Phytochemical Analysis and hypoglycemic potential of Filago hurdwarica (Wall. ex DC.) Wagenitz in alloxan induced diabetic mice.

Plants have profound therapeutic benefits, more economical treatments, fewer side effects, and a relatively cheap cost, making them a source of drugs for protective, preventative, curative, or conducive purposes and creating novel phytomedicines. Plant derived medicines are relatively safe compared to synthetic medicines. Many plants have proved to successfully aid in the treatment of diabetes including Filago hurdwarica (Wall. ex DC.) Wagenitz. The current investigations were therefore designed to assess the phytochemical, antioxidant, antidiabetic, and antihyperlipidemic activities of F. hurdwarica. The phytochemical investigations and antioxidant activities of different extracts were carried out using standard chemical tests, DPPH, and H2O2 scavenging assays. F. hurdwarica plant extract in Hydromethanolic solution were prepared by Soxhletation method and stored in refrigerator at 4°C for two days before use. Swiss Albino mice were made diabetic by a single dose of alloxan (150 mg/kg). Hydromethanolic plant extract and fractions of F. hurdwarica were screened for antidiabetic activity and given to the alloxan-induced diabetic mice at a concentration of 150-250 mg/kg of body weight in different groups of 6 diabetic mice each orally once a day for 15 days. Glibenclamide is also given to another group to as a standard drug to support the result at a dose of 10 mg/kg of body weight orally once a day for 15 days. Blood glucose levels and body weights of mice were measured on 0, 4, 7, 11 and 15th days. The study found that the extract was safe up to the dose level of 2000 mg/kg and the dose response effect of chloroform extract (150-250 mg/kg) of F. hurdwarica showed expressive antihyperglycemic effects and also improved other altered biochemical parameters associated with diabetes. The FTIR and XRD spectra demonstrated the occurrence of phenols, alcohols, alkenes, alkyl halides, ketones, and aromatic compounds and confirmed the amorphous nature of the extract. GC-MS spectral analysis showed the tentative presence of 31 phytochemical constituents in the chloroform extract of F. hurdwarica with different retention time. To conclude, the chloroform extract (250 mg/kg) of F. hurdwarica revealed considerable antioxidant, antihyperglycemic, and antihyperlipidemic potential and is safe for treating diabetes and related complications.

Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer.

Human dihydroorotate dehydrogenase (hDHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent hDHODH inhibitors with low toxicity are urgently needed. Herein, we demonstrate the isolation of 25 ascochlorin (ASC) derivatives, including 13 new ones, from the coral-derived fungus Acremonium sclerotigenum, and several of them showed pronounced inhibitions against hDHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that hDHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via hDHODH inhibition. Furthermore, the novel and potent hDHODH inhibitors (1 and 21) efficiently suppressed tumor growth in patient-derived TNBC xenograft models without obvious body weight loss or overt toxicity in mice. Collectively, our findings offered a novel lead scaffold as the hDHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.

Acetyl-CoA carboxylase 2 inhibition reduces skeletal muscle bioactive lipid content and attenuates progression of type 2 diabetes in Zucker diabetic fatty rats.

Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with development of insulin resistance. In particular, diacylglycerol and ceramide are currently considered as causal bioactive lipids for impaired insulin action. Recently, inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation, has been shown to reduce total IMCL content and improve whole-body insulin resistance. This study aimed to investigate whether ACC2 inhibition-induced compositional changes in bioactive lipids, especially diacylglycerol and ceramide, within skeletal muscle contribute to the improved insulin resistance. In skeletal muscle of normal rats, treatment of the ACC2 inhibitor compound 2e significantly decreased both diacylglycerol and ceramide levels while having no significant impact on other lipid metabolite levels. In skeletal muscle of Zucker diabetic fatty (ZDF) rats, which exhibited greater lipid accumulation than that of normal rats, compound 2e significantly decreased diacylglycerol and ceramide levels corresponding to reduced long chain acyl-CoA pools. Additionally, in the lipid metabolomics study, ZDF rats treated with compound 2e also showed improved diabetes-related metabolic disturbance, as reflected by delayed hyperinsulinemia as well as upregulated gene expression associated with diabetic conditions in skeletal muscle. These metabolic improvements were strongly correlated with the bioactive lipid reductions. Furthermore, long-term treatment of compound 2e markedly improved whole-body insulin resistance, attenuated hyperglycemia and delayed insulin secretion defect even at severe diabetic conditions. These findings suggest that ACC2 inhibition decreases diacylglycerol and ceramide accumulation within skeletal muscle by enhancing acyl-CoA breakdown, leading to attenuation of lipid-induced insulin resistance and subsequent diabetes progression.

