Novel anticancer PdII complexes: The effect of the conjugation of transferrin binding peptide and the nature of halogen coordinated on antitumor activity.

A series of PdII complexes with bis-(2-pyridylmethyl)glycine as a ligand of formula [PdX(bis-(2-pyridylmethyl)glycine)] where X = Cl, Br, I were prepared and the effect of the halogen nature in the antitumor activity of eight tumorigenic and one non-tumorigenic cell line was evaluated. The chloride derivative was further functionalized with a transferrin receptor binding peptide, generating the first PdII based metallopeptide. Its antitumor activity was also evaluated. However, among all the complexes, the chloride and iodine parent compounds showed the lowest GI50 values in the panel evaluated, and lowest GI50 than cisplatin in several cell lines. In contrast, the bromine derivative showed higher values of GI50 than chloride and iodine (around 30 - 50 µM). The same trend was observed for the bovine serum albumin binding constant with higher values for iodine, chlorine, and bromine in this order. In aqueous solution, the chloride is exchanged by water while the bromine and iodine are not. DNA was evaluated as a target and showed no significative interaction for all the compounds. The results suggest sulfur-rich proteins and not DNA as a target. This report represents the first PdII metallopeptide reported, its evaluation in solution and antitumor activity. This work opens the possibilities for further functionalization of PdII complexes and the importance of the halogen coordination in the design of novel metallodrugs.

Linear gold(I) complex with tris-(2-carboxyethyl)phosphine (TCEP): Selective antitumor activity and inertness toward sulfur proteins.

The search for modulating ligand substitution reaction in gold complexes is essential to find new active metallo compounds for medical applications. In this work, a new linear and hydrosoluble goldI complex with tris-(2-carboxyethylphosphine) (AuTCEP). The two phosphines coordinate linearly to the metal as solved by single crystal X-ray diffraction. Complete spectroscopic characterization is also reported. In vitro growth inhibition (GI50) in a panel of nine tumorigenic and one non-tumorigenic cell lines demonstrated the complex is highly selective to ovarium adenocarcinoma (OVCAR-03) with GI50 of 3.04 nmol mL-1. Moreover, non-differential uptake of AuTCEP was observed between OVCAR-03 (tumor) and HaCaT (non-tumor) two cell lines. Biophysical evaluation with the sulfur-rich biomolecules showed the compound does not interact with two types of zinc fingers, bovine serum albumin, N-acetyl-l-cysteine and also l-histidine, revealing to be inert to ligand substitution reactions with these molecules. However, AuTCEP demonstrated to cleave plasmidial DNA, suggesting DNA as a possible target. No antibacterial activity was observed in the strains evaluated. Besides, it inhibits 15% of the activity of a mixture of serine-ß-lactamase and metallo-ß-lactamase from Bacillus cereus in the enzymatic activity assay, similarly to EDTA. These results suggest AuTCEP is selective to metallo-ß-lactamase but the cell uptake is hindered, and the compound does not reach the periplasmic space of Gram-positive bacteria. The unique inert behavior of AuTCEP is interesting and represent the modulation of the reactivity through coordination chemistry to decrease the toxicity associated with AuI complexes and its lack of specificity, generating very selective compounds with unexpected targets.

Reversal of threatening blindness after initiation of eculizumab in Purtscher-like retinopathy secondary to atypical hemolytic uremic syndrome.

Purtscher-like retinopathy, a rare manifestation of systemic thrombotic microangiopathy, is a potentially visually debilitating condition with no effective proven treatment. Distinct pathogenic pathways have been proposed as etiological factors. We revisit the etiology of Purtscher-like retinopathy based on the rapid response and profound visual improvement after initiation of systemic intravenous eculizumab, an inhibitor of the complement cascade, in a patient with Purtscher-like retinopathy secondary to familial atypical hemolytic uremic syndrome (aHUS) due to a mutation in complement factor H. We hypothesize that the efficacy of eculizumab in this patient provides evidence for pathogenic events in the retina similar to those encountered in the renal microvasculature of aHUS patients, namely complement-mediated thromboembolization as a result of activation of the complement cascade in endothelial cells with release of tissue factor and development and amplification of a procoagulant state. To the best of our knowledge, this is the first report in the literature of eculizumab as an effective therapeutic strategy in Purtscher-like retinopathy.

Metabolic surgery for the treatment of type 2 diabetes in pancreas after kidney transplant candidates.

