Association between Circular RNA CDR1as and Post-Infarction Cardiac Function in Pig Ischemic Heart Failure: Influence of the Anti-Fibrotic Natural Compounds Bufalin and Lycorine.

Anti-fibrotic therapies are of increasing interest to combat cardiac remodeling and heart failure progression. Recently, anti-fibrotic circular RNAs (circRNAs) have been identified in human and rodent cardiac tissue. In vivo (rodent) experiments proved cardiac anti-fibrotic effects of the natural compounds bufalin and lycorine by downregulating miRNA-671-5p, associated with a theoretic increase in the tissue level of circRNA CDR1as. Accordingly, we hypothesized that both anti-fibrotic drugs may inhibit focal myocardial fibrosis of the remodeled left ventricle (LV) also in a translational large animal model of heart failure (HF). Domestic pigs were repeatedly treated with subcutaneous injections of either bufalin, lycorine, or saline, (n = 5/group) between days 7-21 post acute myocardial infarction (AMI). At the 2-month follow-up, both bufalin and lycorine led to significantly reduced cardiac fibrosis. Bufalin treatment additionally led to smaller end-diastolic volumes, higher LV ejection fraction (EF), and increased expression of CDR1as of the AMI region. Elevated tissue levels of the circRNA CDR1as in the AMI region of the pig heart correlated significantly with LV and right ventricular EF, LV stroke volume, and negatively with infarct size. In conclusion, we successfully identified the circRNA CDR1as in pig hearts and show a significant association with improved LV and RV function by anti-fibrotic therapies in a translational animal model of HF.

Design, synthesis and antitumour evaluation of pyrrolo[1,2-f]-phenanthridine and dibenzo[f,h]pyrrolo[1,2-b]isoquinoline derivatives.

A series of 1,2-bis(hydroxymethyl)pyrrolo[1,2-f]phenanthridine derivatives and their alkyl (ethyl and isopropyl) carbamates and 12,13-bis(hydroxymethyl)-9,14-dihydro-dibenzo[f,h]pyrrolo[1,2-b]isoquinoline derivatives were synthesized for antiproliferative evaluation. The preliminary antitumour studies revealed that these two types of bis(hydroxymethyl) derivatives showed significant antitumour activities and were able to inhibit the growth of various human tumour cell lines in vitro. Several of the derivatives were demonstrated to cause DNA interstrand cross-links by an alkaline agarose gel shifting assay. These conjugates were cytotoxic to a variety of cancer cell lines by inducing DNA damage, delaying cell cycle progression in the G2/M phase and triggering apoptosis. Compound 21a, dissolved in a vehicle suitable for intravenous administration, was selected for antitumour studies in animal models. We demonstrated that at a dose that did not cause body weight loss in mice, compound 21a could significantly suppress the growth of tumour xenografts of human lung cancer H460 and colorectal cancer HCT-116 cells in nude mice. Our present results confirm the antitumour activities of these conjugates.

Antiviral activity of lycorine against Zika virus in vivo and in vitro.

The emergence and re-emergence of Zika virus (ZIKV), is a cause for international concern. These highly pathogenic arboviruses represent a serious health burden in tropical and subtropical areas worldwide. Despite these burdens, antiviral therapies do not exist, and inhibitors of ZIKV are therefore urgently needed. To elucidate the anti-ZIKV effect of lycorine, we used reverse transcription-quantitative real-time PCR (qRT-PCR), immunofluorescence, Westernwestern blot, and plaque forming assay to analyse viral RNA (vRNA), viral protein, progeny virus counts, and validated inhibitors in vitro using a variety of cell lines. Additionally, we found that lycorine acts post-infection according to time-of-addition assay, and inhibits RdRp activity. Lycorine protected AG6 mice against ZIKV-induced lethality by decreasing the viral load in the blood. Due to its potency and ability to target ZIKV infection in vivo and in vitro, lycorine might offer promising therapeutic possibilities for combatting ZIKV infections in the future.

Novel phenanthridin-6(5H)-one derivatives as potent and selective BET bromodomain inhibitors: Rational design, synthesis and biological evaluation.

Inhibition of BET family of bromodomain is an appealing intervention strategy for several cancers and inflammatory diseases. This article highlights our work toward the identification of potent, selective, and efficacious BET inhibitors using a structure-based approach focused on improving potency. Our medicinal chemistry efforts led to the identification of compound 24, a novel phenanthridin-6(5H)-one derivative, as a potent (IC50 = 0.24 µM) and selective BET inhibitor with excellent cancer cell lines inhibitory activities and favorable oral pharmacokinetic properties.

