Multitargeted C9-substituted ester and ether derivatives of berberrubine for Alzheimer's disease: Design, synthesis, biological evaluation, metabolic stability, and pharmacokinetics.

Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d, display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC50 values of 0.5, 4.3, and 11.9 µM, respectively and excellent BBB permeability (Pe = 8 × 10-6 cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC50 values of 0.44, 3.8, and 17.9 µM, respectively. The ether analog also inhibits self-aggregation of Aß and crosses BBB (Pe = 7.3 × 10-6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC0-∞ of 28,834 ng min/ml. In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.

The role of lymph node revealing solution on the improvement of lymph node harvest in colorectal cancer specimens.

AIM: The correct analysis of lymph node status is one of the most important parameters for the accurate pathological diagnosis of colorectal cancer. Our aim was to evaluate the number of lymph nodes among the specimens obtained from colorectal resections due to colorectal cancer, before and after the routine use of a lymph node revealing solution (LNRS). METHOD: Data from 780 surgical specimens from patients of both genders with colorectal cancer were studied. The cases were divided chronologically into two groups: the conventional group included 497 specimens treated with conventional methods, i.e. without the use of the LNRS (January 2000 to July 2007), and the LNRS group included 283 specimens examined through the routine use of this solution (August 2007 to July 2012). RESULTS: Most patients were female (57.4%) with a median age of 62 years. The median lymph node number was 18, and 75.9% of the cases (592) had 12 or more nodes dissected. Lymph node metastases were noted in 334 cases (42.8%). A median of 24 lymph nodes was dissected in the LNRS group compared to 15 in the conventional group (P < 0.001). The LNRS group had 9.2% of cases with fewer than 12 lymph nodes dissected compared with 32.6% in the conventional group (P < 0.001). CONCLUSIONS: The use of the LNRS increases the number of lymph nodes obtained from colorectal cancer surgical specimens and can help to reduce the number of cases with < 12 lymph nodes.

Daucus carota Pentane/Diethyl Ether Fraction Inhibits Motility and Reduces Invasion of Cancer Cells.

Daucus carota (DC) is a herb used in folklore medicine in Lebanon to treat numerous diseases including cancer. Recent studies in our laboratory on DC oil and its fractions revealed potent anticancer activities in vitro and in vivo. The present study aims to investigate the effect of the most potent DC fraction, pentane/diethyl ether (50:50), on lung, skin, breast and glioblastoma cancer cell motility and invasion. Upon treatment, a pronounced decrease in cancer cell motility was observed in the 4 cell lines. The treatment also led to a decrease in cancer cell invasion and an increased cell adhesion. Additionally, the DC fraction caused a decrease in the activation of the ρ-GTPases Rac and CDC42, a finding that may partially explain the treatment-induced decrease in cell motility. The current study demonstrates a crucial effect of the DC pentane/diethyl ether fraction on cancer cell motility and metastasis, making it a potential candidate for cancer therapy specifically targeting cancer motility and metastasis.

High times, fair maidens, and sweet air: romantic interludes in the life of Dr. Crawford Long.

How does one's knowledge of pain affect the physical "being" of pain? Following German idealist philosophy, unconsciousness to such knowledge would seemingly abdicate the very nature of pain. "Nothing exists but thoughts!--the universe is composed of impressions, ideas, pleasures, and pains!" Humphry Davy exclaimed upon leaping out of the laughing gas chamber where he had breathed some 100 quarts of nitrous oxide. The discovery of nitrous oxide gas as an agent of transubstantiation led to the discovery of the medical science of anesthesia by a genius, but backcountry physician, Dr. Crawford Long in 1841. This paper presupposes that the Romantically introspective effects of diethyl ether inhalation led Dr. Long to yearn melancholically for his lover and underestimate his momentous discovery, as the physical abdication of pain could not quench the doctor's subliminal anguish. Within is an account of the arcane nature of one of medicine and history's most significant discoveries, one wrought out of intelligence and the wondrous curiosity of the Romantic period.

Melanogenesis Inhibitory Activity, Chemical Components and Molecular Docking Studies of Prunus cerasoides Buch.-Ham. D. Don. Flowers.