Metabolic surgery for the treatment of type 2 diabetes mellitus (T2DM) in patients not morbidly obese (BMI <35) has been widely studied. Taking into account that ∼12% of pancreas transplants are performed in patients with T2DM, our goal was to evaluate the impact of metabolic surgery on the management of obese patients with T2DM on waiting lists for a pancreas transplant. We performed a Roux-en-Y gastrointestinal bypass in 5 patients with insulin-dependent T2DM who were candidates for pancreas after kidney transplant and with a BMI <35. Three patients became insulin independent by the end of the first year while the other 2 reduced their insulin requirements by 70%. Furthermore, all patients achieved improved control of lipid levels. We concluded that the surgery was effective in controlling blood glucose and lipid metabolism in these obese T2DM kidney transplant recipients. In this population, a pancreas transplant, along with its associated morbidity, may be avoided.

Chemical composition and free radical-scavenging, anticancer and anti-inflammatory activities of the essential oil from Ocimum kilimandscharicum.

OBJECTIVE: The essential oil from the leaves of Ocimum kilimandscharicum (EOOK), collected in Dourados-MS, was investigated for anticancer, anti-inflammatory and antioxidant activity and chemical composition. MATERIALS AND METHODS: The essential oil was extracted by hydrodistillation, and the chemical composition was performed by gas chromatography-mass spectrometry. The essential oil was evaluated for free radical-scavenging activity using the DPPH assay and was tested in an anticancer assay against ten human cancer cell lines. The response parameter (GI50) was calculated for the cell lines tested. The anti-inflammatory activity was evaluated using carrageenan-induced pleurisy in mice. RESULTS: The chemical composition showed 45 components with a predominance of monoterpenes, such as camphor (51.81%), 1,8 cineole (20.13%) and limonene (11.23%). The EOOK exhibited potent free radical-scavenging activity by the DPPH assay with a GI50 of 8.31 µg/ml. The major constituents, pure camphor (IC50=12.56 µg/ml) and mixture of the limonene: 1, 8 cineole (IC50=23.25 µg/ml) displayed a potent activity. The oral administration of EOOK (at 30 and 100 mg kg(-1)), as well as the pure camphor or a mixture of 1,8 cineole with limonene, significantly inhibited the carrageenan (Cg) induced pleurisy, reducing the migration of total leukocytes in mice by 82 ± 4% (30 mg kg(-1) of EOOK), 95 ± 4% (100 mg kg(-1) of EOOK), 83 ± 9% (camphor) and 80 ± 5% (mixture of 1,8 cineole:limonene 1:1). In vitro cytotoxicity screening against a human ovarian cancer cell line displayed high selectivity and potent anticancer activity with GI50=31.90 mg ml(-1). This work describes the anti-inflammatory, anticancer and antioxidant effects of EOOK for the first time. CONCLUSIONS: The essential oil exhibited marked anti-inflammatory, antioxidant and anticancer effects, an effect that can be attributed the presence of majorital compounds, and the response profiles from chemical composition differed from other oils collected in different locales.

Hydroxyaldimines as potent in vitro anticryptococcal agents.

UNLABELLED: Cryptococcosis, a fungal infection that affects both immunocompromised and immunocompetent individuals, contributes to increasing indices of mortality and morbidity. The development of resistance by Cryptococcus spp., the limited number of commercial antifungal drugs and the various side effects of these drugs cause the treatment of cryptococcosis to be a challenge. The in vitro anticryptococcal activity of nine hydroxyaldimines was evaluated against 24 strains of Cryptococcus spp. Antifungal susceptibility was evaluated using a broth microdilution assay following the Clinical and Laboratory Standards Institute guidelines, using fluconazole as a positive control. Parameters such as the minimum inhibitory concentration and the minimum fungicidal concentration (MIC and MFC, respectively) were also determined. Antiproliferative activity on the normal cell line VERO was assessed 48 h post-compound exposure to determine the selectivity index (SI) of the hydroxyaldimines and fluconazole. All hydroxyaldimines were active against Cryptococcus spp. strains. Compounds 3A9 and 3B7 were the most potent against the Cryptococcus gattii and Cryptococcus neoformans strains. Selectivity indices also revealed that 3B10, 3C3, 3D3 and 3D9 are good candidates for in vivo studies. The in vitro anticryptococcal activity of hydroxyaldimines against various strains of C. gattii and C. neoformans indicates the potential of this class of molecules as lead compound for the development of selective and efficient anticryptococcal agents. SIGNIFICANCE AND IMPACT OF THE STUDY: The effectiveness of hydroxyaldimines for inhibition of Cryptococcus spp. growth and their low toxicity against healthy monkey kidney epithelial cells makes them promising lead compounds for the design of new anticryptococcal agents.