Safety and efficacy of three trypanocides in confirmed field cases of trypanosomiasis in working equines in The Gambia: a prospective, randomised, non-inferiority trial.

BACKGROUND: Globally, working equines have a continued and growing socioeconomic role in supporting the livelihoods of between 300-600 million people in low income countries which is rarely recognised at a national or international level. Infectious diseases have significant impact on welfare and productivity in this population and equine trypanosomiasis is a priority disease due to its severity and prevalence. Strategies are required to improve the prevention, diagnosis, management and treatment of trypanosomiasis in equines and more data are required on the efficacy and safety of current trypanocidal drugs. METHODS: A prospective randomised, open-label non-inferiority trial was performed in The Gambia on horses and donkeys that fulfilled 2/5 clinical inclusion criteria (anaemia, poor body condition, pyrexia, history of abortion, oedema). Following randomised trypanocidal treatment (diminazene diaceturate, melarsomine dihydrochloride or isometamidium chloride), animals were observed for immediate adverse drug reactions and follow-up assessment was performed at 1 and 2 weeks. Blood samples underwent PCR analysis with specific Trypanosoma sp. primers. Treatment efficacy was assessed by measuring changes in clinical parameters, clinicopathological results and PCR-status post-treatment after evaluating for bias. Using PCR status as the outcome variable, non-inferiority of isometamidium treatment was determined if the upper bound limit of a 2-sided 95% CI was less than 10%. RESULTS: There was a significant beneficial effect upon the Trypanosoma sp. PCR positive population following trypanocidal treatment for all groups. The findings of clinical evaluation and PCR status supported a superior treatment effect for isometamidium. Melarsomine dihydrochloride efficacy was inferior to isometamidium. There were immediate, self-limiting side effects to isometamidium in donkeys (26%). Diminazene had the longest duration of action as judged by PCR status. CONCLUSIONS: The data support the continued use of isometamidium following careful dose titration in donkeys and diminazene for trypanosomiasis in equines using the doses and routes of administration reported.

Differential effects of D1 and D2 dopamine agonists on memory, motivation, learning and response time in non-human primates.

Dopamine (DA) plays a critical role in cognition, motivation and information processing. DA action has been shown to both improve and/or impair cognition across different receptor types, species, subjects and tasks. This complex relationship has been described as an inverted U-shaped function and may be due to the differential effects of DA receptor activation in the striatum and prefrontal cortex. We have investigated the effects of selective DA agonists on cognitive performance in healthy monkeys using a touch screen running tasks from the CAmbridge Neuropsychological Test Automated Battery (CANTAB). One of two DA agonist drugs or placebo was administered prior to each daily CANTAB session: Dihydrexidine hydrochloride (selective D1 agonist, 0.4-0.9 mg/kg), or sumanirole maleate (selective D2 agonist 0.05-0.3 mg/kg). Three CANTAB tasks were tested: (a) "self-ordered sequential search task" which tested spatial working memory, (b) "reversal learning task," which tested association learning, cognitive flexibility and attention and (c) "visually guided reaching task," which tested reaction time and accuracy. At high dosages, the D2 agonist improved spatial working memory performance, while impairing reversal learning and slowing reach response latency. No consistent cognitive effects were observed with the D1 agonist across the dosages tested. A significant decrease in trial completion rate was observed at the higher dosages of both the D1 and D2 agonists which were consistent with decreased motivation. These results are consistent with task-specific effects of a D2 agonist as well as dose specific insensitivities of a D1 agonist on cognitive and motor behaviors in a healthy monkey.

Isometamidium chloride and homidium chloride fail to cure mice infected with Ethiopian Trypanosoma evansi type A and B.

