The cellular toxicology of mitragynine, the dominant alkaloid of the narcotic-like herb, Mitragyna speciosa Korth

Mitragyna speciosa Korth (Kratom), a herb of the Rubiaceae family is indigenous to southeast Asia. The plant and its dominant alkaloid mitragynine (MIT) are narcotic/analgesic and illicit consumption is widespread in Asia; the toxicological consequences of consumption are poorly documented. We determined cytotoxicity of MIT on human cell lines and report dose and time-dependent stimulation and inhibition of proliferation. Since MIT has powerful opiate-like activity, we focussed on human neuronal SH-SY5Y cell line and found the colony forming ability of cells treated with MIT showed a dose-dependent trend for reduced survival. Studies using metabolically competent MCL-5 cells and chemical inhibitors indicated that CYP 2E1 and 2A6 were involved in the cytotoxicity. Cytotoxicity was preceded by cell cycle arrest mainly at G1 and S phase. To assess whether arrest was due to DNA damage or mutation, we examined genotoxic potential using the L5178 TK +/− mouse lymphoma assay and found that MIT was not genotoxic at the TK locus, even at doses that were highly cytotoxic. To investigate mechanisms of MIT cytotoxicity, we used flow cytometry and annexin V with 7-amino-actinomycin D staining and show apoptosis and necrotic activity. Apoptosis was further supported as MIT rapidly induced the activity of executioner caspases 3/7. However, cytotoxicity of MIT was partially reduced by inclusion of the opioid receptor antagonist naloxone, a μ and δ opioid receptor antagonist, suggesting that cytotoxicity depends in part on opioid signalling, consistent with the known toxicity of other opiates. Based on consumption of 20 leaves per day of Mitragyna speciosa, we estimated daily human exposure to MIT to be about 17 mg MIT for regular consumers, potentially giving plasma concentrations in of 10−9 to 10 −7 M. Importantly, fatalities after kratom consumption have been reported to occur in individuals with blood mitragynine concentrations of between 0.45–1.0 μM, substantially lower than the threshold of toxicity predicted from this in vitro report. Clearly the implications of these findings to humans consuming Mitragyna speciosa leaves will require further study, but individuals taking large quantities of these opiate-like materials may be at risk, especially those who have a high CYP2E1 activity, such as heavy alcohol users

Palliative Percutaneous Jejunal Stent for Patients with Short Bowel Syndrome

Gastrointestinal obstruction is a common preterminal event in patients with gastric and pancreatic cancer who often undergo palliative bypass surgery. Although endoscopic palliation with self-expandable metallic stents has emerged as a safe and effective alternative to surgery, experience with this technique remains limited. In particular, a proximal jejunal obstruction requires more technical expertise than a duodenal obstruction. Palliative treatment modalities include both surgical and nonsurgical approaches. In this report, we describe the successful placement of self-expandable metallic stents at the proximal jejunum using a combination of percutaneous endoscopic, intraoperative, and transstomal stenting. Usually endoscopy is not indicated in cases of proximal jejunal obstruction, but some cases may require palliative endoscopy instead of bypass operation

Anthraquinones from Morinda elliptica

Phytochemical studies on roots of Morinda elliptica have resulted in the isolation of a new anthraquinone, 2-formyl-1-hydroxyanthraquinone, and 10 known anthraquinones. The structures of the anthraquinones were established based on spectral studies

Granulocyte-colony stimulating factor producing rectal cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Uretero-Internal Pudendal Artery Fistula with Longterm Indwelling of Ureteral Stent: A Case Report

A 74-year-old woman presenting with bilateral ureteral stricture was referred to our hospital. She had undergone radical hysterectomy and adjuvant irradiation therapy for cervical cancer in 2000. Double-J stents were inserted in both the ureters and replaced at regular intervals. Eighteen months after ureteral stenting, she complained of gross hematuria and was managed with hemostatic agents. During a routine replacement of the right double-J stent, massive bleeding was observed from the urethra which continued intermittently. The source of bleeding was not identified on computed tomography and angiography. We kept her at rest, which reduced the bleeding. However, she required intermittent transfusions. Angiography was performed at the time of bleeding on March 5, 2011. A uretero-internal pudendal artery fistula was found, and coil embolization was performed. Thereafter, hematuria did not recur up to the last followup in July 2011

Artelastokromen Suatu Diprenilpiranoflavon dan B-Resorsilaldehid dari Kayu Batang Artocarpus Lanceifolius

Abstrak. Dua senyawa, yaitu artelactokromen (1), suatu diprenil piranoflavon, dan B-resorsilaldehid (2) telah ditemukan untuk pertama kalinya pada kayu batang tumbuhan Artocarpus lanceifolius Roxb. (Moraceae), suatu tumbuhan langka yang endemic untuk Indonesia dan dikenal dengan nama Keledang. Struktur molekul kedua senyawa tersebut telah ditetapkan berdasarkan data fisika dan spektroskopi (MS, 1H dan 13C NMR). Baik artelastokromen (1) maupun B-resorsilaldehid (2) tidak terlalu toksik terhadap nauplii udang Artemia salina Leach., masing-masing dengan LC50 298,2 dan 79,7 ug/mL. Artelastochromene a Diprenylphyranoflavone and Î’-Resorcylaldehyde from the Wood Trunk of Artocarpus LanceifoliusAbstract. Two phenolic constituent, namely artelastochromene (1), a diprenyl pyranoflavone, and β-resorcylaldehyde (2) had been isolated from the wood trunk of Artocarpus lanceifolius Roxb. (Moraceae), an endemic species of Indonesia, locally known as Keledang. The structures of both compounds were elucidated based on physical and spectroscopic data (MS, 1H and 13C NMR). Both artelastochromene (1) and β-resorcylaldehyde (2) showed very slight toxic effect against shrimp nauplii Artemia salina Leach., LC50 298,2 and 79,7 μg/mL, respectively