Safe depigmenting agents are currently increasing in the cosmetic or pharmaceutical industry because various compounds have been found to have undesirable side effects. Therefore, the present study aimed to investigate the melanogenesis inhibitory effects of Prunus cerasoides Buch. -Ham. D. Don. flower extracts and their molecular mechanism in B16F10 mouse melanoma cells. Moreover, we also examined phenolic and flavonoid contents, antioxidant activity, chemical constituents of potential extracts, and molecular docking. The highest phenolic and flavonoid contents with the greatest scavenging activity were found in the butanol extract of the P. cerasoides flower compared to other extracts. From all extracts, only crude, diethyl ether, and butanol extracts showed an inhibition of mushroom tyrosinase activity, cellular tyrosinase activity, and melanin content as well as the downregulation of the gene expression of the microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2) in α-MSH-stimulated B16F10 cells. Based on the molecular docking study, n-hexadecanoic acid, heptadecanoic acid, octadecanoic acid, 9,12-octadecadienoic acid, 9,12,15-octadecanoic acid, and eicosanoic acid might show an inhibitory effect against tyrosinase and MITF. In conclusion, this finding demonstrates that both the diethyl ether and butanol extracts of the P. cerasoides flower can effectively reduce tyrosinase activity and melanin synthesis through the downregulation of the melanogenic gene expression in B16F10 cells and through the molecular docking study. Taken together, the diethyl ether and butanol extracts of the P. cerasoides flower could be an anti-melanogenic ingredient for hyperpigmentary or melasma treatment.

Benzene Amide Ether Scaffold is Active against Non-replicating and Intracellular Mycobacterium tuberculosis.

New drugs to treat tuberculosis which target intractable bacterial populations are required to develop shorter and more effective treatment regimens. The benzene amide ether scaffold has activity against intracellular Mycobacterium tuberculosis, but low activity against extracellular, actively replicating M. tuberculosis. We determined that these molecules have bactericidal activity against non-replicating M. tuberculosis but not actively replicating bacteria. Exposure to compounds depleted ATP levels in non-replicating bacteria and increased the oxygen consumption rate; a subset of molecules led to the accumulation of intrabacterial reactive oxygen species. A comprehensive screen of M. tuberculosis strains identified a number of under-expressing strains as more sensitive to compounds under replicating conditions including QcrA and QcrB hypomorphs. We determined the global gene expression profile after compound treatment for both replicating and nutrient-starved M. tuberculosis. We saw compound-dependent changes in the expression of genes involved in energy metabolism under both conditions. Taken together, our data suggest that the scaffold targets respiration in M. tuberculosis.

Ether Anesthesia in the Austere Environment: An Exposure and Education.

Medical services in the austere and limited environment often require therapeutics and practices uncommon in modern times due to a lack of availability, affordability, or expertise in remote areas. In this setting, diethyl ether, or simply ether anesthesia, still serves a role today as an effective inhalation agent. An understanding of ether as an anesthetic not only illustrates the evolution in surgical anesthesia but also demonstrates ether's surviving function and durable use as a practical agent in developing nations. Although uncommon, it is not unseen, so a working knowledge should be understood if observation and advocacy for patients receiving this method of anesthesia are experienced.

John Snow and the First Second-Gas Effect.

In 1847, British anesthesia pioneer John Snow (1813-1858) observed that patients did not manifest cyanosis during induction with hypoxic mixtures of ether vapor in air. He hypothesized a molecular mechanism that would be understood over a century later as the second gas effect.

Modifications in avoidance reactions of mice, on a second exposure to the hot plate, resist to various amnesia-inducing treatments.

The avoidance responses of mice exposed to the hot plate (55 degrees C) were found to be modified when tested a second time. In fact, when forepaws licking was no longer observed, the rearing was clearly anticipated (7 s instead of 15 s) as well as jumping (24 s instead of 55 s). These modifications of avoidance strategies as well as their latencies were still observed even 24 days after the first exposure. Avoidance responses were prevented by morphine or haloperidol injected prior to the first exposure, but not with scopolamine or diazepam. These modifications were not affected in mice injected with morphine or submitted to either a supramaximal electroshock or to ether anesthesia delivered immediately after the first hot plate exposure. Among the various known types of memory, these modifications could be linked to procedural memory.

