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Protozoan parasites such as Eimeria tenella and Toxoplasma gondii pose significant health challenges in livestock and humans. The limited treatment options and rising drug resistance underscore the urgent need for new therapies. This study investigates myrcene, a monoterpene hydrocarbon classified for its antiprotozoal potential against E. tenella and T. gondii infections. Initially, we examined its effect on the sporulation process of E. tenella oocysts in vitro and its anti-E. tenella activity in vivo. Myrcene significantly reduced the sporulation rate of E. tenella oocysts at 3 and 4 mg/kg. In vivo experiments demonstrated that treatment with 4 mg/kg myrcene significantly reduced E. tenella load and oocyst output, as well as cecal lesion and weight loss caused by E. tenella infection, showing moderate anti-E. tenella activity, with an Anticoccidial Index (ACI) of 161.4. Furthermore, we investigated the anti-T. gondii activity of myrcene both in vitro and in vivo. In vitro studies showed that treatment with myrcene effectively inhibited the invasion rate and intracellular proliferation ability of T. gondii tachyzoite in DF-1 cells in a dose-dependent manner. In vivo administration prolonged the survival time in T. gondii-infected mice, suggesting notable protective effects. Additionally, it mitigated T. gondii-induced hepatosplenic toxicity by reducing parasite load in the liver and spleen, and ameliorating liver function as evidenced by decreased serum transaminase levels. In conclusion, the findings demonstrate promising anti-E. tenella and anti-T. gondii activity exhibited by myrcene warranting further exploration into its mechanisms and potential therapeutic applications.

Ischemic stroke (IS), primarily caused by cerebrovascular occlusion, poses a significant public health challenge with limited effective therapeutic options. Evidence suggests that salvianolic acids (SAs), mainly from Salvia miltiorrhiza Bunge, have been formulated into injections and are widely used in clinical treatments for cardiovascular and cerebrovascular diseases, including stroke. The pharmacological properties of SAs include reducing neuroinflammation, alleviating oxidative stress injury, inhibiting cellular apoptosis, preserving endothelial function, maintaining blood-brain barrier integrity, and promoting angiogenesis. Salvianolic acids for injection (SAFI) serve as a safe and effective treatment option for cardiovascular and cerebrovascular conditions by influencing various signaling pathways and molecular targets associated with these diseases. In this review, we first discuss the pathogenesis of IS, then summarize the classification of SAs, elaborate detailed molecular mechanisms of their efficacy, and the related clinical applications of SAFI. We also emphasize the recent pharmacological advancements and therapeutic possibilities of this promising drug preparation derived from herbs for cerebrovascular conditions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

Myrcene (Myr) has been reported to show neuroprotective effects in cerebral ischemia. In this research work, we investigated the Myr effect on neurobehavioural, and neuropathological alteration in mice induced by Aluminium trichloride (AlCl 3 ) and D - galactose. The administration of AlCl 3 (5 mg/kg; p. o.), and D - galactose (60 mg/kg; i. p.) for 90 days in mice resulted in spatial learning and memory deficits, cognitive decline, as well as neurotoxicity. The treatments with Myr low dose (100 mg/kg), Myr high dose (200 mg/kg), donepezil (2 mg/kg), and Myr low dose + donepezil (100 + 2 mg/kg) were administered via intraperitoneal route for 30 days significantly reversed the neurobehavioral, and neuropathological effects of AlCl 3 and D - galactose in mice. The results of behavioural tests such as Morris water maze, elevated plus maze, and locomotor; biochemical analysis such as malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), nitrite, and acetylcholinesterase (AChE); and ELISA tests such as mouse β - secretase (BACE), amyloid-beta peptide 1-42 (Aβ 1 - 42 ), tumor necrosis factor - α (TNF-α), interleukin - 6 (IL-6), and brain-derived neurotrophic factor (BDNF) demonstrated a significant (p < 0.05) neuroprotective effect of the Myr and donepezil co-treatments. In addition, hematoxylin and eosin staining of the cerebral cortex and hippocampus revealed eosinophilic lesions and hyperchromatic nuclei in Alzheimer's disease mice, but treatments with Myr low dose, Myr high dose, donepezil, and Myr low dose + donepezil reversed these neurodegenerative effects. Myr showed these activities by enhancing synaptic plasticity and cholinergic activity, as well as reducing oxidative damage, neuroinflammation, Aβ 1-42 aggregations, and histopathological damage. Myr alone and in combination with donepezil may serve as a potential candidate for the treatment of Alzheimer's disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Human dihydroorotate dehydrogenase ( h DHODH) is an attractive tumor target essential to de novo pyrimidine biosynthesis. Novel potent h DHODH 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 h DHODH and triple-negative breast cancer (TNBC) cell lines, MDA-MB-231/-468. Interestingly, we found that h DHODH is required for proliferation and survival of TNBC cells, and several ASCs significantly inhibited TNBC cell growth and induced their apoptosis via h DHODH inhibition. Furthermore, the novel and potent h DHODH 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 h DHODH inhibitor for further development of potent anticancer agents and a potential therapeutic strategy for TNBC.