Myrsinoic acid B from Myrsine coriacea reverses depressive-like behavior and brain oxidative stress in streptozotocin-diabetic rats.

AIMS: Major depressive disorder (MDD) affects approximately 322 million people worldwide and is a common comorbidity in patients with diabetes mellitus (DM). A possible pathophysiological mechanism correlating both diseases is the increased oxidative stress in brain regions due to hyperglycemia. Myrsine coriacea (Primulaceae) is popularly known as "capororoca" and studies have been shown that this plant exhibits several pharmacological properties attributed to myrsinoic acid A (MAA) and B (MAB). Indeed, previous results have been shown its effects on the central nervous system, leading us to explore possible psychotropic effects. MAIN METHODS: The effects of treatment with hydroalcoholic extract of the barks from Myrsine coriacea (HEBMC, 150 mg/kg, o.g.), MAA (5 mg/kg, o.g.), and MAB (3 mg/kg, o.g.) were evaluated in streptozotocin (75 mg/kg, i.p.)-induced diabetic female rats. After 28 days of treatments, rats were submitted to the forced swim test (FST) and open field test (OFT). Also, superoxide dismutase (SOD) and catalase (CAT) activities, reduced glutathione (GSH) and lipid hydroperoxides (LOOH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC) of these rats. KEY FINDINGS: The treatment with MAA or MAB increased the latency of first immobility in diabetic rats, and the HEBMC administration decreased the immobility time, and increase the climbing in FST. However, only MAB treatment reduces the immobility time, increases the climbing, and swimming in FST, and increases the crossing of diabetic animals in the OFT. Besides, this behavioral improvement promoted by MAB administration was accompanied by reducing in oxidative stress in the HIP and PFC, but not reducing hyperglycemia in diabetic rats. SIGNIFICANCE: The results suggest that MAB's antioxidant effect in the HIP of diabetic animals may be essential to its antidepressant-like effect.

Neurovascular protection of salvianolic acid B and ginsenoside Rg1 combination against acute ischemic stroke in rats.

Ischemic stroke continues to be a major global health problem associated with considerable mortality and morbidity. Thus, it is still targeted by researchers for developing new strategies or drugs to alleviate the lesion of stroke. In the present study, both the permanent occlusion of the middle cerebral artery (MCAO) model and the restoration of cerebral blood flow after middle cerebral artery occlusion (CI/R) model were set up for evaluating the efficiency of salvianolic acid B and ginsenoside Rg1 combination (SalB-Rg1). SalB-Rg1 decreased infarct area through 3,5-triphenyltetrazolium chloride stain and improved neurological behavior through Longa Score or Left-Biased Swings on both MCAO rats and CI/R rats. Neural protection of SalB-Rg1 against ischemia or ischemic reperfusion injury was evidenced by the inhibition of nucleus pyknosis, liquefaction necrosis through H&E stain and Nissl stain. Furthermore, protection of SalB-Rg1 on blood-brain barrier (BBB) was more significant on CI/R rats, accompanying with the downregulation of matrix metalloproteinase-2 and matrix metalloproteinase-9, and recovery of zonula occludens-1 expression. These results provide compelling evidence that SalB-Rg1 holds the potential to be developed as an optimal therapeutic strategy to alleviate the injury of ischemia or ischemic reperfusion.

Effectiveness and Safety of Posterior Vaginal Repair with Single-Incision, Ultralightweight, Monofilament Propylene Mesh: First Evidence from a Case Series with Short-Term Results.