Anticholinergics, cromolyn, and other occasionally useful drugs.

In asthmatics who are not controlled with beta-adrenergic agonists, theophylline and corticosteroids, the addition of anticholinergics may be beneficial. Cromolyn and the calcium-channel blocking agents are useful in preventing asthma attacks in some patients. Some other agents that have been proposed for the treatment of asthma are discussed briefly.

William Wright, aurist: nineteenth century pneumatic practitioner and a discoverer of anesthesia.

William Wright (1773-1860) was Surgeon-Aurist in Ordinary to Her Majesty Queen Charlotte of England. One interesting feature of his otologic practice was his employment of gases and vapors in treating deafness and other disorders of the ear. Among aeroform substances that he advocated for such uses were nitrous oxide and ether--gases that were destined to become anesthetic agents in another quarter of a century. Wright made the observation that inhalation of ether vapor would suppress the cough elicited by instrumentation of an inflamed and sensitive ear canal. He used ether inhalation beginning about 1820 in his practice for this purpose, and in so doing appears to have administered some of the earliest anesthetics on record.

An unfortunate complication of self-therapy for seborrheic dermatitis.

The death of a young boy who practiced self-therapy of seborrheic dermatitis of the scalp is reported. Practitioners should be aware that peer pressure in today's teenage society, coupled with misinterpretation of therapeutic protocols, may result in the application of unorthodox treatment regimens.

In vitro activity of acetylsalicylic acid on replication of varicella-zoster virus.

Topical application of a mixture of acetylsalicylic acid (ASA) and diethyl ether is effective in the treatment of acute herpes zoster and postherpetic neuralgia. To study whether the other-than-analgesic effects of that treatment could be due to an antiviral activity of ASA the effects of the drug on the replication of varicella zoster virus (VZV) were assessed by the fluorescent focus assay on MRC5 and Vero cells. ASA caused a marked reduction in the spread of infection in MRC5 monolayers while in growing Vero cells the effective dose proved toxic. ASA concentrations (5-10 mM) which were effective in vitro against VZV are higher than the plasma concentrations attained in the standard treatment of chronic inflammatory states, but are consistent with the skin concentration attained by topical application of ASA/diethyl ether mixture. These data support similar findings relating the antiviral activity of acetylsalicylic acid to influenza virus, CMV, and HIV.

[Treatment of generalized peroxisomal disorders with docosahexaenoic acid ethyl ether]. / Tratamiento de las enfermedades peroxisomales generalizadas con etil éster del ácido docosahexaenoico.

INTRODUCTION: We found that patients with the Zellweger syndrome and other generalized peroxisomal disorders have a dramatic decrease of docosahexaenoic acid (DHA, 22:6n-3) in the blood, brain, retina and other tissues. DHA is believed to play an important role in the brain and retina. DEVELOPMENT: Patients with the Zellweger syndrome and its variants have severe cerebral and retinal defects that could be related to their DHA deficiency. With this rationale, we have been treating peroxisomal-disorder patients with a DHA derivative of a high degree of purity (DHA ethyl ester, > 90% pure) since 1991. So far, we have treated 13 DHA-deficient peroxisomal patients, one with the classic Zellweger syndrome and 12 with milder variants of the disease. This paper presents the follow-up of these DHA-treated patients. In summary, we have found important improvements in liver function, in the plasmalogen levels and in the two ratios 26:0/22:0 y 26:1/22:0, diagnostic of the disease. We have also found clear clinical improvements in most cases. Most significantly, magnetic resonance imaging has shown advances in brain myelination, so far in 6 of the treated patients. CONCLUSION: We strongly recommend treatment with DHA ethyl ester in all DHA-deficient patients with generalized peroxisomal disorders. Logically, treatment should be started as soon as possible, in the hope of preventing cerebral and visual damage.

