Rosmarinus plants: Key farm concepts towards food applications

Rosmarinus species are aromatic plants that mainly grow in the Mediterranean region. They are widely used in folk medicine, food, and flavor industries and represent a valuable source of biologically active compounds (e.g., terpenoids, flavonoids, and phenolic acids). The extraction of rosemary essential oil is being done using three main methods: carbon dioxide supercritical extraction, steam distillation, and hydrodistillation. Furthermore, interesting antioxidant, antibacterial, antifungal, antileishmanial, anthelmintic, anticancer, anti‐inflammatory, antidepressant, and antiamnesic effects have also been broadly recognized for rosemary plant extracts. Thus the present review summarized data on economically important Rosmarinus officinalis species, including isolation, extraction techniques, chemical composition, pharmaceutical, and food applications.     

Evaluation of cytotoxic potential of structurally well-characterized RNA targeted ionic non-steroidal anti-inflammatory (NSAID) Cu(ii) & Zn(ii) DACH–mefenamato drug conjugates against human cancer cell lines

New RNA targeted ionic [Cu(DACH)₂(H₂O)₂](mef)₂, 1 and [Zn(DACH)₂(H₂O)₂](mef)₂, 2 drug conjugates were synthesized and characterized by spectroscopic techniques FT-IR, UV-vis, EPR in case of 1 and ¹H and ¹³C NMR in case of 2, ESI-MS, thermogravimetric analysis and single-crystal X-ray structure determination in case of 1. The interaction studies of 1 & 2 with most likely drug targets like ctDNA and tRNA were performed which demonstrated that the complexes 1 and 2 exhibited strong preferential binding to tRNA as compared to ctDNA, K_b = 2.52(±0.04) × 10⁵ M⁻¹, 7.85(±0.02) × 10⁴ M⁻¹, respectively. Scanning electron microscopy analyses of complex-ctDNA/tRNA condensates suggested the interaction of complexes with ctDNA/tRNA had occurred, followed by lengthening of DNA double helix and bulge region of tRNA. Cytotoxic activity of 1 and 2 against human cancer cell lines namely; MCF-7 (breast), HeLa (cervical), MIA-PA-CA 2 (pancreatic), A-498 (kidney), Hep-G2 (hepatoma) was evaluated by SRB assay. The obtained results showed that copper complex 1 was an outstanding cytotoxic agent with remarkably good GI₅₀ value (<10 μg ml⁻¹) against the tested cancer cell lines except for MIA-PA-CA 2, while zinc complex 2 revealed moderate cytotoxicity against all the tested cancer cell lines.

New RNA targeted ionic NSAID drug conjugates were evaluated for their antiproliferative activity against human cancer cell lines.     

Postoperative wound breakdown caused by pyoderma gangrenosum after bilateral simultaneous total knee arthroplasty

Pyoderma gangrenosum is a noninfective necrosis of dermal tissues. Rarely, it occurs after surgery or trauma. However, lack of awareness and its striking similarity to a clinical picture of sepsis usually delay diagnosis and initiation of the correct management. We describe a unique case of its occurrence in both surgical wounds after bilateral total knee arthroplasty and discuss the differential diagnoses and management.     

Enhanced 7-ethyl-10-hydroxycamptothecin (SN-38) lethality by methylselenocysteine is associated with Chk2 phosphorylation at threonine-68 and down-regulation of Cdc6 expression

