Academic literature on the topic 'King of Bitters'

Studies were performed to investigate the prohormone/proprotein convertase (PC)-inhibitory properties of chemical constituents of the medicinally active plant Andrographis paniculata (AP; from the family Acanthaceae), also known as ‘King of Bitters ’. Among the individual components tested against the clinically important convertases, furin and PC1, neoandrographolide (a C3 O-glucoside derivative of the major constituent andrographolide) exhibited the highest inhibitory action with an IC50 of 53.5 µM against furin. The data further revealed that although andrographolide, the major bitter principle of AP, exhibited a relatively small enzyme inhibition (IC50 = 1.0 mM and Ki = 200 µM against furin), upon succinoylation, its inhibitory action against the above convertases was enhanced significantly with a Ki in the low micromolar range (< 30 µM), suggesting that a specific structural modification of the andrographolide skeleton may be exploited to develop a new class of non-peptide inhibitors of PCs. When tested against PC7, these succinoylated derivatives of andrographolide also displayed strong inhibitory action, with Ki values again in the low micromolar range. This potentially interesting observation may be attributed to the reported anti-HIV property of 14-dehydroandrographolide succinic acid monoester (DASM). It is suggested here that DASM, by virtue of this protease inhibitory property, possibly acts by suppressing the proteolytic cleavage of envelope glycoprotein gp160 of HIV, which is known to be PC-mediated, particularly by furin and PC7.

Andrographis paniculata(Burm. F) Nees, generally known as “king of bitters,” is an herbaceous plant in the family Acanthaceae. In China, India, Thailand, and Malaysia, this plant has been widely used for treating sore throat, flu, and upper respiratory tract infections. Andrographolide, a major bioactive chemical constituent of the plant, has shown anticancer potential in various investigations. Andrographolide and its derivatives have anti-inflammatory effects in experimental models asthma, stroke, and arthritis. In recent years, pharmaceutical chemists have synthesized numerous andrographolide derivatives, which exhibit essential pharmacological activities such as those that are anti-inflammatory, antibacterial, antitumor, antidiabetic, anti-HIV, antifeedant, and antiviral. However, what is noteworthy about this paper is summarizing the effects of andrographolide against cardiovascular disease, platelet activation, infertility, and NF-κB activation. Therefore, this paper is intended to provide evidence reported in relevant literature on qualitative research to assist scientists in isolating and characterizing bioactive compounds.

Andrographis paniculata (AP) is commonly known as creat or green chiretta belongs to the family Acanthaceae. It is also known as Kalmegh and popularly called as King of bitters. It was widely used in the traditional system of medicines such as Siddha system, Ayurvedic system and Chinese medicine for the regular treatment of a common cold. Some of the reported health benefits are Antidiabetic, Antipyretic, Hepatoprotective, Antioxidant, Antimalarial, Anti-cancer, Antityphoid, Anti-diarrhoea, antioedema, etc. Whole plant possesses medicinal property and leaves are explicitly used for therapeutic care. The plant contains four major diterpenoids such as andrographolide, neoandrographolide,14-deoxyandrographolide, 14-deoxy-11,12-didehydroandrographolide and also includes other phytoconstituents such as flavonoidssesquiterpene lactones, etc. Andrographolide is found as major constituent in the leaves and reported for a wide variety of pharmacological activities. The purpose of this review is to brief the plant's literature survey via internet sources such as google scholar and PubMed providing a medium to explain the plant's ethnobotany information on conventional usage, essential chemical constituents and selected plant pharmacology activities are obtained from existing research articles to frame the review. The present analysis also illustrates the pharmacological and phytochemical characteristics of Andrographis paniculata from which researchers may get benefited for further qualitative research.

