111 research outputs found
A protocol for the emergency department management of acute undifferentiated febrile illness in India
Identification and Analysis of the Active Phytochemicals from the Anti-Cancer Botanical Extract Bezielle
Bezielle is a botanical extract that has selective anti-tumor activity, and has shown a promising efficacy in the early phases of clinical testing. Bezielle inhibits mitochondrial respiration and induces reactive oxygen species (ROS) in mitochondria of tumor cells but not in non-transformed cells. The generation of high ROS in tumor cells leads to heavy DNA damage and hyper-activation of PARP, followed by the inhibition of glycolysis. Bezielle therefore belongs to a group of drugs that target tumor cell mitochondria, but its cytotoxicity involves inhibition of both cellular energy producing pathways. We found that the cytotoxic activity of the Bezielle extract in vitro co-purified with a defined fraction containing multiple flavonoids. We have isolated several of these Bezielle flavonoids, and examined their possible roles in the selective anti-tumor cytotoxicity of Bezielle. Our results support the hypothesis that a major Scutellaria flavonoid, scutellarein, possesses many if not all of the biologically relevant properties of the total extract. Like Bezielle, scutellarein induced increasing levels of ROS of mitochondrial origin, progressive DNA damage, protein oxidation, depletion of reduced glutathione and ATP, and suppression of both OXPHOS and glycolysis. Like Bezielle, scutellarein was selectively cytotoxic towards cancer cells. Carthamidin, a flavonone found in Bezielle, also induced DNA damage and oxidative cell death. Two well known plant flavonoids, apigenin and luteolin, had limited and not selective cytotoxicity that did not depend on their pro-oxidant activities. We also provide evidence that the cytotoxicity of scutellarein was increased when other Bezielle flavonoids, not necessarily highly cytotoxic or selective on their own, were present. This indicates that the activity of total Bezielle extract might depend on a combination of several different compounds present within it
Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1
The wogonin-containing herb Scutellaria baicalensis has successfully been used for curing various diseases in traditional Chinese medicine. Wogonin has been shown to induce apoptosis in different cancer cells and to suppress growth of human cancer xenografts in vivo. However, its direct targets remain unknown. In this study, we demonstrate for the first time that wogonin and structurally related natural flavones, for example, apigenin, chrysin and luteolin, are inhibitors of cyclin-dependent kinase 9 (CDK9) and block phosphorylation of the carboxy-terminal domain of RNA polymerase II at Ser2. This effect leads to reduced RNA synthesis and subsequently rapid downregulation of the short-lived anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) resulting in apoptosis induction in cancer cells. We show that genetic inhibition of Mcl-1 or CDK9 expression by siRNA is sufficient to mimic flavone-induced apoptosis. Pull-down and in silico docking studies demonstrate that wogonin directly binds to CDK9, presumably to the ATP-binding pocket. In contrast, wogonin does not inhibit CDK2, CDK4 and CDK6 at doses that inhibit CDK9 activity. Furthermore, we show that wogonin preferentially inhibits CDK9 in malignant compared with normal lymphocytes. Thus, our study reveals a new mechanism of anti-cancer action of natural flavones and supports CDK9 as a therapeutic target in oncology
Synthesis of 1,2-bis(2-oxazolinyl-2)ethane and its application as chain extender for poly(ethylene terephthalate)
The Flavonoid Luteolin Inhibits Fcγ-Dependent Respiratory Burst in Granulocytes, but Not Skin Blistering in a New Model of Pemphigoid in Adult Mice
Bullous pemphigoid is an autoimmune blistering skin disease associated with autoantibodies against the dermal-epidermal junction. Passive transfer of antibodies against BP180/collagen (C) XVII, a major hemidesmosomal pemphigoid antigen, into neonatal mice results in dermal-epidermal separation upon applying gentle pressure to their skin, but not in spontaneous skin blistering. In addition, this neonatal mouse model precludes treatment and observation of diseased animals beyond 2–3 days. Therefore, in the present study we have developed a new disease model in mice reproducing the spontaneous blistering and the chronic course characteristic of the human condition. Adult mice were pre-immunized with rabbit IgG followed by injection of BP180/CXVII rabbit IgG. Mice pre-immunized against rabbit IgG and injected 6 times every second day with the BP180/CXVII-specific antibodies (n = 35) developed spontaneous sustained blistering of the skin, while mice pre-immunized and then treated with normal rabbit IgG (n = 5) did not. Blistering was associated with IgG and complement C3 deposits at the epidermal basement membrane and recruitment of inflammatory cells, and was partly dependent on Ly-6G-positive cells. We further used this new experimental model to investigate the therapeutic potential of luteolin, a plant flavonoid with potent anti-inflammatory and anti-oxidative properties and good safety profile, in experimental BP. Luteolin inhibited the Fcγ-dependent respiratory burst in immune complex-stimulated granulocytes and the autoantibody-induced dermal-epidermal separation in skin cryosections, but was not effective in suppressing the skin blistering in vivo. These studies establish a robust animal model that will be a useful tool for dissecting the mechanisms of blister formation and will facilitate the development of more effective therapeutic strategies for managing pemphigoid diseases