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., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: All authors have no conflicts of interest to disclose., (Copyright © 2021 Francesco Deltetto et al.)

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.

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.

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- κ B), 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.

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 TNF‑α, IL‑1β, IL‑6, IL‑10 and PGE 2 were detected by ELISA method. The expressions of p‑AMPK, p‑NF‑κB p65, p‑IκBα, Nrf2, HO‑1 and NQO1 proteins were examined by Western blot analysis. The nuclear translocation of NF‑κB p65 was studied by immunofluorescence assay. The specific Nrf2 siRNA was used to clarify the interaction between Nrf2 and NF‑κB 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 NF‑κB p65 in rat brains and microglia cells. SalC reversed the inflammatory response induced by LPS and inhibited the NF‑κB activation. SalC also upregulated the expression of p‑AMPK, Nrf2, HO‑1 and NQO1. But the anti-inflammation and NF‑κB 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 NF‑κB activation through the activation of AMPK/Nrf2 signaling both in vivo and in vitro., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

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 C max of ME is 3-fold higher compared to C max 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.

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., (© 2017 International Society for Neurochemistry.)

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., (Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 Aβ42, Aβ40 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 Aβ42 and Aβ40 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 Aβ42, Aβ40, carbohydrate and vitamin metabolites in the hippocampus and LDL-C and CHOL in the plasma.

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.

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.

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., (© 2017 Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2016. Published by Elsevier Inc.)

The present study was designed to investigate the potential therapeutic effect of trikatu, an herbal compound and its underlying molecular mechanism in rats with adjuvant-induced arthritis (AIA). Our results indicate that trikatu (1000 mg/kg/b.wt. oral) administration suppressed the production of pro-inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein (MCP)-1) and downregulated the mRNA expression levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-17, MCP-1, receptor activator of nuclear factor kappa B ligand (RANKL), cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS)) and transcription factors (nuclear factor kappa B 65 (NFкB-p65) and activator protein-1 (AP-1)) in cultured AIA-fibroblast like synoviocytes and synovial tissue of AIA rats. Consistently, the protein expression of NFкB-p65, IL-17, TNF-α, COX-2, and RANKL was also dramatically reduced in cultured AIA-fibroblast like synoviocytes and synovial tissue of AIA rats by trikatu treatment. In addition, trikatu suppressed the expression and phosphorylation of NFкB-p65 similar to the Bay 11-7082 (NFкB inhibitor) in cultured AIA-fibroblast like synoviocytes. Furthermore, trikatu alleviated the histopathology of joint of arthritic rats. Overall, these data highlights that trikatu could be a promising alternative modality for the possible treatment of rheumatoid arthritis and other inflammatory diseases., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To establish the beneficial effects of salvianolic acid and fluoxetine on the improvement of cognitive function and amelioration of depression-like symptoms of rats with chronic stress-induced depression., Methods: Ninety-nine male Sprague-Dawley rats were randomly divided into 5 groups--a control group with no stress challenge and 4 chronic stress groups. Rats assigned to chronic stress groups were exposed to stress for 3 weeks, and then were given placebo, fluoxetine (20 mg/kg), salvianolic acid (40 mg/kg), or combined fluoxetine and salvianolic acid. Body weight of each rat was recorded throughout the study. Sucrose preference test and water maze experiment were performed after chronic stress challenge and after drug treatment to assess the effect of drug treatments on depressive-like symptoms and cognitive function. The sucrose preference test was also performed before chronic stress exposure for baseline measurement., Results: Exposure of rats to chronic stress for 3 weeks significantly reduced body weight and sucrose preference values compared with the no stress control. The water maze experiment showed that chronic stress impaired the spatial learning of rats as well. Treatment of stress-challenged rats with fluoxetine and fluoxetine combined with salvianolic acid resulted in shorter training latency and longer time spent in the target quadrant during the exploration stage of the water maze experiment compared with placebo treatment. Effect of the combined regimen was found more obvious., Conclusions: Combination therapy of salvianolic acid and fluoxetine could alleviate depression-like symptoms and cognitive deficit induced by chronic stress., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ocimum gratissimum is used in popular medicine to treat painful diseases. The antihypernociceptive properties of O. gratissimum essential oil and two of its active components (eugenol and myrcene) were tested in a model of neuropathic pain induced by a chronic constriction injury of the sciatic nerve. In tests to determine chronic antinociception, adult male C57BL/6 J mice were treated orally with corn oil (control group), O. gratissimum essential oil at doses of 10, 20, or 40 mg/kg or eugenol or myrcene at doses of 1, 5, or 10 mg/kg for 14 days after surgery. Pregabalin (20 mg/kg) was used as a standard in this study. The treatment with 20 and 40 mg/kg of O. gratissimum essential oil and at doses of 5 and 10 mg/kg of the active components were able to promote antihypernociception in both mechanical (von Frey) and thermal (hot plate) tests. The treatment with the essential oil of the plant or eugenol was effective in reducing the levels of interleukin-1β in the sciatic nerve. Our findings demonstrate that O. gratissimum essential oil and its isolated active components possess antihypernociceptive activity in neuropathic pain models., (Georg Thieme Verlag KG Stuttgart · New York.)