BACKGROUND: Trypanosoma evansi is mechanically transmitted by biting flies and affects camels, equines, and other domestic and wild animals in which it causes a disease called surra. At least two types of Trypanosoma evansi circulate in Ethiopia: type A, which is present in Africa, Latin America and Asia, and type B, which is prevalent in Eastern Africa. Currently, no information is available about the drug sensitivity of any Ethiopian T. evansi type. METHODOLOGY/PRINCIPAL FINDINGS: This study was conducted with the objective of determining the in vivo drug sensitivity of two T. evansi type A and two type B stocks that were isolated from camels from the Tigray and Afar regions of Northern Ethiopia. We investigated the efficacy of four trypanocidal drugs to cure T. evansi infected mice: melarsamine hydrochloride (Cymelarsan), diminazene diaceturate (Veriben and Sequzene), isometamidium chloride (Veridium) and homidium chloride (Bovidium). Per experimental group, 6 mice were inoculated intraperitoneally with trypanosomes, treated at first peak parasitemia by daily drug injections for 4 consecutive days and followed-up for 60 days. Cymelarsan at 2 mg/kg and Veriben at 20 mg/kg cured all mice infected with any T. evansi stock, while Sequzene at 20 mg/kg caused relapses in all T. evansi stocks. In contrast, Veridium and Bovidium at 1 mg/kg failed to cure any T. evansi infection in mice. CONCLUSIONS/SIGNIFICANCE: We conclude that mice infected with Ethiopian T. evansi can be cured with Cymelarsan and Veriben regardless of T. evansi type. In contrast, Veridium and Bovidium are not efficacious to cure any T. evansi type. Although innate resistance to phenanthridines was previously described for T. evansi type A, this report is the first study to show that this phenomenom also occurs in T. evansi type B infections.

ZYH005, a novel DNA intercalator, overcomes all-trans retinoic acid resistance in acute promyelocytic leukemia.

Despite All-trans retinoic acid (ATRA) has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological cancer, there remains a clinical challenge that many high-risk APL patients who fail to achieve a complete molecular remission or relapse and become resistant to ATRA. Herein, we report that 5-(4-methoxyphenethyl)-[1, 3] dioxolo [4, 5-j] phenanthridin-6(5H)-one (ZYH005) exhibits specific anticancer effects on APL and ATRA-resistant APL in vitro and vivo, while shows negligible cytotoxic effect on non-cancerous cell lines and peripheral blood mononuclear cells from healthy donors. Using single-molecule magnetic tweezers and molecule docking, we demonstrate that ZYH005 is a DNA intercalator. Further mechanistic studies show that ZYH005 triggers DNA damage, and caspase-dependent degradation of the PML-RARa fusion protein. As a result, APL and ATRA-resistant APL cells underwent apoptosis upon ZYH005 treatment and this apoptosis-inducing effect is even stronger than that of arsenic trioxide and anticancer agents including 5-fluorouracil, cisplatin and doxorubicin. Moreover, ZYH005 represses leukemia development in vivo and prolongs the survival of both APL and ATRA-resistant APL mice. To our knowledge, ZYH005 is the first synthetic phenanthridinone derivative, which functions as a DNA intercalator and can serve as a potential candidate drug for APL, particularly for ATRA-resistant APL.

The antithrombotic, anticoagulant activity and toxicity research of ambinine, an alkaloid from the tuber of Corydalis ambigua var. amurensis.

Ambinine, the major alkaloid of the tuber of Corydalis ambigua var. amurensis, has protective effects on H9C2 myocardial cells. In the present paper, we observed that ambinine demonstrates activities of both anticoagulation and thrombolysis in vitro by significantly degrading the blood clot and delaying the plasma recalcification time (PRT) in a dose-dependent manner (0.5-2 mg/mL). We further studied its safety profile of acute and subacute toxicity by repeated-dose intravenous injection. The median lethal dosage (LD50) of mice given by oral and intravenous administration of ambinine were approximate 800, 41.60 mg/kg, respectively. The acute toxicity research results suggested that compared with an intravenous administration, the oral route is safer to administer ambinine as the promising lead compound for thrombosis. In subacute toxicity research, when mice were given ambinine at doses of 1.40 and 2.10 mg/kg for 7 days by injection, significant alteration of the relative kidney weight, the relative liver weight and serum biochemistry parameters and marked histopathological changes of them were found.

Aberrant use and poor quality of trypanocides: a risk for drug resistance in south western Ethiopia.