Brain architecture in the terrestrial hermit crab Coenobita clypeatus (Anomura, Coenobitidae), a crustacean with a good aerial sense of smell
<p>Abstract</p> <p>Background</p> <p>During the evolutionary radiation of Crustacea, several lineages in this taxon convergently succeeded in meeting the physiological challenges connected to establishing a fully terrestrial life style. These physiological adaptations include the need for sensory organs of terrestrial species to function in air rather than in water. Previous behavioral and neuroethological studies have provided solid evidence that the land hermit crabs (Coenobitidae, Anomura) are a group of crustaceans that have evolved a good sense of aerial olfaction during the conquest of land. We wanted to study the central olfactory processing areas in the brains of these organisms and to that end analyzed the brain of <it>Coenobita clypeatus </it>(Herbst, 1791; Anomura, Coenobitidae), a fully terrestrial tropical hermit crab, by immunohistochemistry against synaptic proteins, serotonin, FMRFamide-related peptides, and glutamine synthetase.</p> <p>Results</p> <p>The primary olfactory centers in this species dominate the brain and are composed of many elongate olfactory glomeruli. The secondary olfactory centers that receive an input from olfactory projection neurons are almost equally large as the olfactory lobes and are organized into parallel neuropil lamellae. The architecture of the optic neuropils and those areas associated with antenna two suggest that <it>C. clypeatus </it>has visual and mechanosensory skills that are comparable to those of marine Crustacea.</p> <p>Conclusion</p> <p>In parallel to previous behavioral findings of a good sense of aerial olfaction in C. clypeatus, our results indicate that in fact their central olfactory pathway is most prominent, indicating that olfaction is a major sensory modality that these brains process. Interestingly, the secondary olfactory neuropils of insects, the mushroom bodies, also display a layered structure (vertical and medial lobes), superficially similar to the lamellae in the secondary olfactory centers of <it>C. clypeatus</it>. More detailed analyses with additional markers will be necessary to explore the question if these similarities have evolved convergently with the establishment of superb aerial olfactory abilities or if this design goes back to a shared principle in the common ancestor of Crustacea and Hexapoda.</p
A Flavonoid, Luteolin, Cripples HIV-1 by Abrogation of Tat Function
Despite the effectiveness of combination antiretroviral treatment (cART) against HIV-1, evidence indicates that residual infection persists in different cell types. Intensification of cART does not decrease the residual viral load or immune activation. cART restricts the synthesis of infectious virus but does not curtail HIV-1 transcription and translation from either the integrated or unintegrated viral genomes in infected cells. All treated patients with full viral suppression actually have low-level viremia. More than 60% of treated individuals also develop minor HIV-1 –associated neurocognitive deficits (HAND) due to residual virus and immune activation. Thus, new therapeutic agents are needed to curtail HIV-1 transcription and residual virus. In this study, luteolin, a dietary supplement, profoundly reduced HIV-1 infection in reporter cells and primary lymphocytes. HIV-1inhibition by luteolin was independent of viral entry, as shown by the fact that wild-type and VSV–pseudotyped HIV-1 infections were similarly inhibited. Luteolin was unable to inhibit viral reverse transcription. Luteolin had antiviral activity in a latent HIV-1 reactivation model and effectively ablated both clade-B- and -C -Tat-driven LTR transactivation in reporter assays but had no effect on Tat expression and its sub-cellular localization. We conclude that luteolin confers anti–HIV-1 activity at the Tat functional level. Given its biosafety profile and ability to cross the blood-brain barrier, luteolin may serve as a base flavonoid to develop potent anti–HIV-1 derivatives to complement cART
Mortality of Kalliapseudes schubartii in unvegetated soft bottoms of the estuarine region of the Lagoa dos Patos
Fibers of generic Brauer-Severi schemes
AbstractIn this note we investigate the fibers of Van den Bergh's Brauer–Severi schemeBSm,n↠ηVm,nof the trace ring ofmgenericn×nmatrices over the variety of matrix-invariants. If ξ∈Vm,nis a point of representation type (m1,n1;…;mr,nr), then the reduced variety of η−1(ξ) has (∑mi)!/∏mi! irreducible components each of dimension [equation
Kupplung von Amadori-Verbindungen mit Diazoniumsalzen Darstellung von Lactulose aus Lactose
1-Dezoxy-1-arylamino-ketosen kuppeln in Pyridin/Methanol mit Diazoniumsalzen zu schwer wasserlöslichen, kristallinen Diazoaminoverbindungen (Triazenen). Die Reaktion ist zur Abscheidung von Amadori-Verbindungen aus Gemischen mit N-Glykosiden und deren Zersetzungsprodukten geeignet. Es werden 14 Triazene von 7 verschiedenen Zuckern beschrieben. Salzsäure in Gegenwart von J-Ionen spaltet die Triazene in Aryljodid und Amadori-Verbindung. Katalytische Hydrierung der letzteren und Desaminierung der gebildeten 1-Desoxy-1-amino-ketosen führt zu den entsprechenden Ketosen. Aus Lactose erhält man auf diesem Wege in einer Gesamtausbeute von 17% d. Th. kristallisierte Lactulose
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