OBJECTIVE: The use of transvaginal mesh is controversial, and over time, multiple surgical methods for the treatment of posterior vaginal prolapse (PVP) have been proposed including different surgical approaches and techniques. To date, no clear conclusion has been reached about the use of mesh for reinforcing transvaginal posterior repair. The aim of this study was to evaluate the feasibility, safety, and effectiveness of a novel, ultralightweight mesh for the treatment of PVP. METHODS: We performed a single-center, prospective observational study on consecutive patients referred for primary or recurrent, symptomatic stage II PVP (according to the international Pelvic Organ Prolapse Quantification System) from April 2017 to September 2018. In all patients, transvaginal posterior repair was augmented with a single-incision, isoelastic polypropylene mesh. Data about the postoperative outcomes were collected until December 2019. RESULTS: A total number of 15 patients were included. The median follow-up after surgery was 18 months (IQR = 14). Surgery was completed in all cases without complications. Regarding the anatomical outcomes (as measured according to POP-q classification), a significant improvement was observed in terms of Bp, D, and C (p < 0.05). The functional outcomes were significantly ameliorated after surgery, with a reduction of bulge symptom, stypsis, incomplete evacuation, and excessive staining (p < 0.05). The quality of life was significantly improved in the majority of patients (p < 0.05). Median patients' satisfaction rate was 100% (IQR = 22.5%). Neither early nor late postoperative complications occurred. CONCLUSIONS: Single-incision, ultralightweight polypropylene meshes were safe and highly effective in the treatment of PVP. As our study has some limitations, further large, controlled studies are needed.

Dienone Compounds: Targets and Pharmacological Responses.

The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review in vitro and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613. A common property of these compounds is their targeting of the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. Gene expression profiling experiments have shown induction of responses characteristic of UPS inhibition, and experiments using cellular reporter proteins have shown that proteasome inhibition is associated with cell death. Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models.

The efficacy and safety of salvianolic acids on acute cerebral infarction treatment: A protocol for systematic review and meta analysis.

BACKGROUND: Salvianolic acids (SA) has been widely used for the treatment of acute cerebral infarction (ACI) combined with basic western medicine therapy in China. This study was aimed to evaluate the efficacy and safety of SA on ACI treatment and its influence on neurological functions, activity of daily living, and cognitive functions. METHODS: We retrieved related articles from PubMed, the Cochrane Center Controlled Trials Register, EMBASE, Medline, Ovid, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wanfang Database without date and language restrictions. Finally, 58 randomized controlled trials were included from 239 retrieved records. Two researchers extracted the basic information and data from included articles and assessed the quality and analysis of data by using Review Manager 5.3. RESULTS: The administration of SA significantly increased the total clinical effective rate of ACI treatment (P < .001) and improved the National Institute of Health Stroke Scale scores, modified Rankin Scale scores, and Barthel Index scores after treatment and 3 months after ACI (P < .05). The activities of daily living scores in the SA group were significantly increased after treatment (P < .001), whereas they were remarkably decreased 3 months after ACI (P < .001) compared with that in the control group. Besides, SA profoundly promoted the recovery of Montreal Cognitive Assessment scores (P < .001). However, the use of SA increased the risk of adverse events occurrence (P = .007). CONCLUSION: SA combined with basic western medicine treatment could promote neurological functions, daily living activities, and cognitive functions recovery of ACI patients. Although SA increased the risk of adverse events occurrence, these adverse events were easily controlled or disappeared spontaneously.

Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling.