BACKGROUND: Trypanocidal drugs have been used to control African animal trypanosomosis for several decades. In Ethiopia, these drugs are available from both authorized (legal) and unauthorized (illegal) sources but documentation on utilization practices and quality of circulating products is scanty. This study looked at the practices of trypanocidal drug utilization by farmers and the integrity of active ingredient in trypanocides sold in Gurage zone, south western Ethiopia. The surveys were based on a structured questionnaire and drug quality determination of commonly used brands originating from European and Asian companies and sold at both authorized and unauthorized markets. One hundred farmers were interviewed and 50 drug samples were collected in 2013 (Diminazene aceturate = 33 and Isometamidium chloride = 17; 25 from authorized and 25 from unauthorized sources). Samples were tested at the OIE-certified Veterinary Drug Control Laboratory (LACOMEV) in Dakar, Senegal, by using galenic standards and high performance liquid chromatography. RESULTS: Trypanosomosis was found to be a major threat according to all interviewed livestock keepers in the study area. Diminazene aceturate and isometamidium chloride were preferred by 79% and 21% of the respondents respectively, and 85% of them indicated that an animal receives more than six treatments per year. About 60% of these treatments were reported to be administered by untrained farmers. Trypanocidal drug sources included both unauthorized outlets (56%) and authorized government and private sources (44%). A wide availability and usage of substandard quality drugs was revealed. Twenty eight percent of trypanocidal drugs tested failed to comply with quality requirements. There was no significant difference in the frequency of non-compliance between diminazene-based and isometamidium chloride products (P = 0.87) irrespective of the marketing channel (official and unofficial). However, higher rates of non-compliant trypanocides were detected for drugs originating from Asia than from Europe (P = 0.029). CONCLUSION: The findings revealed the presence of risk factors for the development of drug resistance, i.e. wide distribution of poor quality drugs as well as substandard administration practices. Therefore, it is strongly recommended to enforce regulatory measures for quality control of veterinary drugs, to expand and strengthen veterinary services and to undertake trypanocidal drug efficacy studies of wider coverage.

Lycorine possesses notable anticancer potentials in on-small cell lung carcinoma cells via blocking Wnt/ß-catenin signaling and epithelial-mesenchymal transition (EMT).

Lycorine, an natural isoquinoline alkaloid has reportedly that possesses multi-anticancer activity. However, to date, the anticancer feature of lycorine in non-small cell lung carcinoma (NSCLC) has still not fully been spelled out. The present study mainly focused on the molecular mechanism of lycorine against NSCLC in vitro and vivo. The results showed that lycorine evidently inhibited proliferation of A549 and H460 with IC50 values were 10.83 ± 1.14 µM and 12.35 ± 1.13 µM, while caused slight cytotoxicity in normal pulmonary epithelial Beas-2B cells, and arrested cell cycle in G0/G1 phase. Hoechst DNA-binding staining showed that typical characteristics of nuclear morphology apoptosis, AnnexinV-FITC/PI staining revealed the early-period apoptosis and the dissipation of mitochondrial membrane potential (Δψm) were also captured after lycorine treatment. Moreover, lycorine effectively repressed the Wnt/ß-catenin signaling and reversed epithelial-mesenchymal transition (EMT). In addition, lycorine also intervened the caspase-mediated mitochondrial apoptosis pathway. Furthermore, A549/Luc tumor xenograft model was also corroborated that lycorine significantly suppressed the growth and metastasis of the lung tumor. These data highlight the significance of lycorine as potential anti-neoplastic agents to combat NSCLC.

Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides.

Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and ß-catenin, but promotes ß-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects.

Striatal dopamine D1 receptor suppression impairs reward-associative learning.

Dopamine (DA) is required for reinforcement learning. Hence, disruptions in DA signaling may contribute to the learning deficits associated with psychiatric disorders. The DA D1 receptor (D1R) has been linked to learning and is a target for cognitive/motivational enhancement in patients with schizophrenia. Separating the striatal D1R contribution to learning vs. motivation, however, has been challenging. We suppressed striatal D1R expression in mice using a D1R-targeting short hairpin RNA (shRNA), delivered locally to the striatum via an adeno-associated virus (AAV). We then assessed reward- and punishment-associative learning using a probabilistic learning task and motivation using a progressive-ratio breakpoint procedure. We confirmed suppression of striatal D1Rs immunohistochemically and by testing locomotor activity after the administration of (+)-doxanthrine, a full D1R agonist, in control mice and those treated with the D1RshRNA. D1RshRNA-treated mice exhibited impaired reward-associative learning, while punishment-associative learning was spared. This deficit was unrelated to general learning impairments or amotivation, because the D1shRNA-treated mice exhibited normal Barnes maze learning and normal motivation in the progressive-ratio breakpoint procedure. Suppression of striatal D1Rs selectively impaired reward-associative learning whereas punishment-associative learning, aversion-motivated learning, and appetitive motivation were spared. Because patients with schizophrenia exhibit similar reward-associative learning deficits, D1R-targeted treatments should be investigated to improve reward learning in these patients.

