in 2009 for its use in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AREAS COVERED: This article focuses on the preclinical profile of prasugrel. Using published preclinical and clinical studies, the authors summarize the pharmacokinetics, pharmacodynamics, and pharmacogenomics of prasugrel and their distinguishing features in efficacy and safety. EXPERT OPINION: Prasugrel has a more rapid, more potent antiplatelet effect with less interindividual response variability when compared to clopidogrel. Those therapeutic advantages are attributed to features of its chemical structure that favor the metabolic conversion of prasugrel to its active metabolite. However, the increased risk of bleeding has been associated with a greater antiplatelet effect and dosing profile; this is especially the case in those patients who are at a higher risk of bleeding complications. It is therefore important for an optimal dosing strategy of prasugrel to be identified to provide a formulation that has the best balance for efficacy and safety.