ABSTRAK<br />Sambiloto (Andrografis paniculata Nees) secara alami hidup subur<br />di antara tegakan hutan. Hal ini megindikasikan bahwa tanaman ini toleran<br />terhadap naungan. Kajian pola tanam jagung dan sambiloto diharapkan<br />mendorong efisiensi produksi dan meningkatkan daya saing. Percobaan<br />dilaksanakan di Kebun Percobaan Cimanggu Bogor pada tanah Latosol,<br />ketinggian 240 m dpl, tipe iklim A. Penanaman pada bulan Nopember<br />2003 dan panen mulai bulan Maret 2004 selama 5 kali panen dengan<br />selang setiap 2 bulan. Penelitian menggunakan rancangan acak kelompok<br />(RAK) 6 kali ulangan dengan 4 perlakuan, yaitu : (1) monokultur<br />sambiloto, (2) sambiloto + jagung jarak tanam 150 cm x 20 cm, (3)<br />sambiloto + jagung jarak tanam 120 cm x 20 cm, (4) sambiloto + jagung<br />jarak tanam 90 cm x 20 cm. Bibit sambiloto disemaikan selama 2 bulan<br />dan ditanam dengan jarak tanam 30 cm x 40 cm, dipupuk dengan 10 ton<br />pupuk kandang, 150 kg urea, 150 kg SP-36, dan 150 kg KCl per ha.<br />Pupuk kandang, SP-36, dan KCl seluruhnya diberikan pada saat tanam.<br />Urea diberikan masing-masing 1/3 bagian pada umur 0, 1, dan 2 BST<br />(Bulan Sesudah Tanam). Untuk setiap ha tanaman jagung dipupuk dengan<br />5 ton pupuk kandang, 300 kg SP-36, dan 200 kg KCl yang diberikan pada<br />saat tanam, dan 300 kg urea diberikan masing-masing 1/2 bagian pada<br />umur 0, dan 1 BST. Benih jagung (Hibrida lokal R-01) ditanam 2 butir per<br />lubang tanam, ditanam 2 kali selama musim tanam yaitu pertama 2 minggu<br />sebelum penanaman sambiloto, dan penanaman kedua 75 hari setelah<br />penanam jagung yang pertama. Data input-output usahatani dianalis secara<br />deskriptif dilanjutkan dengan analisis B/C rasio dan sensitivitas. Hasil<br />penelitian menunjukkan mutu simplisia semua pola tanam memenuhi<br />standard Materia Medika Indonesia. Produktivitas sambiloto per m 2 makin<br />menurun dengan kerapatan pola tanam; pada pola monokultur diperoleh<br />hasil 1,1 kg/m 2 sedangkan pada pola tanam dengan jagung jarak tanam 90<br />cm x 20 cm menghasilkan 0,5 kg/m 2 terna basah. Produktivitas jagung per<br />m 2 meningkat dengan makin rapatnya pola tanam yaitu mencapai 13,3<br />tongkol pada jagung jarak tanam 150 cm x 20 cm, dan 22,2 tongkol pada<br />jarak tanam jagung 90 cm x 20 cm. Biaya produksi sambiloto sebagian<br />besar untuk bibit (Rp. 300/tanaman); biaya bibit tertinggi pada pola tanam<br />monokultur yaitu 66,5% dari total biaya usahatani dan terendah pada pola<br />tanam dengan jagung jarak tanam 90 cm x 20 cm yaitu 36%. Untuk<br />menekan biaya usahatani disarankan petani melakukan penyemaian benih<br />sendiri. Pola tanam sambiloto dengan jagung jarak tanam 90 cm x 20 cm,<br />paling layak secara finansial dengan pendapatan bersih mencapai<br />Rp1.188.360 dan B/C rasio 1,45 per 1.000 m2 lahan dan memberikan<br />sumbangan lebih dari 20% terhadap pendapatan petani sebagai manager<br />usahatani, mempunyai daya adaptasi yang cukup fleksibel terhadap<br />perubahan biaya produksi dan harga produk, serta memberikan tambahan<br />pendapatan bersih (keuntungan sebesar) Rp.51.675/1.000 m 2 lahan<br />dibandingkan pola monokultur.