Acetaminophen (APAP) overdose is one of the most common causes of drug-induced acute liver failure in humans. To investigate the hepatoprotective effect of salvianolic acid C (SAC) on APAP-induced hepatic damage, SAC was administered by daily intraperitoneal (i.p.) injection for 6 days before the APAP administration in mice. SAC prevented the elevation of serum biochemical parameters and lipid profile including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), total cholesterol (TC), and triacylglycerol (TG) against acute liver failure. Additionally, SAC reduced the content of malondialdehyde (MDA), the cytochrome P450 2E1 (CYP2E1), and the histopathological alterations and inhibited the production of proinflammatory cytokines in APAP-induced hepatotoxicity. Importantly, SAC effectively diminished APAP-induced liver injury by inhibiting nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinases (MAPKs) activation signaling pathway. Moreover, SAC enhanced the levels of hepatic activities of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in APAP-induced mice. SAC mainly inhibited the activation of apoptotic pathways by reduction of cytochrome c, Bax, and caspase-3 protein expression. Taken together, we provide the molecular evidence that SAC protected the hepatocytes from APAP-induced damage by mitigating mitochondrial oxidative stress, inflammatory response, and caspase-mediated antiapoptotic effect through inhibition of the Keap1/Nrf2/HO-1 signaling axis.

Activation of Nrf2 signaling by salvianolic acid C attenuates NF­κB mediated inflammatory response both in vivo and in vitro.

Neurodegenerative diseases are closely related to neuroinflammation. Drugs targeting inflammation have been proved to be effective in many animal models. Salvianolic acid C (SalC) is a compound isolated from Salvia miltiorrhiza Bunge, a plant with reported effects of inhibiting inflammation. However, the anti-inflammation effects and biological mechanisms of SalC on LPS-stimulated neuroinflammation remain unknown. The aim of this paper was to study its protective effects and its anti-inflammation mechanisms. LPS was used both in vivo and in vitro to induce neuroinflammation in SD rats and microglia cells. MTT assay was carried out to detect cell viability. The levels of TNF­α, IL­1ß, IL­6, IL­10 and PGE2 were detected by ELISA method. The expressions of p­AMPK, p­NF­κB p65, p­IκBα, Nrf2, HO­1 and NQO1 proteins were examined by Western blot analysis. The nuclear translocation of NF­κB p65 was studied by immunofluorescence assay. The specific Nrf2 siRNA was used to clarify the interaction between Nrf2 and NF­κB p65. The AMPK inhibitor Compound C was used study the upstream protein of Nrf2. Results showed that LPS induced the overexpression of inflammatory cytokines and mediated the phosphorylation and nuclear translocation of NF­κB p65 in rat brains and microglia cells. SalC reversed the inflammatory response induced by LPS and inhibited the NF­κB activation. SalC also upregulated the expression of p­AMPK, Nrf2, HO­1 and NQO1. But the anti-inflammation and NF­κB inhibition effects of SalC were attenuated by transfection with specific Nrf2 siRNA or interference with the potent AMPK inhibitor Compound C. In conclusion, SalC inhibited LPS-induced inflammatory response and NF­κB activation through the activation of AMPK/Nrf2 signaling both in vivo and in vitro.

Aryl Butenes Active against K562 Cells and Lacking Tyrosinase Inhibitory Activity as New Leads in the Treatment of Leukemia.

BACKGROUND & OBJECTIVE: The inhibitory effects of four series of aryl butene derivatives, active against breast cancer, on the monophenolase activity of tyrosinase, in melanin-free ink from Sepia officinalis, have been studied. Hydroxytamoxifen 1, ferrociphenol 17 and several aryl butene analogs have shown strong antiproliferative activity on hormone-dependent and hormone-independent breast cancer cells and were evaluated in leukemia K562 cell proliferation. Their potential to induce skin depigmentation by evaluating their anti-tyrosinase activity was also estimated. In order to better rationalize the tyrosinase inhibitory action and the binding mode of the compounds, docking studies were carried out. CONCLUSION: Hydroxytamoxifen and some aryl butenes showed strong antiproliferative effects against K562 cells at 1 µM without showing tyrosinase inhibition. If phenolic compounds 16 and 17 showed the best antiproliferative activity on K562, Hydroxytamoxifen and compounds 5, 10, 20 and 21 have been identified as candidates for further development against chronic myeloid leukemia (CML), and are predicted to not induce depigmentation of the skin, a side effect encountered with imatinib, conventionally used for the treatment of CML.

Prescription Optimization and Oral Bioavailability Study of Salvianolic Acid Extracts W/O/W Multiple Emulsion.