Objective: TSI is a new drug derived from Chinese medicine for treatment of ischemic stroke in China. The aim of this study was to verify the therapeutic effect of TSI in a rat model of MCAO, and further explore the mechanism for its effect., Methods: Male Sprague-Dawley rats were subjected to right MCAO for 60 minutes followed by reperfusion. TSI (1.67 mg/kg) was administrated before reperfusion via femoral vein injection. Twenty-four hours after reperfusion, the fluorescence intensity of DHR 123 in, leukocyte adhesion to and albumin leakage from the cerebral venules were observed. Neurological scores, TTC staining, brain water content, Nissl staining, TUNEL staining, and MDA content were assessed. Bcl-2/Bax, cleaved caspase-3, NADPH oxidase subunits p47(phox)/p67(phox)/gp91(phox), and AMPK/Akt/PKC were analyzed by Western blot., Results: TSI attenuated I/R-induced microcirculatory disturbance and neuron damage, activated AMPK, inhibited NADPH oxidase subunits membrane translocation, suppressed Akt phosphorylation, and PKC translocation., Conclusions: TSI attenuates I/R-induced brain injury in rats, supporting its clinic use for treatment of acute ischemic stroke. The role of TSI may benefit from its antioxidant activity, which is most likely implemented via inactivation of NADPH oxidase through a signaling pathway implicating AMPK/Akt/PKC., (© 2014 John Wiley & Sons Ltd.)

Introduction: Trikatu is composed of dried fruits of Piper nigrum L and Piper retrofractum Vahl, and dried rhizomes of Zingiber officinale R. Although this preparation has been used to relieve pruritis, pain, and inflammation for a long time, there is no clinical evidence to confirm its efficacy and safety. Therefore, we performed a double-blind, within person-randomized controlled study of 30 healthy volunteers to determine efficacy and safety of topical Trikatu on mosquito bite reactions., Methods: All subjects were bitten by Aedes aegypti laboratory mosquitoes on their forearms and they were randomly assigned arms to apply either Trikatu or reference product on the mosquito bite papule. The main outcome was the difference of papule size reduction at 30 min, measured by a caliper, between the Trikatu and reference arms. Pruritis, redness, pain, and patient satisfaction were assessed at 15, 30, 60, 180, and 360 min as secondary outcomes., Results: There were no significant differences between treatment and reference arms on any outcome at any time of measurement., Conclusion: Trikatu did not show additional effects for relieving mosquito bite reaction as compared with the reference product containing camphor, menthol, and eucalyptus. For further study, it is very important to consider a proper selection of subjects, comparator product, and concentration of extract when Trikatu preparation is investigated., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Gout is an inflammatory joint disorder characterized by hyperuricaemia and precipitation of monosodium urate crystals in the joints. In the present study, we aimed to investigate the anti-inflammatory effect of trikatu, a herbal compound in monosodium urate crystal-induced inflammation in rats, an experimental model for acute gouty arthritis. Paw volume and levels/activities of lysosomal enzymes, lipid peroxidation, anti-oxidant status and histopathological examination of ankle joints were determined in control and monosodium urate crystal-induced rats. In addition, analgesic (acetic acid-induced writhing response), anti-pyretic (yeast-induced pyrexia) and gastric ulceration effects were tested. The levels of lysosomal enzymes, lipid peroxidation and paw volume were significantly increased, and anti-oxidant status was found to be reduced in monosodium urate crystal-induced rats, whereas the biochemical changes were reverted to near normal levels upon trikatu (1000 mg/kg b.wt) administration. The trikatu has also been found to exhibit significant analgesic and anti-pyretic effects with the absence of gastric damage. In conclusion, the present results clearly indicated that trikatu exert a potent anti-inflammatory effect against monosodium urate crystal-induced inflammation in rats in association with analgesic and anti-pyretic effects in the absence of gastrointestinal damage., (Copyright © 2013 John Wiley & Sons, Ltd.)

Type 2 diabetes patients have an increased risk of developing hepatic fibrosis. Salvianolic acid A (SalA) has been reported to be a strong polyphenolic anti-oxidant and free radical scavenger. The aim of the present study was to evaluate the effect of SalA on the pathological progression of hepatic fibrosis in high-fat diet (HFD)-fed and streptozotocin (STZ)-induced diabetic rats and to clarify the underlying mechanisms. Type 2 diabetic animal model with hepatic fibrosis was developed by a high-sucrose, HFD and low-dose STZ injection (i.p.). Diabetic rats were randomly divided into SalA group (0.3 mg/kg/day) and diabetic control groups fed with a HFD. After administration for four months, SalA reversed the hyperlipidemia and reduced hepatic triglyceride (TG). Hematoxylin-Eosin (HE) and Picro acid-Sirius red staining results indicated that SalA significantly alleviated the lesions of hepatic steatosis and fibrosis, with the reduction of type I and III collagens. The expression of α-smooth-muscle-actin (α-SMA) and transforming growth factor β1 (TGF-β1) in the liver were markedly down-regulated by SalA treatment. TUNEL staining showed that SalA reduced apoptosis in hepatocytes. In addition, SalA improved hepatic mitochondrial respiratory function in diabetic rats. Taken together, these findings demonstrated that SalA could prevent the pathological progression of hepatic fibrosis in HFD-fed and STZ-induced diabetic rats. The underlying mechanisms may be involved in reducing oxidative stress, suppressing α-SMA and TGF-β1 expression, as well as exerting anti-apoptotic and mitochondria-protective effects.

Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese medicinal herb danshen, is commonly used for the prevention and treatment of cardiovascular disease. The present study was performed to investigate the effect of Sal B on the blood-spinal cord barrier (BSCB) after spinal cord injury (SCI) in a rat model. Sal B (1, 10, and 50 mg/kg i.v.) was administered to rats immediately following SCI. The permeability of the BSCB and spinal cord tissue water content were evaluated. Additionally, the expression levels of tight junction proteins and heme oxygenase-1 (HO-1) were monitored by Western blot analysis. Enzyme-linked immunosorbent assay analysis of spinal cord tissue homogenates was performed 24 h post-SCI to evaluate the expression of inflammation-related cytokines. In addition, the motor recovery of SCI rats was assessed using the Basso, Beattie, and Bresnahan scoring system. Compared to the SCI group, rats treated with Sal B (10, 50 mg/kg) exhibited significantly reduced spinal cord tissue water content and BSCB permeability. Further, the motor function of rats was also greatly improved by Sal B administration. The expression of pro-inflammatory factors TNF-α and NF-κB was found to be greatly increased 24 h post-SCI, and this upregulation was significantly attenuated by Sal B treatment. The expression of ZO-1 and occludin was upregulated by Sal B (10 mg/kg) treatment after SCI, and this effect was blocked by the HO-1 inhibitor ZnPP. Taken together, our results clearly indicate that Sal B attenuates SCI by promoting the repair of the damaged BSCB, demonstrating that this molecule is a novel and promising therapeutic agent for human SCI.

Background: Mitrella kentii (M. kentii) (Bl.) Miq, is a tree-climbing liana that belongs to the family Annonaceae. The plant is rich with isoquinoline alkaloids, terpenylated dihydrochalcones and benzoic acids and has been reported to possess anti-inflammatory activity. The purpose of this study is to assess the gastroprotective effects of desmosdumotin C (DES), a new isolated bioactive compound from M. kentii, on gastric ulcer models in rats., Methods: DES was isolated from the bark of M. kentii. Experimental rats were orally pretreated with 5, 10 and 20 mg/kg of the isolated compound and were subsequently subjected to absolute ethanol-induced acute gastric ulcer. Gross evaluation, mucus content, gastric acidity and histological gastric lesions were assessed in vivo. The effects of DES on the anti-oxidant system, non-protein sulfhydryl (NP-SH) content, nitric oxide (NO)level, cyclooxygenase-2 (COX-2) enzyme activity, bcl-2-associated X (Bax) protein expression and Helicabacter pylori (H pylori) were also investigated., Results: DES pre-treatment at the administered doses significantly attenuated ethanol-induced gastric ulcer; this was observed by decreased gastric ulcer area, reduced or absence of edema and leucocytes infiltration compared to the ulcer control group. It was found that DES maintained glutathione (GSH) level, decreased malondialdehyde (MDA) level, increased NP-SH content and NO level and inhibited COX-2 activity. The compound up regulated heat shock protein-70 (HSP-70) and down regulated Bax protein expression in the ulcerated tissue. DES showed interesting anti-H pylori effects. The efficacy of DES was accomplished safely without any signs of toxicity., Conclusions: The current study reveals that DES demonstrated gastroprotective effects which could be attributed to its antioxidant effect, activation of HSP-70 protein, intervention with COX-2 inflammatory pathway and potent anti H pylori effect.

FAAH-like anandamide transporter (FLAT) regulates anandamide transport for hydrolysis and may be an attractive drug target for pain regulation. We aimed to discover potential FLAT antagonists from traditional Chinese medicine (TCM) using virtual screening, ligand-based drug design and molecular dynamics simulation (MD). Guineensine and Retrofractamide A exhibited high Dock Scores in FLAT. Consensus from multiple linear regression (MLR; R(2) = 08973) and support vector machine (SVM; R(2) = 0.7988) showed similar bioactivities for Guineensine and the FAAH-1 inhibitor (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Contour of Guineensine to CoMFA and CoMSIA features also imply bioactivity. MD revealed shake or vibration in the secondary structure of FLAT complexed with Guineensine and (9Z)-1-(5-pyridin-2-yl-1,3,4-oxadiazol-2-yl)octadec-9-en-1-one. Ligand movement might contribute to protein changes leading to vibration patterns. Violent vibrations leading to an overall decrease in FLAT function could be the underlying mechanism for Guineensine. Here we suggest Guineensine as a drug-like compound with potential application in relieving neuropathic pain by inhibiting FLAT.