<br />Kata kunci : Sambiloto, Andrografis paniculata Nees, jagung, polatanam,<br />usahatani, produksi, Jawa Barat<br />ABSTRACT<br />Feasibility study of king bitter and corn cropping pattern<br />King bitter (Andrografis paniculata Nees) is naturally grown wildly<br />under forest trees. This indicates that the plant is shade tolerant. The<br />cropping pattern of the plant with corn was expected to improve its<br />production efficiency and compatibility. The experiment was conducted in<br />the Cimanggu Experimental Garden Bogor, Latosol soil type, elevation<br />240 m above sea level, climate type A of Schmidt and Fergusson. Planting<br />was done November 2003. The experiment was designed in a randomized<br />block with 6 replications. Treatments were (1) monoculture of king bitter<br />cropping pattern, (2) king bitter and corn (in a plant spacing 150 cm x 20<br />cm) cropping pattern, (3) king bitter and corn (in a plant spacing 120 cm x<br />20 cm) cropping pattern, (4) king bitter and corn (in a plant spacing 90 cm<br />x 20 cm) cropping pattern. King bitter was planted at 30 cm x 40 cm<br />spacing, fertilized with 10 tons manure + 150 kg SP-36 + 150 kg KCl and<br />150 kg urea fertilizer was applied one of third dosage in 0, 1, and 2 months<br />after planting. Corn was grown twice during the experiment; first was<br />planted 2 weeks prior to planting of the king bitter, and second was 75<br />days after the first planting. Corn was fertilized with 5 tons manure + 300<br />kg SP36 + 200 kg KCl per ha, and 300 kg urea fertilizer was applied half<br />dosage in 0, and 1 months after planting. First harvest of the king bitter<br />was done in March 2004, followed with 5 harvests every 2 months.<br />Farming efficiency was analyzed using descriptive analysis, B/C ratio and<br />sensitivity analysis. The results showed that quality of dry raw material of<br />king bitter matched with MMI standard. Productivity of king bitter<br />decreased by the increasing population of corn in cropping pattern, in<br />monoculture bitter king productivity was 1.1 kg/m 2 decreased to 0.5 kg/m 2<br />in cropping pattern king bitter and corn (in a plant spacing 90 cm x 20 cm).<br />In opposite, the productivity of corn increased by the increasing<br />population of corn in cropping pattern, that were 13.3 cobs/m 2 in cropping<br />pattern king bitter and corn (in a plant spacing 150 cm x 20 cm) increased<br />to 22.2 cobs /m 2 in cropping pattern king bitter and corn (in a plant spacing<br />90 cm x 20 cm). Most of king bitter production cost (Rp. 300/polybag),is<br />for seedlings. In monoculture of king bitter, seedling cost of king bitter<br />was 66,5% of production cost, and in cropping pattern king bitter and corn<br />(in a plant spacing 90 cm x 20 cm) the seedling cost was 36% of<br />production cost. To reduce production cost, farmers suggested to produce<br />the seedlings by themselves. The study suggested that the best cropping<br />pattern was king bitter planted with corn at 90 cm x 20 cm planting space.<br />This cropping pattern financially acceptable as it raised income as much as<br />Rp.1,188,360, B/C ratio 1,45 per 1.000 m2 and gave more then 20% of<br />management income which was more adaptable to fluctuation production<br />cost and price of product, and gave Rp. 51,675/1.000 m 2 net benefit<br />compared to monoculture of king bitter<br />Key words: Sambiloto, Andrografis paniculata Nees, corn, cropping<br />pattern, farming, production, West Java