[Increase in the cAMP content of mouse brain cells in ischemia and inhibition of this effect by certain biologically active compounds]. / Uvelichenie soderzhaniia tsAMF v kletkakh golovnogo mozga myshei pri ishemii i tormozhenie étogo éffekta pod vliianiem nekotorykh biologicheski aktivnykh soedinenii.

Anoxia (during 2 minutes after decapitation) produced a significant elevation of cAMP contents (up to 410%) in mouse brain cells. This effect was abolished by an intraperitoneal injection of alloxan (A), morphine (M), and ethanol (E) 30 minutes before decapitation, and after a 2 minutes diethyl ether (DE) inhalation. It was found that anoxia produced some decrease in phosphodiesterase (FDE) activity. A preliminary injection of A and E produced an activation of FDE; M and DE did not change FDE significantly. Mechanisms of action of all the four agents on the cAMP content under anoxia are different. A and E produced a rapid cAMP hydrolysis on stimulating the activity of FDE, M and DE inhibited apparently adenylate cyclase. The activation of adenylate cyclase due to anoxia is considered as one of the initial steps in the cell injury extention.

Composite fatty acid ether amides suppress growth of liver cancer cells in vitro and in an in vivo allograft mouse model.

BACKGROUND: The heterogeneity of liver cancer, in particular hepatocellular carcinoma (HCC), portrays the requirement of multiple targets for both its treatment and prevention. Multifaceted agents, minimally or non-toxic for normal hepatocytes, are required to address the molecular diversity of HCC, including the resistance of putative liver cancer stem cells to chemotherapy. METHODS: We designed and synthesized two fatty acid ethers of isopropylamino propanol, C16:0-AIP-1 and C18:1-AIP-2 (jointly named AIPs), and evaluated their anti-proliferative effects on the human HCC cell line Huh7 and the murine hepatoma cell line BNL 1MEA.7R.1, both in vitro and in an in vivo allograft mouse model. RESULTS: We found that AIP-1 and AIP-2 inhibited proliferation and caused cell death in both Huh7 and BNL 1MEA.7R.1 cells. Importantly, AIP-1 and AIP-2 were found to block the activation of putative liver cancer stem cells as manifested by suppression of clonal 'carcinosphere' development in growth factor-free and anchorage-free medium. The AIPs exhibited a relatively low toxicity against normal human or rat hepatocytes in primary cultures. In addition, we found that the AIPs utilized multifaceted pathways that mediate both autophagy and apoptosis in HCC, including the inhibition of AKTs and CAMK-1. In immune-competent mice, the AIPs significantly reduced BNL 1MEA.7R.1 cell-driven tumor allograft development, with a higher efficiency than sorafenib. A combination of AIP-1 + AIP-2 was most effective in reducing the tumor allograft incidence. CONCLUSIONS: AIPs represent a novel class of simple fatty acid derivatives that are effective against liver tumors via diverse pathways. They show a low toxicity towards normal hepatocytes. The addition of AIPs may represent a new avenue towards the management of chronic liver injury and, ultimately, the prevention and treatment of HCC.

Generation of a focused poly(amino ether) library: polymer-mediated transgene delivery and gold-nanorod based theranostic systems.

A focused library of twenty-one cationic poly(amino ethers) was synthesized following ring-opening polymerization of two diglycidyl ethers by different oligoamines. The polymers were screened in parallel for plasmid DNA (pDNA) delivery, and transgene expression efficacies of individual polymers were compared to those of 25 kDa polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery. Seven lead polymers that demonstrated higher transgene expression than PEI in pancreatic and prostate cancer cells lines were identified from the screen. All seven lead polymers showed highest transgene expression at a polymer:pDNA weight ratio of 5:1 in the MIA PaCa-2 pancreatic cancer cell line. Among the conditions studied, transgene expression efficacy correlated with minimal polymer cytotoxicity but not polyplex sizes. In addition, this study indicated that methylene spacing between amine centers in the monomers, amine content, and molecular weight of the polymers are all significant factors and should be considered when designing polymers for transgene delivery. A lead effective polymer was employed for coating gold nanorods, leading to theranostic nanoassemblies that possess combined transgene delivery and optical imaging capabilities, leading to potential theranostic systems.