Living organisms have developed a wide variety of energy metabolism to survive within the specialized environments. There is a remarkable diversity in mitochondrial electron transport system, which might be potential targets for chemotherapy. Atovaquone, clinically used to treat malaria and pneumocystis pneumonia, is a specific inhibitor of Qo site in the cytochrome bc(1) complex of Plasmodium falciparum and Pneumocystis jirovecii. Phytopathogenic fungus, Ascochyta viciae produces two antibiotics, ascochlorin and ascofuranone. Ascochlorin specifically binds to inhibit the electron transport of both Qi and Qo sites in cytochrome bc(1) complex. Besides the unique respiratory inhibition, further investigation is in progress to elucidate the effects on cancer cells. On the other hand, ascofuranone specifically inhibits cyanide-insensitive trypanosome alternative oxidase, which is a sole terminal oxidase in the mitochondrion of Trypanosoma brucei, causative of African trypanosomiasis. In vivo study suggests that ascofuranone is a promising candidate for chemotherapeutic agents to treat African trypanosomiasis.

Herein we report the antiproliferative effects of a series of 28 compounds against the MDA-MB-231 breast cancer cell line, including the synthesis of seven new [3]ferrocenophanyl and four new ferrocenyl compounds. For each p-R-phenyl substitution pattern investigated, the [3]ferrocenophanyl derivatives were more cytotoxic than the corresponding ferrocenyl derivative, with the highest activity found for compounds with protic substituents. Theoretical calculations of the HOMO-LUMO gap for the molecules in the Fe³(+) oxidation state suggest a higher reactivity for the [3]ferrocenophanyl derivatives. A lead compound from each series, a [3]ferrocenophanyl and a ferrocenyl compound, possessing two phenol groups, were screened against the NCI/DTP 60-cell-line panel. The mean activity over all cell lines was better than cisplatin for both compounds, and both compounds showed subpanel selectivity for leukemia, CNS cancer, and renal cancer. Low systemic toxicity and lack of interaction with DNA (when in the reduced form), suggest that the compounds may act as prodrugs.

The purpose of this study was to determine the therapeutic effect of salvianolic acid b and paeonol on coronary disease. The ischemia myocardial animal model is induced by administering pituitrin (20 μg·kg(-1)) intravenously via the abdominal vein. A combination of salvianolic acid b and paeonol (CSAP) (5, 10 and 15 mg/kg BW) was administrated to experimental rabbits. Biochemical indices were evaluated during six weeks of intervention. We found that the compound of salvianolic acid b and paeonol (5, 10 and 15 mg/kg BW) can markedly and dose-dependently reduce fibrinogen and malonaldehyde levels, increase the HDL level, improve blood viscosity and plasma viscosity in rabbits. In addition, the medicine can still reduce the ratio of NO/ET and the contents of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) in a dose-dependent manner. This study demonstrates that compound of salvianolic acid b and paeonol (5, 10 and 15 mg/kg BW) can improve the blood hemorrheology, decrease oxidative injury and repair the function of blood vessel endothelium, and subsequently prevent the development of Coronary disease.

A series of (2E,2'E)-1,1'-(3-hydroxy-5-methylbiphenyl-2,6-diyl)-bis(3-pheylprop-2-ene-1-ones (5-33) were prepared by the reaction of 1,3-diacetyl biphenyls (1-4) with different aldehydes in presence of catalytic amount of solid KOH in ethanol in excellent yields. The compounds were evaluated for anticancer activity against human breast cancer MCF-7 (estrogen responsive proliferative breast cancer model) and MDA-MB-231 (estrogen independent aggressive breast cancer model) cell lines, HeLa (cervical cancer) cell line, and human embryonic kidney (HEK-293) cells. Most of the compounds preferentially inhibited the growth of the aggressive human breast cancer cell lines, MDA-MB-231 in the range of 4.4-30 μM. The two compounds 9 and 29 proved to be better anticancer agents than the standard drug tamoxifen against the MDA-MB-231 cell lines. Mode of action of these compounds was established to be apoptosis, cell cycle arrest and loss of mitochondrial membrane potential., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Myrsinoic acid B (AMB) is a prenylated-benzoic acid derivative isolated from the Rapanea genus. Recent studies suggest that AMB has antihyperalgesic and antinociceptive properties in different animal models. The present study was designed to investigate the mechanisms involved in antinociception elicited by AMB (60 mg/kg) when administered by intraperitonial route (i.p.) in mice. The antinociceptive response of the compound was characterized by a reduction in contractions of the abdominal muscle, together with stretching of the hind limbs in response to i.p. injection of acetic acid (0.6%, 0.45 ml/mouse). The antinociception caused by AMB in the acetic acid test was significantly attenuated by i.p. treatment of mice with nitric oxide precursor, (L-arginine, 600 mg/kg), alpha2 and alpha1-adrenoceptor antagonists (yohimbine, 0.2 mg/kg/prazosin, 0.2 mg/kg), p-chlorophenylalanine (PCPA) an inhibitor of serotonin synthesis (100 mg/kg), 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine (NAN 190), a 5-HT1(A) selective receptor antagonist (0.5 mg/kg) and a non-selective cholinergic antagonist (atropine, 10 mg/kg). Its action was also modulated by the adrenal-gland hormones. In contrast, antinociception was not affected by naloxone (non-selective opioid receptor antagonist, 1.0 mg/kg), phaclofen (2.0 mg/kg) and bicuculline (1.0 mg/kg) GABA(B) and GABA(A) receptor antagonists, respectively, ondansetron (0.3 mg/kg) and ketaserin (1.0 mg/kg), (5-HT3 and 5-HT2 receptors, respectively) and haloperidol (0.2 mg/kg), a non-selective dopaminergic receptor. The antinociceptive effects are not related to muscle-relaxant or sedative action. These results indicate that AMB produces antinociception through mechanisms that involve interaction with L-arginine-nitric oxide, the serotonergic and cholinergic systems, as well as interaction with the alpha-adrenoceptors.