Andrographis paniculata (family Acanthaceae), also known as “King of Bitters” or Kalmegh, is an important medicinal plant used for the treatment of various diseases. It has antimicrobial, antiviral, anti-inflammatory, hepatoprotective, antidiabetic, antihyperglycemic, and antioxidant properties (1). During June 2014, while performing a routine survey of the commercial trial fields of Kalmegh at Central Institute of Medicinal and Aromatic Plants (CIMAP), Lucknow, India, typical phytoplasma disease symptoms such as virescence, proliferation, and witches' broom along with little leaf and stunted growth were observed. The disease incidence was estimated to be approximately 7 to 10%. To ascertain the presence of phytoplasma, 16 samples of leaves were collected from nine different field sites, and total genomic DNA was extracted from the symptomatic and symptomless Kalmegh plants by the CTAB method. Direct and nested PCR assays were performed targeting the 16S rDNA using generic phytoplasma primer pairs P1/P6 followed by R16F2n/R16R2 (2). Resulting bands of the expected size (1.5 kb and 1.2 kb, respectively) were amplified from symptomatic plants. No amplification was observed with DNA from asymptomatic plant samples. The purified nested PCR products were cloned into E. coli DH5α, using the pGEM-T Easy vector (Promega, United States) and sequenced with primers M13For/M13Rev using an automatic sequencer (ABI Prism, Perkin Elmer) at CIMAP. The sequence was analyzed by BLASTn and found to share 99% similarity with Echinacea witches'-broom phytoplasma and Sesame phyllody phytoplasma strain (GenBank Accession Nos. JF340080 and KF612966, respectively), which belong to the 16SrII-D group. The sequence was deposited in NCBI as GenBank Accession No. KM359410. A phylogenetic tree using MEGA v5.0 (4) was constructed with 16S rDNA; consensus sequences of phytoplasmas belonging to distinct groups revealed that the present phytoplasma clustered with the 16SrII group. iPhyClassifier software was used to perform sequence comparison and generate a virtual restriction fragment length polymorphism (RFLP) profile (5). On the basis of iPhyClassifier, the 16S rDNA sequence analysis of our isolate showed 99.2% similarity with that of the ‘Candidatus Phytoplasma australasiae’ reference strain (GenBank Accession No. Y10097), which belongs to 16Sr group II. The virtual RFLP pattern of F2n/R2 fragment was most similar to the 16SrII-D subgroup (similarity coefficient of 0.91) but showed a difference in profile with HpaI, HhaI, and MseI enzymes. Several bacterial/fungal and viral diseases have been reported on A. paniculata (3); however, to our knowledge, this is the first report of witches' broom disease in India and the first record of a 16SrII-D group phytoplasma on Kalmegh. Its presence in Kalmegh is of great significance due to its commercial interest. References: (1) S. Akbar. Altern. Med. Rev. 16:1, 2011. (2) D. E. Gundersen and M. Lee. Phytopathol. Mediterr. 35:144, 1996. (3) A. Khan and A. Samad. Plant Dis. 98:698, 2014. (4) K. Tamura et al. Mol. Biol. Evol. 28:2731, 2011. (5) Y. Zhao et al. Int. J. Syst. Evol. Microbiol. 59:2582, 2009.