Evaluation of the antioxidant and antiproliferative potential of bioflavors.

α-Terpineol is a relatively cheap and abundant aroma compound. It is widely used in food, cosmetics, and household products. Many of its monoterpene counterparts have been applied in antiproliferative assays, leading to promising results in the prevention or even treatment of cancers. However, despite its theoretic potential, no paper reports the evaluation of antiproliferative capacity of this alcohol. Thus, antioxidant potential of three monoterpenoids (carvone, perillyl alcohol, and α-terpineol) was measured using two methods: DPPH and ORAC. Also, the antiproliferative effect of these monoterpenoids against nine cancerous cell lines were performed and compared to limonene and doxorubicin. Results showed that all samples tested had very low antioxidant activity in the DPPH assay, but α-terpineol (2.72µmolTrolox equiv./µmol) could be compared to commercial antioxidants in the ORAC assay. The antiproliferative results obtained encourage future in vivo studies for α-terpineol, since this monoterpenoid presented cytostatic effect against six cell lines, especially for breast adenocarcinoma and chronic myeloid leukemia, in a range of 181-588µM.

Cephalic duodenopancreatectomy in the treatment of a bleeding duodenal ulcer in a pancreas recipient: a case report.

Pancreas transplantation is currently the only known therapy to restore glycemic metabolism in type 1 diabetic patients. Its most prevalent indication is in association with kidney transplantation (simultaneous pancreas and kidney transplantation SPK) for patients with type 1 diabetes mellitus (DM1) and nephropathy, who are under dialysis treatment. Surgical reinterventions, especially those resulting from complications of bladder exocrine pancreatic drainage, are associated with considerable morbidity and mortality. In this report, we present a clinical case of a 31-year-old Caucasian man with DM1 from 12 years of age and hemodialysis for 2 years before undergoing SPK 2 years prior. He then developed massive hematuria owing to a bleeding duodenal graft ulcer. The use of a segmental pancreatic technique with pancreaticocystostomy for exocrine pancreatic drainage allowed the maintenance of the graft and an euglycemic state in the patient, free of exogenous insulin.

Styryl lactones and their derivatives: biological activities, mechanisms of action and potential leads for drug design.

Nature is an inexhaustible source of natural compounds with interesting biological activities. In general, natural products are an important source of new compounds with a variety of structural arrangements and singular properties. Styryl lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess interesting biological properties, in particular antiproliferative activity against cancer cells. In general, the cytotoxicity of styryl lactones appears to be specific against cancer cells since insignificant effects of these compounds on normal cells are reported. A large body of evidence suggests that the antiproliferative activity of styryl lactones is associated with the induction of apoptosis in target cells. In the first part of this review we discuss the biological activities of styryl lactones focusing on cancer cells, the causal agent of Chagas' disease and the vectors for yellow fever and human lymphatic filariasis. Stru described in detail for ninety styryl lactones. The last part describes the molecular targets of styryl lactones for inducing apoptosis, as well as immunosuppressive and inflammatory processes. Overall, understanding how these compounds exert their activities in biological system is essential for future development and application of styryl lactones for human health.

Antiproliferative effect of Baylis-Hillman adducts and a new phthalide derivative on human tumor cell lines.

In this work we report our results concerning the study on the in vitro antiproliferative activity of 18 Baylis-Hillman adducts and some derivatives against a panel of humor tumor cell lines. A brief qualitative structure-activity relationship study indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring are essential for the activity. A quinoline-phthalide derivative has exhibited a potent effect on the proliferation of all cell lines. It is interesting to note their special cytotoxic activity against NCIADR cell line.

Antiulcerogenic activity of crude ethanol extract and some fractions obtained from aerial parts of Artemisia annua L.