Background: The quality of life has been greatly influenced and the cost of medical expenses is very high in patients with irritable bowel syndrome (IBS). The etiology and pathogenesis of IBS are still unclear, and the prevention and treatment of this disease still lack of effective methods., Objective: To explore and analyze the effects of Tiaohe Ganpi Hexin Decoction (TGHD), a compound traditional Chinese herbal medicine for regulating the liver and spleen, on IBS patients with diarrhea., Design, Setting, Participants and Interventions: All 40 IBS patients came from the First Hospital of Jinan University, Guangzhou Red Cross Hospital, and the First Affiliated Hospital of Guangzhou University of Chinese Medicine, and were randomly divided into two groups. Patients in the treatment group (n=20) were given TGHD, while those in the control group (n=20) were prescribed oral pinaverium with a four-week treatment period., Main Outcome Measures: Traditional Chinese medicine (TCM) syndrome score, total obviously effective rate, disappearance rate of symptoms, and clinical symptom score in the two groups were evaluated before and after four-week treatment., Results: After the treatment, TCM syndrome scores in both groups were decreased (P<0.01), and the TCM syndrome score in the treatment group was significantly lower than that in the control group (P<0.01). There was a significant difference in the total obviously effective rate between the two groups (P<0.01), and the total obviously effective rates in the treatment and control groups were 85%(17/20) and 45%(9/20) respectively. The disappearance rates of abdominal pain, abdominal distention, poor stool output, stool frequency, stool character and mucous stool in the treatment group were higher than those in the control group (P<0.05). The symptom scores of abdominal pain, abdominal distention, poor stool output, stool frequency, stool character and mucous stool in the treatment group were lower than those in the control group (P<0.05)., Conclusion: TGHD can significantly improve the clinical symptoms in IBS patients with diarrhea.

Closure of uterine incisions in a variety of gynecological procedures, specifically in myomectomy operations, is associated with significant hemorrhage. Excessive suturing to control bleeding may have negative effects on wound healing and might increase peritoneal adhesions. Moreover, difficulty of handling uterine tissue in laparoscopic procedures is not only a factor for suboptimal closure and inadequate control of bleeding but also a significant factor for surgeons for choosing laparotomy over laparoscopic approach. Cyanoacrylates are a group of molecules used as industrial adhesives. Newer cyanoacrylates are widely used in medicine. These agents are excellent biological adhesives due to strong adhesive action, hemostatic action, and antibacterial properties. Moreover, the presence of blood and tissue fluids enhances the activity of cyanoacrylates. In this study, 2-octyl cyanoacrylate, polypropylene, and polyglactin 910 sutures were compared in terms of adhesive strength, control of hemorrhage and postoperative intraabdominal adhesions in a rat model. Wound healing was excellent in all groups. Cyanoacrylates were associated with significantly lower total adhesion scores. This is the first report proposing the use of cyanoacrylates in gynecologic surgeries with supporting evidence for clinical use. Cyanoacrylates might be the first choice for the closure of uterine incisions and for the control of hemorrhage especially in laparoscopic procedures.

Estrogen receptor-negative breast cancers generally are highly malignant, resistant to chemotherapy and poorly prognostic. Here we demonstrate that estrogen receptor-negative human breast cancer cell lines highly express Fra-1, c-Fos and c-Jun, components of the transcription factor, activator protein-1 (AP-1). Retrospective observation of breast cancer tissues obtained by core needle biopsy before surgery from stages II and III patients demonstrates that Fra-1 expression is high in estrogen receptor-negative human breast cancers, and negatively correlated to paclitaxel sensitivity. Ascochlorin, which suppresses cellular AP-1 activity, selectively kills estrogen receptor-negative human and mouse breast cancer cell lines, and prolongs the survival time of mice implanted with an estrogen receptor-negative mammary carcinoma. These results suggest that chemotherapy targeting AP-1 activity is a potent strategy for estrogen receptor-negative human breast cancers.