Abstract Introduction: Andrographolide is a diterpenoid lactone isolated from Andrographis paniculata (King of Bitters), an herbal medicine used in Asia. It has been reported to have anti-inflammatory, antihypertensive, antiviral, and immune-stimulant properties. Furthermore, it has been shown to inhibit cancer cell proliferation and induce apoptosis in lymphoma, leukemia and other solid tumor cell lines. We have shown that Andro caused ROS-dependent apoptosis in lymphoma cell lines and in primary tumor samples that was mediated through mitochondrial pathways and enhanced by depletion of GSH and inhibited by NAC or the pan-caspase inhibitor Z-VAD-FMK (Yang et al Clin Cancer Res 2010; 16(19):4755). We hypothesized that the tumor suppressor, FOXO3a may be involved in signaling pathways that lead to apoptosis and to test that hypothesis we investigated the role of FOXO3A in Andro induced signaling in lymphoma. Methods: We studied the Burkitt p53-mutated Ramos cell line, the mantle cell lymphoma (MCL) line Granta, the transformed follicular lymphoma (FL) cell line HF-1, and the diffuse large B-cell lymphoma (DLBCL) cell line SUDHL4, as well as primary cells from patients with FL and MCL. We transfected shRNA FOXO3a by electroporation to build stable cells with constant knockdown of FOXO3a in Ramos and SUDHL4 cell lines. We then compared the cell viability (MTT and Golgi fragmentation), apoptosis (Annexin V by flow), c-MYC and Bcl2 expression, death receptors 4 (DR4) expression and cell cycle related proteins in wild type and FOXO3a knockdowns. Results: We found that Andro resulted in nuclear translocation of FOXO3a in Ramos at early time points. We found that shRNA stable knockdown of FOXO3a in Ramos and SUDHL4 cell lines protected cells (Ramos and SUDHL4) from Andro-induced apoptosis (Figure 1). Moreover, in multiple cell lines, we found that Andro decreased c-MYC expression, which was abrogated in part by FOXO3A knockdown compared with wild type cells. Similarly, reduction in mitochondrial membrane potential by Andro is abrogated in the FOXO 3a knockdown cells. These data suggest that FOXO3a regulates c-MYC stabilization by mitochondrial proteins (for example TFAM and MAD-1). In the Granta cell line, derived from Mantle Cell Lymphoma (MCL) and in an MCL patient sample, Andro reduced c-MYC expression. We also found that Andro induced Death Receptor 4 (DR4) at the mRNA and protein level in Granta cells in a dose-dependent manner. The cell cycle control proteins Aurora, p21, p27 (the latter 2 regulated by FOXO3a), are also increased by Andro. When cell death was measured by Golgi fragmentation and subsequent collapse, we found that Andro induced Golgi fragmentation in Granta and SUDHL4 cells Conclusion: Andro-induced lymphoma cell apoptosis is mediated through multiple signaling pathways, including FOXO3a, which appears to play a significant role, perhaps by regulating c-MYC stabilization and BCL2 expression and cell cycle proteins. These data suggest that this novel diterpenoid lactone compound deserves further pre-clinical and clinical testing in malignant lymphoma. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 2710 Poster Board II-686 Introduction/Background: Andrographolide is a diterpenoid lactone isolated from Andrographis paniculata (King of Bitters), an important herbal medicine used in China and other Asian countries to treat a range of diseases, such as respiratory infection, fever, bacterial dysentery and diarrhea. The major bioactive component extracted from Andrographis paniculata is andrographolide. The three hydroxyls at C-3, C-19 and C-14 are responsible for its biological activities. Recently, the anti-cancer properties of andrographolide have been recognized, and it has been tested in human patients. We hypothesized that the mechanism of cell death may depend on caspase activation and mitochondrial mediated cell death pathways. Methods: Using cells lines Ramos (p53 mutated Burkitts lymphoma (BL)), HF-1 (follicular lymphoma (FL)), SUDHL-4 (diffuse large B-cell lymphoma (DLBCL)) and Granta (mantle cell lymphoma (MCL)) we measured cellular cytotoxicity by MTT and apoptosis and quantified by Annexin V-FITC and PI with flow cytometry using FACS. Reactive oxygen species (ROS) production was determined by oxidation of H2DCFDA to dichlorofluorescein (DCF) and quantified by fluorescence intensity and read by flow cytometry. We investigated the mechanism of apoptosis in lymphoma cell lines and patient samples by measuring caspase activation and PARP cleavage by Western blot and Bax conformational change by immunoflourescence. Further, we dissected the influence of the Bax/Bak pathway by using Bax−/−/Bak−/− mouse endothelial fibroblasts (MEFS). Results: We found that andrographolide inhibited survival in all cell lines and was dose and time dependent (IC50 from 15-40uM in cell lines), and was accompanied by ROS production. Cell death was a result of apoptosis and was also dose and time dependent and inhibited by the anti- oxidant N-acetyl-L-cysteine (NAC) and by the pan-caspase inhibitor Z-VAD-FMK and enhanced by the glutathione (GSH) depleting agent buthionine sulfoximine (BSO) and accompanied by PARP cleavage. Similar data were extant in fresh samples from patients with FL, DLBCL, and MCL and there was activation of caspases 3, 8 and 9 in all cell lines and in all patient samples. In order to determine if mitochondrial pathways are involved in cell death, we studied Bax conformational change with the 6A7 monoclonal antibody, which specifically binds Bax protein with conformational change. We found that andrographolide induced Bax conformational change in SUDHL4 and HF1 and similarly in diffuse large B-cell lymphoma and follicular lymphoma pt samples and that this was accompanied by translocation of Bax to the mitochondria in SUDHL-4 (Figure bottom left) and HF-1 (Figure bottom right). Next, using mouse endothelial fibroblast (MEFs) Bax/Bak knockouts (MEFBAX−/−/BAK−/−), we found that andrographolide-induced apoptosis (Figure top left) and change in mitochondrial membrane potential (Figure top right) was mediated through Bax/Bak. Conclusion: This is the first demonstration that andrographolide causes ROS-dependent apoptosis in lymphoma cell lines and in primary tumor samples, and the mechanism appears to proceed through intrinsic and extrinsic caspase pathways and is associated with Bax/Bak mitochondrial translocation. Further studies of diterpenoid lactones in lymphoma are warranted. Disclosures: Gordon: Cure Tech: Membership on an entity's Board of Directors or advisory committees.