Artoindonesianin-E suatu senyawa baru turunan flavanon dari tumbuhan Artocarpus Champeden

Sari. Suatu senyawabaru turunan flavanon, yakni 5,7-dihidroksi-2',4',6'-trimetoksiflavanon yang diberi nama artoindonesianin-E(1 ), telah ditemukan untuk pertama kalinya bersama-samad engan artokarpin (2) dan heteroflavanon-A (3) pada ekstrak benzena kulit batang tumbuhan Artocarpus champeden Spreng (Moraceae), suatu tumbuhan yang endemik untuk Indonesia, serta dikenal dengan narna Cempedak. Struktur molekul senyawa tersebut telah ditetapkan berdasarkan data fisika dan spekroskopi (MS, 1H dan 13C NMR).Artoindonesianin-E a New Flavanone Derivative from Artocarpus ChampedenAbstract. A new flavanone derivative, 5,7-dihydroxy-2',4',6'-trimethoxyflavanone named artoindonesianin-E (1) had been isolated for the first time, together with artocarpin (2) and heteroflavanone-A (3) from benzene extract of the tree bark of Artocarpus champeden Spreng. (Moraceae), a species endemic to Indonesia and locally known as Cempedak. The structure of this compound was elucidated based on physical and spectroscopic data (MS, 1H and 13C NMR)

Percutaneous endoscopic gastrojejunostomy for a patient with an intractable small bowel injury after repeat surgeries: a case report

<p>Abstract</p> <p>Introduction</p> <p>The management of intestinal injury can be challenging, because of the intractable nature of the condition. Surgical treatment for patients with severe adhesions sometimes results in further intestinal injury. We report a conservative management strategy using percutaneous endoscopic gastrojejunostomy for an intractable small bowel surgical injury after repeated surgeries.</p> <p>Case presentation</p> <p>A 78-year-old Japanese woman had undergone several abdominal surgeries including urinary cystectomy for bladder cancer. After this operation, she developed peritonitis as a result of a small bowel perforation thought to be due to an injury sustained during the operation, with signs consistent with systemic inflammatory response syndrome: body temperature 38.5°C, heart rate 92 beats/minute, respiratory rate 23 breaths/minute, white blood cell count 11.7 × 10⁹/L (normal range 4-11 × 10⁹/μL). Two further surgical interventions failed to control the leak, and our patient's clinical condition and nutritional status continued to deteriorate. We then performed percutaneous endoscopic gastrojejunostomy, and continuous suction was applied as an alternative to a third surgical intervention. With this endoscopic intervention, the intestinal leak gradually closed and oral feeding became possible.</p> <p>Conclusion</p> <p>We suggest that the technique of percutaneous endoscopic gastrojejunostomy combined with a somatostatin analog is a feasible alternative to surgical treatment for small bowel leakage, and is less invasive than a nasojejunal tube.</p

Reduction of N-Glycolylneuraminic Acid in Human Induced Pluripotent Stem Cells Generated or Cultured under Feeder- and Serum-Free Defined Conditions

BACKGROUND: The successful establishment of human induced pluripotent stem cells (hiPSCs) has increased the possible applications of stem cell research in biology and medicine. In particular, hiPSCs are a promising source of cells for regenerative medicine and pharmacology. However, one of the major obstacles to such uses for hiPSCs is the risk of contamination from undefined pathogens in conventional culture conditions that use serum replacement and mouse embryonic fibroblasts as feeder cells. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a simple method for generating or culturing hiPSCs under feeder- and serum-free defined culture conditions that we developed previously for human embryonic stem cells. The defined culture condition comprises a basal medium with a minimal number of defined components including five highly purified proteins and fibronectin as a substrate. First, hiPSCs, which were generated using Yamanaka's four factors and conventional undefined culture conditions, adapted to the defined culture conditions. These adapted cells retained the property of self renewal as evaluated morphologically, the expression of self-renewal marker proteins, standard growth rates, and pluripotency as evaluated by differentiation into derivatives of all three primary germ layers in vitro and in vivo (teratoma formation in immunodeficient mice). Moreover, levels of nonhuman N-glycolylneuraminic acid (Neu5Gc), which is a xenoantigenic indicator of pathogen contamination in human iPS cell cultures, were markedly decreased in hiPSCs cultured under the defined conditions. Second, we successfully generated hiPSCs using adult dermal fibroblast under the defined culture conditions from the reprogramming step. For a long therm culture, the generated cells also had the property of self renewal and pluripotency, they carried a normal karyotype, and they were Neu5Gc negative. CONCLUSION/SIGNIFICANCE: This study suggested that generation or adaption culturing under defined culture conditions can eliminate the risk posed by undefined pathogens. This success in generating hiPSCs using adult fibroblast would be beneficial for clinical application

Transient activation of c-MYC expression is critical for efficient platelet generation from human induced pluripotent stem cells

A specific kinetic pattern of c-MYC expression is essential for optimal generation of functional platelets from human induced pluripotent stem cells