The association between cruciferous vegetables and cancer prevention has been linked to glucosinolate derivatives. These phytochemicals enhance endogenous detoxification, leading to inactivation of potential carcinogens before initiation occurs. Two derivatives, indole-3-carbinol (I3C) and 1-cyano-2-hydroxy-3-butene (crambene) were shown in rats to induce a synergistic enhancement of detoxification enzyme activity. To follow up on these findings, a short-term carcinogenicity study using aflatoxin B1 (AFB(1)) was performed in which male F344 rats were fed diets supplemented with these 2 compounds alone or in combination. Groups included a negative control group (no AFB(1), crambene, or I3C), a crambene group (diet 0.150% crambene), an I3C group (diet 0.165% I3C), a high-dose group (diet 0.150% crambene, 0.165% I3C) a low-dose group (diet 0.030% crambene, 0.033% I3C), and a positive control group (AFB(1) treatment only). AFB(1) was administered after 2 wk of dietary pretreatment. Liver sections were scored for lesions including karyomegaly, apoptosis, and biliary hyperplasia and evaluated for expression of the preneoplastic marker glutathione S-transferase-pi (GSTP). I3C and crambene groups were protected against AFB(1) toxicity whereas the low-dose group was not. The high-dose group had scores close to those of the negative controls. For log(10) transformed 2- and 3-dimensional GSTP data, the high-dose group demonstrated synergistic reduction in GSTP-positive area and an additive reduction in GSTP-positive volume compared with the crambene and I3C groups. The low-dose group had no effect. In conclusion, high combination dietary doses of I3C and crambene demonstrated enhanced protection from AFB(1). Low combination doses, as might be realistically in the diet, were not effective.

Aims: This work was conducted to report an interventional non-comparative pilot study using Oxane HD, a mixture of ultra-purified silicone oil and RMN3, a partially fluorinated olefin, as heavier-than-water internal tamponade., Methods: Twenty-eight consecutive patients were recruited for this study. Indications included recurrent retinal detachment (RD) with proliferative vitreoretinopathy (PVR) (stage > or =C2) arising from inferior or posterior tears, recurrences after vitreoretinal surgery, penetrating trauma and combined rhegmatogenous and choroidal detachment. The patients underwent a pars plana vitrectomy, membrane peeling, and Oxane HD was used as long-term internal tamponade., Results: Oxane was removed after 88 days (range 45-96 days) and exchanged with BSS in five eyes, long-acting gas in 14 eyes and with silicone oil in nine eyes. Retinal reattachment was achieved in 15 eyes. The overall anatomical success rate obtained using Oxane HD was 53.5%. In 15 patients with previous marked scleral buckling, the success rate was 26%: in nine patients recurrent RD occurred in the inferior sector, in five patients new tears were detected in the lower sectors; membrane formation was observed in 15 eyes. In 13 patients without marked scleral indent, the success rate was 84.6%. There was no evidence of dispersion and excessive inflammation., Conclusion: Oxane HD may be a useful tool in complicated RD with large inferior breaks, inferior PVR or combined rhegmatogenous, and choroidal detachment without marked scleral buckling, which put the eye profile out of shape, led to a higher failure rate and reduced the tamponading effectiveness of Oxane HD.

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4-10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 x 10(8) CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p <0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p <0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates.

A group of acyclic 2-alkyl-1,1-diphenyl-2-(4-methylsulfonylphenyl)ethenes was designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition structure-activity studies identified 1,1-diphenyl-2-(4-methylsulfonylphenyl)hex-1-ene as a highly potent (IC(50) = 0.014 microM), and an extremely selective [COX-2 selectivity index (SI) > 7142], COX-2 inhibitor that showed superior anti-inflammatory (AI) activity (ID(50) = 2.5 mg/kg) relative to celecoxib (ID(50) = 10.8 mg/kg). This initial study was extended to include the design of a structurally related group of acyclic triaryl (Z)-olefins possessing an acetoxy (OAc) substituent at the para-position of the C-1 phenyl ring that is cis to a C-2 4-methylsulfonylphenyl substituent. COX-1 and COX-2 inhibition studies showed that (Z)-1-(4-acetoxyphenyl)-1-phenyl-2-(4-methylsulfonylphenyl)but-1-ene [(Z)-13b] is a potent (COX-1 IC(50) = 2.4 microM; COX-2 IC(50) = 0.03 microM), and selective (COX-2 SI = 81), COX-2 inhibitor which is a potent AI agent (ID(50) = 4.1mg/kg) with equipotent analgesic activity to celecoxib. A molecular modeling (docking) study showed that the SO(2)Me substituent of (Z)-13b inserts deep inside the 2 degrees -pocket of the COX-2 active site, where one of the O-atoms of SO(2) group undergoes a H-bonding interaction with Phe(518). The p-OAc substituent on the C-1 phenyl ring is oriented in a hydrophobic pocket comprised of Met(522), Gly(526), Trp(387), Tyr(348), and Tyr(385), and the C-2 ethyl substituent is oriented towards the mouth of the COX-2 channel in the vicinity of amino acid residues Arg(120), Leu(531), and Val(349). Structure-activity data acquired indicate that a (Z)-olefin having cis C-1 4-acetoxyphenyl (phenyl) and C-2 4-methylsulfonylphenyl substituents, and a C-1 phenyl substituent in conjunction with either a C-2 hydrogen or short alkyl substituent provides a novel template to design acyclic olefinic COX-2 inhibitors that, like aspirin, have the potential to acetylate COX-2.