Ethno botanical surveys have revealed that Brunei Darussalam has a rich source of tropical medicinal plants. As 80% of the country's land is covered by tropical rainforest, Brunei Darussalam may have some medicinal plants with unique characteristics of secondary metabolites. Some plants such as Catharanthus roseus (L.) G. Don and Eurycoma longifolia Jack have long been used by the local communities to treat various disease conditions. However, no research has been done in terms of the constituents or biological activities of the Brunei Darussalam medicinal plants. We have investigated the genetic variability diversity and pharmacological actions of Andrographis paniculata (Burm.f.) Nees [1] also known as Daun Pahit or Chuan Xin Lian or King of Bitters by an interdisciplinary approach, involving DNA-based RAPD and RFLP analyses, HPLC-based chemical analysis as well as cell culture and tissue-based bioassays. We have demonstrated that Andrographis paniculata extr acts exhibited a range of actions including antioxidant, anti-allergies, anti-inflammatory and anti-cancer effects. Some of the pharmacological actions of Andrographis paniculata are co-related with their active constituents Andrographolide (A) and Dehydroandrographolide (D). The study is valued not only in obtaining experimental evidence for supporting traditional use of native medicinal plants but also in establishing a platform for studying other medicinal plants in Brunei Darussalam.

This collection brings together seventeen of Kipling's early stories, written between 1885 and 1888, when Kipling was working as a journalist in India. Wry comedies of British officialdom alternate with glimpses into the harsh lives of the common soldiers and the Indian poor, revealing Kipling's legendary powers of observation and, in ‘Baa Baa, Black Sheep’ his own miserable childhood. From Mrs Hauksbee's Simla drawing-room to Mulvaney's cot in barracks, to the wild hills of Kafiristan, Kipling re-creates the India he knew in stories by turns ironic and sentimental, compassionate and bitter, displaying the brilliance that has captivated readers for over a century.

A fugitive from the law, Tijerina lived undercover in New Mexico for the next five years while his wife supported him and their six children. This time period amounted to a five-year sabbatical that gave him the time to understand American expansion as a bitter conquest that had robbed the region’s Spanish-speakers of their lands after the U.S.-Mexico War of 1846-1848 by violating the peace treaty that ended the war, the Treaty of Guadalupe Hidalgo. He reached this conclusion after conducting additional research in Mexico and learning from nuevomexicanos, Spanish-speaking New Mexicans, whose families had experienced widespread land dispossession. In 1963, as the statute of limitations for his arrest drew near, Tijerina publicly founded the Alianza Federal de Mercedes (Federal Alliance of Land Grants,) whose purpose was to resurrect the 1848 treaty.

In New Mexico, Reies López Tijerina saw long-held aspirations—to secure a piece of land, to find ultimate justice, and even to establish and protect a cultural haven—hit fertile ground. Within two years of the 1963 Alianza Federal de Mercedes founding, he convinced thousands to join his new organization by spreading a three-part land-grant gospel that: 1) upheld Spanish colonial documents as a sign of legitimate ownership; 2) blasted American ownership of land grants as fraudulent; and 3) accused Americans not only of land theft but “cultural genocide.” Many land-poor Spanish-speakers in New Mexico responded to Tijerina’s fearless accusations and, as Tijerina turned to his preacher past, his religious allusions. Many shared his deep faith. More importantly, they bitterly recalled how their ancestors had once used the land without interference.

William IV’s life (1765–1837) overlaps the period of Paul Langford’s A Polite and Commercial People, and encompasses several of its key themes. William’s sexual adventures, complex family life, and struggle to find a suitable wife recall the challenges facing both his Hanoverian relatives and other elite men of his generation, including fellow naval officers. Yet William’s life also illuminates the changing public attitudes to politics and rulers which marked the uneven transition from the Georgian to the Victorian period. Bitter attacks on William’s relationship with his wife Adelaide alternated with mostly sympathetic accounts of his role in the movements for Catholic Emancipation and parliamentary reform. Ultimately, if oddly, William was held up as a national hero and commercial symbol of Britain’s early nineteenth-century progress. Above all, William’s life was chronicled through caricature, which A Polite and Commercial People drew attention to as a distinctive and significant element of Georgian culture. An assessment of his representation in both caricatures and other engravings, including new forms such as lithographs, helps us to better understand William’s contemporary significance, and in turn the political, social, and cultural changes and continuities of the Georgian and Victorian periods.