The resulting enriched sesquiterpene lactone fraction and the crude ethanol extract of Artemisia annua L. aerial parts, showed antiulcerogenic activity when administered orally, on the indomethacin induced ulcer in rats. The sesquiterpene lactone fraction yielded three different polarity fractions on column chromatography as follows: non-polar, medium polarity and polar fraction, When submitted to the same indomethacin-induced ulcer in rats they resulted in different levels of inhibition of the ulcerative lesion index. The participation of nitric oxide was evaluated on an ethanol-induced ulcer model which had a previous administration of L-NAME, a NO-synthase inhibitor. Under these conditions, the medium polarity fraction maintained the antiulcerogenic activity, suggesting that nitric oxide could not be involved in the antiulcerogenic activity. When the animal groups were treated with N-ethylmaleimide, an alkylator of sulphhydryl groups, using the same experimental model, the medium polarity fraction maintained its antiulcerogenic activity, suggesting that the pharmacological mechanism is not related to non-protein sulphydryl compounds. On the ethanol-induced ulcer with previous indomethacin treatment, the medium polarity fraction lost its antiulcerogenic activity indicating that the active compounds of Artemisia annua L. increase the prostaglandin levels in the gastric mucosa. This hypothesis was reinforced by an increase of adherent mucus production by the gastric mucosa, produced by the medium polarity fraction on the hypothermic restraint stress induced ulcer model.

Evaluation of the antiulcerogenic activity of friedelan-3beta-ol and friedelin isolated from Maytenus ilicifolia (Celastraceae).

An easy methodology for triterpene isolation is shown. Evaluation in rats for antiulcer activity of friedelan-3beta-ol 1 and friedelin 2. The two triterpenes isolated from the leaves of Maytenus ilicifolia, did not decrease gastric ulcers when tested on indometacine induced ulcer model in rats.

Antiulcerogenic activity of crude hydroalcoholic extract of Rosmarinus officinalis L.

Rosmarinus officinalis L. crude hydroalcoholic (70%) extract was evaluated for antiulcerogenic activity employing different experimental models. The crude hydroalcoholic extract (CHE) decreased the ulcerative lesion index produced by indomethacin, ethanol and reserpine in rats. No antisecretory activity was observed on pyloric ligation model. The previous administration of L-NAME, a NO-synthase inhibitor, did not reduce the antiulcerogenic activity of CHE in ethanol induced ulcer model, suggesting that the pharmacological mechanism has no relationship with nitric oxide (NO). Whereas when the animal groups were treated with indomethacin, using the same experimental model, CHE did not reduce the antiulcerogenic activity, suggesting that the pharmacological mechanism has no relationship with prostaglandins. The previous treatment with N-ethymaleimide, a thiol blocker, including mucosal nonprotein sulfhydryl groups, reduced the anitulcerogenic activity of CHE on ethanol induced ulcer model. This result suggests that the crude hydroalcoholic extract of R. officinalis L. has active substances that increase the mucosal nonprotein sulfhydryl groups content. In another hypothesis, the pharmacological mechanism could be attributed to the activity of antioxidant compounds found in the crude hydroalcoholic extract which can react with N-ethylmaleimide.

Effect of Maytenus ilicifolia Mart.ex. Reiss on spermatogenesis.

The effect of the ethanolic extract of Maytenus ilicifolia Mart.ex. Reiss leaves on spermatogenesis was studied in Swiss mice by evaluating morphological characteristics by light and electron microscopy. The extract was administered at a dose of 200 mg/kg/day intraperitoneally for 20 days, and at a dose of 800 mg/kg/day orally for 30 days. Structural analysis of the germ epithelium showed that treated animals were not noticeably different from control animals. The alterations included some exfoliated immature germ cells, occasional germ cell death (recognized as pyknotic nuclei) and a few vacuolized seminiferous tubules. Ultrastructurally, enlarged lipid droplets were found in Sertoli cells and swollen acrosomes occurred in early spermatids of animals treated with the higher dose. Sperm production indicated that the ethanolic extract of M. ilicifolia leaves did not contain substances sufficient to arrest spermatogenesis.

PIP: Several plant extracts used to regulate female fertility have proved effective for the male reproductive system as well. Maytenus ilicifolia Mart.ex. Reiss, a plant native to parts of South America, has been used as a contraceptive, abortifacient, and emmenagogue by women in Paraguay and Argentina. The present study evaluated the effect of the ethanolic extract of Maytenus ilicifolia Mart.ex. Reiss leaves on spermatogenesis in Swiss mice. The extract was administered at doses of 200 mg/kg/day intraperitoneally for 20 days and 800 mg/kg/day orally for 30 days. Light microscopy revealed apparently normal spermatogenesis in the seminiferous tubules of treated animals. Although the spermatogenic process was not altered, ultrastructural alterations were observed, including some exfoliated immature germ cells, occasional germ cell death, and a few vacuolized seminiferous tubules. Enlarged lipid droplets were found in Sertoli cells and swollen acrosomes occurred in early spermatids of mice treated with the higher dose. However, sperm production indicated that the ethanolic extract did not contain substances sufficient to arrest spermatogenesis. Thus, the indigenous use of Maytenus ilicifolia as a medicinal plant probably does not cause a disturbance of spermatogenesis as a side effect.