Inhibiting aggregation and deposition of amyloid beta-peptide (Abeta) in brain is a therapeutic strategy for Alzheimer's disease (AD). A Congo-red-like molecule, X-34, is reported to bind to Abeta deposits. Oxidative stress associated with Abeta is hypothesized to be critical for the neurotoxic properties of this peptide. The present study was undertaken to test the hypothesis that X-34, with its salicylate groups, would act as an antioxidant. When challenged by hydroxyl or peroxyl free radicals or Abeta(1-42), oxidative stress and neurotoxicity occurred in neural systems as assessed by several indices. However, pretreatment of synaptosomes and primary neuronal cell culture with X-34 greatly ameliorated lipid peroxidation induced by these free radicals and Abeta(1-42). Protein oxidation was not prevented by X-34. These results are discussed in terms of potential therapeutic use of X-34 and related compounds in AD.

Non-small cell lung cancers remain difficult to treat and have a high death rate and poor 5-year survival. New therapeutic strategies are urgently needed, which should be more specific for the cancer cell and less toxic for normal cells. In this respect, induction of the terminal differentiation of tumor cells appears to be a particularly suitable approach, which can only be achieved after proliferation arrest in G1 phase. This study describes the activity of a chemical compound with an original structure, namely methyl-4-methoxy-3-(3-methyl-2-butanoyl) benzoate (VT1), which induced irreversible proliferation arrest in G1 phase of two lung cancer lines, NSCLC-N6 and NSCLC-derived A549 cells. The p53 gene is now unanimously regarded as a key gene for cell cycle arrest in G1 phase, and A549 cells possess a wild-type p53 gene. The similarity of effects obtained on both lines led us to consider whether the p53/p21 cascade was activated in NSCLC-N6 cells during VT1 treatment. The mutational status of p53 gene was first established in the NSCLC-N6 line using a PCR SSCP technique, and a reporter gene was then used to assess the functionality of P53 protein.

Study Objectives: To determine the selective vasodilatory effects of two inhaled "NONOate" aerosols in a closed chest pig model of acute pulmonary hypertension (APH)., Methods: APH was induced by IV infusion of the prostaglandin H(2)/thromboxane A(2) receptor agonist (U46619). Aerosolized diethylenetriamine nitric oxide (NO) adduct (DETA/NO, n = 4), dipropylenetriamine NO adduct (DPTA/NO, n = 4) [60 micro mol each], or placebo (n = 4) was delivered via the trachea. Hemodynamic parameters and blood samples were measured before and after inhalation therapy., Results: Compared to control animals, pulmonary vascular resistance and pulmonary arterial pressure were significantly reduced from 10 to 105 min after DETA/NO administration and from 10 to 45 min after DPTA/NO aerosol administration (p < 0.05). Both aerosols had no significant effect on systemic vascular resistance or systemic BP. Serum nitrite significantly increased after the inhalation of both NONOates (p < 0.01). There was a tendency for reduced intrapulmonary shunting, particularly after treatment with DETA/NO., Conclusion: Both DETA/NO and DPTA/NO administered as aerosols selectively reduced pulmonary hypertension induced by U46619.

A new alkaloid, pipersintenamide ( 1), together with fourteen known compounds, have been isolated from the whole plant of Piper sintenense. The structures of these compounds were elucidated by spectroscopic analysis. Pipersintenamide, sintenpyridone, sarmentine, and 1-(3,4-methylenedioxyphenyl)-1 E-dodecene at 20 microg/ml exhibited effective cytotoxicities (cell survival < 15 %) against CCRF-CEM, HL-60, PC-3, and HA22T cell lines.

Silicone oxygenators are the standard devices used for Extracorporeal Life Support (ECLS), but they have some limitations. Microporous polypropylene hollow fiber oxygenators overcome many of these problems but, unfortunately, develop plasma leak. Polymethyl-pentene (PMP) is a novel oxygenator material. We report our initial experience with the Medos Hilite 7000LT, a PMP hollow fiber oxygenator, in six adult respiratory ECLS patients with these characteristics: age, mean 32.2 (+/-13) years; weight, mean 81.2 (+/-17) kg; PaO2/FIO2, mean 62.8 [+/-33] mm Hg; Murray Score, mean 3.4 [+/-0.3]; and sepsis related organ failure assessment score, mean 9.6 [+/-2.3]. One patient was cannulated within 10 hours of multiple trauma and 1 hour after thoracolaparotomy; another patient was cannulated 12 hours after a thoracotomy. All six patients survived. Heparin was infused (7.8-32.5 u/kg/hr) to maintain activated clotting time at 162 to 238 seconds; international normalized ratio was 0.9 to 3.4. Two of the six patients required transfusions of fresh frozen plasma, receiving one and five units, respectively. Fibrinogen was 1.4 to 6 g/dl; no cryoprecipitate was needed. Platelet counts were between 65 and 306, and very little platelet transfusion (mean 2.33; +/-3.03 units per patient) was required to maintain these levels. Two patients did not require any platelet transfusion. Maximum blood flow was 5.3 L/min, sweep was 3 to 10 L/min, and resistance was 11 to 43 Paul Wood Units. There were no oxygenator failures. Mean duration of ECLS was 151.7 hours (+/-75.6). Our initial experience with PMP oxygenators in adults was satisfactory, and platelet consumption and resistance to blood flow seem to be greatly reduced with PMP.