Chapter 3 argues that Shakespeare exposes the formal underpinnings of the fantasy of unstoppable individual critical agency through his depiction of wise fools. In Twelfth Night, Timon of Athens, and King Lear, Shakespeare’s citation of diogeneana gives form to a series of wise fools designed to provoke a collision between his period’s antithetical assessments of Cynic critical activity: one that reckons Diogenes’ freedom of speech to be singularly effective, and one that lambasts Diogenes for being inconsequential, a mere parasite-jester who has renounced all claims to seriousness. This double gesture is most evident in a passage unique to the Quarto Lear in which the Fool defines, and simultaneously performs, the critical activity of a “bitter fool.” Here, especially, Shakespeare’s composite characterization of the Cynic stance challenges viewers to comprehend that the “bitter fool” offers only the appearance of a robust critical practice—that its stridently critique-oriented posture exists in form but not in substance.

This chapter examines the making of Alfred Hitchcock's Frenzy (1972). Hitchcock called the writer Anthony Shaffer on New Year's Eve of 1970 to ask him to write the screenplay for Frenzy. Shaffer seems to have got on well with Hitchcock; so well in fact that they planned future collaborations, although the director's failing health would prevent this. The director's first choice for the role of Bob Rusk was Michael Caine, who had a strong resemblance to Neville Heath. However, Caine found the script ‘disgusting’, so Hitchcock settled on Barry Foster. The other actors cast in the film include Jon Finch, Vivian Merchant, and Billie Whitelaw. Meanwhile, the plot recycles a number of Hitchcock themes and motifs, but the events follow Arthur La Bern's novel closely. Some of the digressions in the novel are either left out or cut-down and the bitter misanthropy has been replaced by a slightly less bitter kind of black comedy.

Henry VIII, king of England from 1509 to 1547, ought to be held responsible for the “guy” and “guys” we say nowadays. Guy Fawkes’s terrorist attack in 1605 would not even have been imaginable in the peaceable religious climate of England before 1533. Until then, Henry had been an informed, devout Catholic. But in the 1530s, wanting a male heir that his first wife Catherine couldn’t provide, he asked the pope for an annulment of that marriage so he could marry Anne Boleyn and have a legitimate male heir with her. When the pope wouldn’t oblige, Henry disavowed allegiance to the pope and declared himself supreme head of the church in England. Until then, everyone in England had been Catholic; now officially nobody could. That caused bitter conflicts. After Henry’s death in 1547 the church became strongly Protestant under King Edward VI, then strongly Catholic under Mary, and more moderate, though still staunchly anti-papal, under Elizabeth. For good measure, the English church was under attack on the other flank by the extreme Protestant Puritans. None of the Protestant versions satisfied Catholics, who tried plot after plot to unseat the queen and restore Catholicism. That was the explosive fuel that ignited the Gunpowder Treason Plot of 1605.

This chapter examines a development in European diplomacy that proved critical to Western–Byzantine relations: between the seventh and eighth centuries, successive bishops of Rome abandoned their traditional alliance with Constantinople and turned instead to the Franks. Since 731 bishops of Rome had condemned the iconoclast policy adopted in the Eastern capital, which led to more increasingly bitter correspondence between Old Rome and New. Religious antagonism then led to the decision to involve the major force north of the Alps in the defense of Rome, which was increasingly threatened by the Lombards, established in northern Italy. To counter this break with tradition, Emperor Constantine V sought to win over the Franks to a more considered position. The chapter discusses the efforts of several embassies to persuade the Frankish king Pippin III and later Charles/Charlemagne into an alliance with Byzantium that would be sealed by a marriage.

During the final decade of his life, Twain received several devastating blows—the death of his beloved wife in 1904, the death of his daughter Jean in 1909, and his own declining health. These and other problems have led some scholars to portray him as a bitter, cynical, disillusioned codger who was hamstrung by his misfortunes and angry as his creative powers diminished and his health deteriorated. This, they say, led him to repudiate Christianity, adopt a deterministic worldview, and savagely rail against an implacable, depraved God, a hypocritical, heartless Christianity and the damned human race. Twain’s writings during his final decade allegedly displayed his relentless despair as he embraced social and spiritual nihilism. At the same time, his criticisms of various groups including missionaries, villains, especially Russian Czar Nicholas II and Belgian King Leopold II, and several ideologies—militarism, imperialism, anti-Semitism—became increasingly caustic.