Methylselenocysteine (MSC) is an organic selenium compound in preventative clinical trials involving prostate, lung, and colon carcinoma. We found that methioninase-activated MSC potentiates 7-ethyl-10-hydroxycamptothecin (SN-38)-induced cell lethality in vitro in the p53-defective human head and neck carcinoma A253 cells. Activated MSC increases chk2 phosphorylation at threonine-68 induced by SN-38, with no significant effect on chk1 phosphorylation. Cell cycle arrest induced by SN-38, however, was not abrogated or potentiated by MSC. These results suggest that the enhanced cellular lethality of SN-38 by MSC was not associated with cell cycle regulation pathways. Because chk2, in addition to its role in cell cycle arrest, can induce apoptosis by phosphorylation/activation, we examined whether increased chk2 phosphorylation could induce preapoptotic DNA fragmentation. DNA damage analysis showed that megabase DNA fragmentation is decreased, accompanied by the increased 30 to 300 kilobase pairs of DNA fragmentation after exposure to SN-38 with MSC, compared with SN-38 alone. No significant changes in the amount of DNA fragments were observed in cells treated with SN-38 or MSC alone. Moreover, proteolytic destruction of DNA replication-associated proteins cdc6, MCM2, and cdc25A may induce a DNA damage checkpoint response. The observed down-regulation of DNA replication proteins cdc6, MCM2, and cdc25A after exposure to SN-38 with MSC further indicates a relationship between drug response and DNA damage. Exposure to SN-38 with MSC resulted in a significant increase of poly(ADP-ribose) polymerasecleavage and caspase 3 activation. All together, the data support the hypothesis that enhanced lethality of this combination is associated with increased chk2 phosphorylation at Thr68 and down-regulation of specific DNA replication-associated proteins, which result in poly(ADP-ribose) polymerase cleavage, caspase 3 activation, and the induction of 30 to 300 kilobase pairs of DNA fragmentation.     

Synthesis, antibacterial, antifungal activity and interaction of CT-DNA with a new benzimidazole derived Cu(II) complex

The ligand [C(16)H(10)O(2)N(4)S(2)] L has been synthesized by the condensation reaction of 2-mercaptobenzimidazole and diethyloxalate. The ligand L was allowed to react with bis(ethylenediamine)Cu(II)/Ni(II) complexes to yield [C(20)H(22)N(8)S(2)Cu]Cl(2)1 and [C(20)H(22)N(8)S(2)Ni]Cl(2)2 complexes. The Ni(II) complex was synthesized only to elucidate the structure of the complex. The complexes 1 and 2 were characterized by elemental analyses, IR, NMR, EPR, UV-vis spectroscopy and molar conductance measurements. Both the complexes are ionic in nature and possess square-planar geometry. The binding of the complex 1 to calf thymus DNA was investigated spectrophotometrically. The absorption spectra of complex 1 exhibits a slight red shift with "hyperchromic effect" in presence of CTDNA. Electrochemical analysis and viscosity measurements were also carried out to ascertain the mode of binding. The complex 1 in the absence and in presence of CT DNA in aqueous solution exhibits one quasi-reversible redox wave corresponding to Cu(II)/Cu(I) redox couple at a scan rate of 0.2 V s(-1). The shift in DeltaE(p), E(1/2) and I(pa)/I(pc) values ascertain the interaction of calf thymus DNA with copper(II) complex. There is decrease in viscosity of CTDNA which indicates that the complex 1 binds to CTDNA through a partial intercalative mode. The antibacterial and antifungal studies of the [C(7)H(6)N(2)S], [C(4)H(16)N(4)Cu]Cl(2,) [C(16)H(10)N(4)S(2)O(2)] and [C(20)H(22)N(8)S(2)Cu]Cl(2) were carried out against S. aureus, E. coli and A. niger. All the results reveal that the complex 1 is highly active against the bacterial strains and also inhibits fungal growth.     