The purpose of this study is to develop a new method of preparing salvianolic acid extracts (SAE) water-in-oil-in-water (W/O/W) multiple emulsion (ME). SAE injection is used in the treatment of brain infarct and promotion of blood circulation in China. However, the injection is not convenient, and the oral preparation has poor bioavailability. Hence, a new preparation that is convenient and stable with good biological availability is required. SAE ME was prepared by two-step emulsification method. Combined with single-factor investigation and orthogonal test, the embedding rate and centrifugal retention rate were taken as the comprehensive indexes to optimize the formulation of SAE ME. The ME size was tested by laser particle size analyzer. The pharmacokinetic studies were conducted in Sprague-Dawley rats with HPLC-MS/MS method. The blood coagulation and hemorheology tests were conducted to assess the effect of preparation in rats. The best preparation technique for SAE ME is by the use of trospium chloride; SAE represent 12% of water in the phase, lipophilic emulsifier hydrophilic lipophilic balance value=4.3, lipophilic emulsifier is 20% of the oil phase. The median diameter of particle is (0.608±0.05) µm and the Cmax of ME is 3-fold higher compared to Cmax of free drug. The oral biavailability of ME is 26.71-fold higher than that of free drug with good effect on blood circulation. SAE ME is stable hence, improves the biological availability and slows down drug release.

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice.

Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2'-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway.

Salvianolic Acid Exerts Cardioprotection through Promoting Angiogenesis in Animal Models of Acute Myocardial Infarction: Preclinical Evidence.

Radix Salviae miltiorrhizae, danshen root (danshen), is one of the widely used Chinese herbal medicines in clinics, containing rich phenolic compounds. Salvianolic acid is the main active compound responsible for the pharmacologic effects of danshen. Here, we aimed to evaluate the effects of salvianolic acid on cardioprotection through promoting angiogenesis in experimental myocardial infarction. Studies of salvianolic acid in animal models of myocardial infarction were obtained from 6 databases until April 2016. The outcome measures were vascular endothelium growth factor (VEGF), blood vessel density (BVD), and myocardial infarct size. All the data were analyzed using Rev-Man 5.3 software. Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P < 0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving BVD compared with the control group (P < 0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P < 0.01). In conclusion, these findings demonstrated that salvianolic acid can exert cardioprotection through promoting angiogenesis in animal models of myocardial infarction.

Molecular Targets of Ascochlorin and Its Derivatives for Cancer Therapy.

Cancer is an extremely complex disease comprising of a multitude of characteristic hallmarks that continue to evolve with time. At the genomic level, random mutations leading to deregulation of diverse oncogenic signal transduction cascades and polymorphisms coupled with environmental as well as life style-related factors are major causative agent contributing to chemoresistance and the failure of conventional therapies as well as molecular targeted agents. Hence, there is an urgent need to identify novel alternative therapies based on alternative medicines to combat this dreaded disease. Ascochlorin (ASC), an isoprenoid antibiotic isolated initially from the fermented broth of Ascochyta viciae, and its synthetic derivatives have recently demonstrated substantial antineoplastic effects in a variety of tumor cell lines and mouse models. The major focus of this review article is to briefly analyze the chemopreventive as well as therapeutic properties of ASC and its derivatives and to identify the multiple molecular targets modulated by this novel class of anticancer agent.

Amelioration of cognitive impairments in APPswe/PS1dE9 mice is associated with metabolites alteration induced by total salvianolic acid.