Novel Dopamine Therapeutics for Cognitive Deficits in Schizophrenia.

Schizophrenia is characterized by profound cognitive deficits that are not alleviated by currently available medications. Many of these cognitive deficits involve dysfunction of the newly evolved, dorsolateral prefrontal cortex (dlPFC). The brains of patients with schizophrenia show evidence of dlPFC pyramidal cell dendritic atrophy, likely reductions in cortical dopamine, and possible changes in dopamine D1 receptors (D1R). It has been appreciated for decades that optimal levels of dopamine are essential for dlPFC working memory function, with many beneficial actions arising from D1R stimulation. D1R are concentrated on dendritic spines in the primate dlPFC, where their stimulation produces an inverted-U dose response on dlPFC neuronal firing and cognitive performance during working memory tasks. Research in both academia and the pharmaceutical industry has led to the development of selective D1 agonists, e.g., the first full D1 agonist, dihydrexidine, which at low doses improved working memory in monkeys. Dihydrexidine has begun to be tested in patients with schizophrenia or schizotypal disorder. Initial results are encouraging, but studies are limited by the pharmacokinetics of the drug. These data, however, have spurred efforts toward the discovery and development of improved or novel new compounds, including D1 agonists with better pharmacokinetics, functionally selective D1 ligands, and D1R positive allosteric modulators. One or several of these approaches should allow optimization of the beneficial effects of D1R stimulation in the dlPFC that can be translated into clinical practice.

Antioxidant Effect of Ukrain Versus N-Acetylcysteine Against Acute Biliary Pancreatitis in An Experimental Rat Model.

Purpose/Aim: Oxidative stress plays an important role in the pathogenesis of acute pancreatitis (AP). We compared the therapeutic effects of Ukrain (NSC 631570) and N-acetylcysteine (NAC) in rats with AP. MATERIALS AND METHODS: Forty male Sprague Dawley rats were divided into four groups: controls; AP; AP with NAC; and AP with Ukrain. AP was induced via the ligation of the bile-pancreatic duct; drugs were administered intraperitoneally (i.p.) 30 min and 12 h after AP induction. Twenty-four hours after AP induction, animals were sacrificed and the pancreas was excised. Levels of malondialdehyde (MDA) and nitric oxide (NO), and activity levels of tumor necrosis factor (TNF)-α, and myeloperoxidase (MPO) were measured in tissue samples. Total oxidant status (TOS), total antioxidant status (TAS), and total bilirubin, as well as activity levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), amylase and lipase were measured in serum samples. Pancreatic tissue histopathology was also evaluated. RESULTS: Test drugs reduced levels of MDA, NO, TNF-α, total bilirubin, AST, ALT, TOS and MPO, amylase and lipase activities (P < 0.001), and increased TAS (P < 0.001). Rats treated with test drugs attenuated AP-induced morphologic changes and decreased pancreatic damage scores compared with the AP group (P < 0.05). Both test drugs attenuated pancreatic damage, but the therapeutic effect was more pronounced in rats that received Ukrain than in those receiving NAC. CONCLUSIONS: These results suggest that treatment with Ukrain or NAC can reduce pancreatic damage via anti-inflammatory and antioxidant effects.

Lycorine Downregulates HMGB1 to Inhibit Autophagy and Enhances Bortezomib Activity in Multiple Myeloma.

Multiple myeloma (MM) is largely incurable and drug-resistant. Novel therapeutic approaches such as inhibiting autophagy or rational drug combinations are aimed to overcome this issue. In this study, we found that lycorine exhibits a promising anti-proliferative activity against MM in vitro and in vivo by inhibiting autophagy. We identified High mobility group box 1 (HMGB1), an important regulator of autophagy, as the most aberrantly expressed protein after lycorine treatment and as a critical mediator of lycorine activity. Gene expression profiling (GEP) analysis showed that higher expression of HMGB1 is linked with the poor prognosis of MM. This correlation was further confirmed in human bone marrow CD138+ primary myeloma cells and MM cell lines. Mechanistically, proteasomal degradation of HMGB1 by lycorine inhibits the activation of MEK-ERK thereby decreases phosphorylation of Bcl-2 resulting in constitutive association of Bcl-2 with Beclin-1. In addition, we observed higher HMGB1 expression in bortezomib resistant cells and the combination of bortezomib plus lycorine was highly efficient in vitro and in vivo myeloma models as well as in re-sensitizing resistant cells to bortezomib. These observations indicate lycorine as an effective autophagy inhibitor and reveal that lycorine alone or in combination with bortezomib is a potential therapeutic strategy.