Synergistic antitumor activity of capecitabine in combination with irinotecan

5-Fluorouracil (5-FU) and capecitabine alone and in combination with irinotecan/oxaliplatin are clinically active in the treatment of colorectal and other solid tumors. Studies of the antitumor activity and toxicity of capecitabine or irinotecan alone and in combination with each other, were compared with 5-FU and raltitrexed in human tumor xenografts of colorectal and squamous cell carcinoma of the head and neck using clinically relevant schedules. Antitumor activity and toxicity were evaluated in nude mice bearing human colon carcinomas of HCT-8 and HT-29 and in head and neck squamous cell carcinomas of A253 and FaDu xenografts using the maximum tolerable dose of single-agent capecitabine, 5-FU, or raltitrexed, or each of the drugs in combination with irinotecan. Mice were treated with capecitabine and irinotecan alone or in combination using 2 different schedules: (1) capecitabine orally once a day for 7 days and a single dose of irinotecan (50 mg/kg intravenously [I.V.]), with each drug alone or in combination, and (2) capecitabine orally 5 days a week for 3 weeks and irinotecan 50 mg/kg (I.V. injection) once a week for 3 weeks, with each drug alone or in combination. For comparative purposes, the antitumor activity of single-agent capecitabine, 5-FU, or raltitrexed, or each drug in combination with irinotecan was carried out at its maximum tolerated dose (MTD) using a 3-week schedule. Results indicated that HT-29 and A253 xenografts were de novo resistant (no cure) to capecitabine and irinotecan alone at the MTD, whereas HCT-8 and FaDu xenografts were relatively more sensitive, yielding 10%-20% cures. The combination of irinotecan/capecitabine was much more active than either drug alone against all 4 tumor models. The cure rates were increased from 0 to 20% in A253 and HT-29 xenografts and from 10%-20% to 80%-100% in HCT-8 and FaDu tumor xenografts, respectively. Irinotecan/capecitabine had clear advantage over irinotecan/5-FU and irinotecan/raltitrexed in efficacy and selectivity in that they were more active and less toxic. The extent of synergy with irinotecan/capecitabine appears to be tumor-dependent and independent of the status of p53 expression. The potential impact of the preclinical results on clinical practice for the use of these drugs in combination needs clinical validation.     

Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy.

PURPOSE: Combination chemotherapy with irinotecan (CPT-11; 50 mg/kg/week x 4 intravenously), followed 24 hour later by 5-fluorouracil (50 mg/kg/week x 4 intravenously), results in 10 and 100% cure rates of animals bearing human head and neck squamous cell carcinoma xenografts A253 and FaDu, respectively. A253 consists of 30% well-differentiated and avascular and 70% poorly differentiated regions with low microvessel density (10/x400), whereas FaDu is uniformly poorly differentiated with higher microvessel density (19/x400). Studies were carried out for determining the role of well-differentiated and avascular regions in drug resistance in A253 and detection of such regions with noninvasive functional magnetic resonance (fMR) imaging. EXPERIMENTAL DESIGN: Tumors were harvested for histopathologic evaluation and immunohistochemistry (CD31, CD34; differentiation marker: involucrin; hypoxia markers: carbonic anhydrase IX, pimonidazole; vascular endothelial factor (VEGF) and Ki67) immediately after fMR imaging following the 3rd dose of chemotherapy. High-performance liquid chromatography determination of intratumoral drug concentration of 7-ethyl-10-hydroxyl-camptothecin and autoradiography with (14)C-labeled CPT-11 was done 2 hours after CPT-11 administration. RESULTS: Although A253 xenografts showed three times higher concentration of 7-ethyl-10-hydroxyl-camptothecin, FaDu was more responsive to therapy. After therapy, A253 tumor consisted mostly (approximately 80%) of well-differentiated regions (positive for involucrin) lacking microvessels with a hypoxic rim (positive for carbonic anhydrase IX and pimonidazole) containing few proliferating (Ki67 positive) poorly differentiated cells. Autoradiography revealed that well-differentiated A253 tumor regions showed 5-fold lower (14)C-labeled CPT-11 concentrations compared with poorly differentiated areas (P < 0.001). Blood oxygen level dependant fMR imaging was able to noninvasively distinguish the hypoxic and well-vascularized regions within the tumors. CONCLUSION: Avascular-differentiated regions in squamous cell carcinoma offer sanctuary to some hypoxic but viable tumor cells (carbonic anhydrase IX and Ki67 positive) that escape therapy because of limited drug delivery. This study provides direct evidence that because of a specific histologic structure, avascular, well-differentiated hypoxic regions in tumors exhibit low drug uptake and represent a unique form of drug resistance.     

The Chemical Composition and Biological Activities of Essential Oil from the Leaves of Philadelphus x purpureomaculatus Lemoine

Pharmaceutical Chemistry Journal - The essential oil from the leaves of Philadelphus x purpureomaculatus Lemoine was obtained by hydrodistillation and analyzed by high-resolution gas-liquid...