PURPOSE: Total salvianolic acid (TSA) is extracted from salvia miltiorrhiza; however, to date, there has been limited characterization of its effects on metabolites in Alzheimer's disease model-APPswe/PS1dE9 mice. The main objective of this study was to investigate the metabolic changes in 7-month-old APPswe/PS1dE9 mice treated with TSA, which protects against learning and memory impairment. METHODS: APPswe/PS1dE9 mice were treated with TSA (30 mg/kg·d and 60 mg/kg·d, i.p.) and saline (i.p.) daily from 3.5 months old for 14 weeks; saline-treated (i.p.) WT mice were included as the controls. The effects of TSA on learning and memory were assessed by a series of behavioral tests, including the NOR, MWM and step-through tasks. The FBG and plasma lipid levels were subsequently assessed using the GOPOD and enzymatic color methods, respectively. Finally, the concentrations of Aß42, Aß40 and metabolites in the hippocampus of the mice were detected via ELISA and GC-TOF-MS, respectively. RESULTS: At 7 months of age, the APPswe/PS1dE9 mice treated with TSA exhibited an improvement in the preference index (PI) one hour after the acquisition phase in the NOR and the preservation of spatial learning and memory in the MWM. Treatment with TSA substantially decreased the LDL-C level, and 60 mg/kg TSA decreased the CHOL level compared with the plasma level of the APPswe/PS1dE9 group. The Aß42 and Aß40 levels in the hippocampus were decreased in the TSA-treated group compared with the saline-treated APPswe/PS1dE9 group. The regulation of metabolic pathways relevant to TSA predominantly included carbohydrate metabolism, such as sorbitol, glucose-6-phosphate, sucrose-6-phosphate and galactose, vitamin metabolism involved in cholecalciferol and ascorbate in the hippocampus. CONCLUSIONS: TSA induced a remarkable amelioration of learning and memory impairments in APPswe/PS1dE9 mice through the regulation of Aß42, Aß40, carbohydrate and vitamin metabolites in the hippocampus and LDL-C and CHOL in the plasma.

Production of taxadiene by engineering of mevalonate pathway in Escherichia coli and endophytic fungus Alternaria alternata TPF6.

Taxol (paclitaxel) is a diterpenoid compound with significant and extensive applications in the treatment of cancer. The production of Taxol and relevant intermediates by engineered microbes is an attractive alternative to the semichemical synthesis of Taxol. In this study, based on a previously developed platform, the authors first established taxadiene production in mutant E. coli T2 and T4 by engineering of the mevalonate (MVA) pathway. The authors then developed an Agrobacterium tumefaciens-mediated transformation (ATMT) method and verified the strength of heterologous promoters in Alternaria alternata TPF6. The authors next transformed the taxadiene-producing platform into A. alternata TPF6, and the MVA pathway was engineered, with introduction of the plant taxadiene-forming gene. Notably, by co-overexpression of isopentenyl diphosphate isomerase (Idi), a truncated version of 3-hydroxy-3-methylglutaryl-CoA reductase (tHMG1), and taxadiene synthase (TS), the authors could detect 61.9 ± 6.3 µg/L taxadiene in the engineered strain GB127. This is the first demonstration of taxadiene production in filamentous fungi, and the approach presented in this study provides a new method for microbial production of Taxol. The well-established ATMT method and the known promoter strengths facilitated further engineering of taxaenes in this fungus.

A mini-network balance model for evaluating the progression of cardiovascular complications in Goto-Kakizaki rats.

Cardiovascular complications represent a leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). During such complicated progression, subtle variations in the cardiovascular risk (CVR)-related biomarkers have been used to identify cardiovascular disease at the incipient stage. In this study we attempt to integrally characterize the progression of cardiovascular complications and to assess the beneficial effects of metformin combined with salvianolic acid A (Sal A), in Goto-Kakizaki (GK) rats with spontaneous T2DM. The rats were treated with metformin (200 mg·kg-1·d-1, ig) alone or in combination with Sal A (1 mg·kg-1·d-1, ip) at ages from 8 to 22 weeks. During the treatment, the levels of asymmetric dimethylarginine, L-arginine, superoxide dismutase, malondialdehyde, glucose, high density lipoprotein and low density lipoprotein were assessed. Based on alterations in these biomarkers, a mini-network balance model was established using matrixes and vectors. Radar charts were created to visually depict the disruption of CVR-related modules (endothelial function, oxidative stress, glycation and lipid profiles). The description for the progression of cardiovascular disorder was quantitatively represented by u, the dynamic parameter of the model. The modeling results suggested that untreated GK rats tended to have more severe cardiovascular complications than the treatment groups. Metformin monotherapy retarded disease deterioration, whereas the combination treatment ameliorated the disease progression via restoring the balance. The current study, which focused on the balance of the mini-network and interactions among CVR-related modules, proposes a novel method for evaluating the progression of cardiovascular complications in T2DM as well as a more beneficial intervention strategy.