Antispermatogenic effect of Achillea millefolium L. in mice.

The effect of an ethanolic extract (200 mg/kg/day, intraperitoneally, for 20 days) and a hydroalcoholic extract (300 mg/kg/day, orally, for 30 days) of Achillea millefolium L. (yarrow) flowers on the spermatogenesis of Swiss mice was studied by evaluating morphologic characteristics with the light and electron microscopes. The alterations observed were exfoliation of immature germ cells, germ cell necrosis, and seminiferous tubule vacuolization. Animals treated with the extracts had an increased number of metaphases in the germ epithelium that might be due to cytotoxic substances or substances stimulating cell proliferation.

[Hemoptysis and the adult respiratory distress syndrome as the causes of death in leptospirosis. Changes in the clinical and anatomicopathological patterns]. / Hemoptise/s e síndrome de angústia respiratória do adulto como causas de morte na leptospirose. Mudanças de padrões clínicos e anatomopatológicos.

Human leptospirosis, one of the main urban endemics/epidemics in Brazil, has dramatically grown in the last three decades, especially after floods caused by summer rains. This presentation describes recent changes in the clinical patterns of this pathology in our region, expressed by the emergence of massive haemoptysis and acute respiratory distress syndrome, or both conditions associated. The evident changes in the respiratory structures emerged as a serious life threat and death mechanisms, becoming the main cause of death in leptospirosis among us because of their high incidence. This new face of the disease demands a revision of current concepts about its seriousness and raises speculations about the pathogenesis of such alterations.

[Pulmonary compromise in leptospirosis]. / Comprometimento pulmonar na leptospirose.

To study the pulmonary complications in leptospirosis case records of 23 such patients admitted at the Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, Brasil, were reviewed. Hemoptysis were seen in 21.7% and sputal blood in 30.4% of patients. Arterial gasometry detected hypoxemia and hypocapnia in most cases. Thoracic radiology showed an alveolar pattern in 60% of the patients, alveolo-interstitial in 20%, interstitial in 6%, and in 14% the lungs were considered to be normal. Necropsy of 13 cases showed edema, congestion and hemorrhage in the lungs in all cases. Hyaline membrane was found in 30% and fibrin thrombi in 46% of these cases, resulting in a diagnosis of adult respiratory distress syndrome and acute disseminated intravascular coagulation (consumption coagulopathy) in leptospirosis.

Cardiac glycosides isolated from the Indian-snuff, Maquira sclerophylla Ducke.

The hydroalcoholic extract of the powdered bark of the Indian-snuff Maquira sclerophylla Duck was purified by column chromatography in silica-gel and the major cardenolide isolated from preparative TLC was identified by 1H-NMR, 12C-NMR and IR analyses. The spectra showed that the active substance has strophanthidin as the aglycone.

Pharmacology of an Indian-snuff obtained from Amazonian Maquira sclerophylla.

The powdered bark of Maquira sclerophylla is consumed as snuff in north Brazil. Both the crude and the purified hydrosoluble extract (WP) injected i.p. in the dose range of 0.05-0.5 g/kg induced hyperexcitability, tremors, motor incoordination, ataxia, quietness and muscle relaxation in rats. The effects were progressive, dose-related and reversed after 30 min. Anesthetized rats, guinea-pigs and dogs injected with the purified extract (10-50 mg/kg, i.v.) showed a biphasic change of carotid blood pressure. The early and transient hypotension was blocked by atropine but not by vagotomy: the secondary hypertension was long lasting and sustained for over 30 min. The hypertension was shortened but not blocked after ganglionic blockade or reserpine treatment. Either pithing or alpha receptor blockade with yohimbine reduced both effects of the extract. Guinea-pigs and dogs were more responsive than rats and died by heart arrest. Incubation of WP (20 micrograms/ml) increased both the rate and force of contraction of isolated guinea-pig right atria by 2 and 5 times, respectively. Propranolol (4 micrograms/ml) blocked the chronotropic effect but did not decrease the inotropic effect. In electrically driven guinea-pig left atria, WP (10 micrograms/ml) increased the force of contraction by 80% and the maximum rate of force development by 60%, but did not change the time to peak tension, the time to 50% relaxation, or the rate of relaxation. These cardiovascular effects resemble those of digitalis-like drugs. Cardenolides were detected in WP by phytochemical screening.