Tobacco Mosaic Virus Delivery of Phenanthriplatin for Cancer therapy.

Phenanthriplatin, cis-[Pt(NH3)2Cl(phenanthridine)](NO3), is a cationic monofunctional DNA-binding platinum(II) anticancer drug candidate with unusual potency and cellular response profiles. Its in vivo efficacy has not yet been demonstrated, highlighting the need for a delivery system. Here we report tobacco mosaic virus (TMV) as a delivery system for phenanthriplatin. TMV forms hollow nanotubes with a polyanionic interior surface; capitalizing on this native structure, we developed a one-step phenanthriplatin loading protocol. Phenanthriplatin release from the carrier is induced in acidic environments. This delivery system, designated PhenPt-TMV, exhibits matched efficacy in a cancer cell panel compared to free phenanthriplatin. In vivo tumor delivery and efficacy were confirmed by using a mouse model of triple negative breast cancer. Tumors treated with PhenPt-TMV were 4× smaller than tumors treated with free phenanthriplatin or cisplatin, owing to increased accumulation of phenanthriplatin within the tumor tissue. The biology-derived TMV delivery system may facilitate translation of phenanthriplatin into the clinic.

Lycorine induces programmed necrosis in the multiple myeloma cell line ARH-77.

Lycorine, a natural alkaloid, has been widely reported to possess potential efficacy against cancer. However, the anti-multiple myeloma mechanism of lycorine is not fully understood. In this study, the results demonstrated that lycorine is effective against multiple myeloma cell line ARH-77 via inducing programmed necrosis. The mechanisms of lycorine on the multiple myeloma cell line ARH-77 are associated with G1 phase cell cycle arrest, mitochondrial dysfunction, reactive oxygen species (ROS) generation, ATP depletion, and DNA damage. Our results elucidate the new mechanism of lycorine against multiple myeloma.

Novel lycorine derivatives as anticancer agents: synthesis and in vitro biological evaluation.

Lycorine, which is the most abundant alkaloid isolated from the Amaryllidaceae family of plants, reportedly exhibits promising anticancer activities. Herein, a series of novel lycorine derivatives were synthesized and evaluated for their in vitro inhibitory activities against seven different cancer cell lines, including A549, HCT116, SK-OV-3, NCI-H460, K562, MCF-7 and HL-60. The results indicated that compounds bearing diverse amine substituents at the C-2 position demonstrated good anticancer activities. The selectivity towards different cancer cell lines of the synthesized derivatives is discussed.

Comparison of the D1 dopamine full agonists, dihydrexidine and doxanthrine, in the 6-OHDA rat model of Parkinson's disease.

RATIONALE: Preclinical evidence indicates that D1 dopamine receptor full agonists have potential as therapeutic agents for a variety of neurological conditions. Dihydrexidine (DHX) was the first high potency selective D1 dopamine receptor full agonist and has been studied as a possible treatment for Parkinson's disease (PD). Recently, we discovered doxanthrine (DOX), an oxygen bioisostere of DHX that has even greater selectivity for the D1 dopamine receptor. OBJECTIVES: Using the unilateral 6-hydroxydopamine-lesioned rat model of PD, DOX and DHX were compared at several doses (0.625, 1.25, 2.5, or 5.0 mg/kg) for their ability to elicit contralateral rotation by either intraperitoneal injection or oral gavage. RESULTS: After intraperitoneal administration, both DOX and DHX showed robust contralateral rotation at doses of 2.5 and 5.0 mg/kg compared to vehicle. In addition, after intraperitoneal administration at doses of 2.5 and 5.0 mg/kg, DHX had a significantly longer duration of action than DOX (p < 0.05). Areas under the curves (AUC) for DOX and DHX were not significantly different, however, indicating that DOX and DHX have similar potency after intraperitoneal administration. By contrast, after oral administration, 2.5 and 5.0 mg/kg of DOX produced significant contralateral rotations (p < 0.05), whereas DHX showed no significant activity after oral administration of any dose. CONCLUSION: These results demonstrate that although DHX and DOX have similar activity after intraperitoneal administration, DOX demonstrated greater activity after oral administration compared to DHX. Despite its catechol functionality, DOX may possess sufficient oral availability for development as a human therapeutic agent.