The effect of Chinese herbs and its effective components on coronary heart disease through PPARs-PGC1α pathway.

BACKGROUND: DanQi pill (DQP) is prescribed widely in China and has definite cardioprotective effect on coronary heart disease. Our previous studies proved that DQP could effectively regulate plasma levels of high density lipoprotein (HDL) and low density lipoprotein (LDL). However, the regulatory mechanisms of DQP and its major components Salvianolic acids and Panax notoginseng saponins (DS) on lipid metabolism disorders haven't been comprehensively studied so far. METHODS: Rat model of coronary heart disease was induced by left anterior descending (LAD) artery ligation operations. Rats were divided into sham, model, DQP treated, DS treated and positive drug (clofibrate) treated groups. At 28 days after surgery, cardiac functions were assessed by echocardiography. Expressions of transcription factors and key molecules in energy metabolism pathway were measured by reverse transcriptase polymerase chain reaction or western blotting. RESULTS: In ischemic heart model, cardiac functions were severely injured but improved by treatments of DQP and DS. Expression of LPL was down-regulated in model group. Both DQP and DS could up-regulate the mRNA expression of LPL. Membrane proteins involved in lipid transport and uptake, such as FABP4 and CPT-1A, were down-regulated in ischemic heart tissues. Treatment with DQP and DS regulated lipid metabolisms by up-regulating expressions of FABP4 and CPT-1A. DQP and DS also suppressed expression of cytochrome P450. Furthermore, transcriptional factors, such as PPARα, PPARγ, RXRA and PGC-1α, were down-regulated in ischemic model group. DQP and DS could up-regulate expressions of these factors. However, DS showed a better efficacy than DQP on PGC-1α, a coactivator of PPARs. Key molecules in signaling pathways such as AKT1/2, ERK and PI3K were also regulated by DQP and DS simultaneously. CONCLUSIONS: Salvianolic acids and Panax notoginseng are the major effective components of DanQi pill in improving lipid metabolism in ischemic heart model. The effects may be mediated by regulating transcriptional factors such as PPARs, RXRA and PGC-1α.

Amelioration of salvianolic acid C on aortic structure in apolipoprotein E-deficient mice treated with angiotension II.

AIMS: Aortic aneurysm is a disastrous vascular disease with high morbidity and mortality. Matrix metalloproteinases (MMPs), especially MMP-9, is implicated in the development of aortic aneurysm, but the effective MMP inhibitors are far from development. To develop new candidate compound for aortic aneurysm therapy, we evaluated the effects of salvianolic acid C (SalC) against the formation of aortic aneurysm. MATERIALS AND METHODS: Aortic aneurysm was induced by implantation of angiotension II (AngII) minipump in apolipoprotein E-deficient (ApoE-/-) mice. MMPs activity was evaluated by enzyme kinetic analysis in vitro and in-gel gelatin zymography in vivo. The formation of aortic aneurysm was confirmed based on aortic maximum diameter. Hematoxylin and eosin stain was used to evaluate aortic structure, picrosirius red stain was for collagen deposition, and orcein stain was for elastin fragmentation. Macrophage infiltration was detected by CD68 immunohistochemistry. KEY FINDINGS: Firstly, SalC showed significant inhibition on the activity of MMP-2 and MMP-9. Aortic aneurysm was defined as >50% increase in maximum diameter of aorta, and the down-regulated tendency of 20mg/kg SalC against formation of aortic aneurysm was detected. Also, 22.2% rupture was detected in ApoE-/- mice, while no rupture of aortic aneurysm was found with 20mg/kg SalC treatment. Then, SalC was detected to maintain the integrity of aortic structure and protect elastin against fragmentation. Finally, SalC considerably inhibited infiltration of macrophage in the injury site of aorta. SIGNIFICANCE: SalC significantly ameliorated the progression of aortic aneurysm in ApoE-/- mice, and held great potential for aortic aneurysm therapy.