Synthesis and photodynamic activity of unsymmetrical A3B tetraarylporphyrins functionalized with l-glutamate and their Zn(II) and Cu(II) metal complex derivatives

Four novel unsymmetrical A₃B porphyrins 1, 2, 3 and 4 were synthesized following Lindsey procedure. Porphyrins 3 and 4 include one and three l-glutamate groups, respectively, and all porphyrins were metallated with Zn(II) (1a–4a) or Cu(II) (1b–4b). Porphyrins and metalloporphyrins presented values of singlet oxygen quantum yields (ΦD) ranging from 0.21 to 0.67. The tetraaryl derivatives in this study showed phototoxicity in SiHa cells with IC₅₀ values ranging from <0.01 to 6.56 ± 0.11 μM, the metalloporphyrin 4a showed the lowest IC₅₀ value. Comparing the phototoxic activity between all porphyrins, functionalization of porphyrins with glutamate increased 100 times phototoxic activity (1 (IC₅₀ 4.81 ± 0.34 μM) vs. 3 (IC₅₀ 0.04 ± 0.02 μM) and 2 (IC₅₀ 5.19 ± 0.42 μM) vs. 4 (IC₅₀ 0.05 ± 0.01 μM)). This increased activity could be attributed to reduced hydrophobicity and increased ΦΔ, given by functionalization with l-glutamate. Metalloporphyrins 3a (IC₅₀ 0.04 ± 0.01 μM) and 4a (IC₅₀ <0.01 μM) presented the best values ​​of phototoxic activity. Therefore, functionalization and zinc metalation increased the phototoxic activity. SiHa cells treated with porphyrins 3, 4, 3a and 4a at a final concentration of 10 μM, showed increased activity of caspase-3 enzyme compared to the negative control; indicating the induction of apoptosis. Differential gene expression pattern in SiHa cells was determined; treatments with metalloporphyrins 4a and 4b were performed, respectively, comparing the expression with untreated control. Treatments in both cases showed similar gene expression pattern in upregulated genes, since they share about 25 biological pathways and a large number of genes. According to the new photophysical properties related to the structural improvement and phototoxic activity, these molecules may have the potential application as photosensitizers in the photodynamic therapy.     

Improved cisplatin delivery in cervical cancer cells by utilizing folate-grafted non-aggregated gelatin nanoparticles

PurposeCisplatin is highly effective in the treatment of cervical cancer. However, in therapeutic doses, cisplatin induces several adverse effects due to undesirable tissue distribution. Therefore, it is worth targeting cisplatin in cervical cancer cells by implicating non-aggregated ligand-modified nanotherapeutics.Methods and resultsHere, we report the preparation of non-aggregated folic acid-conjugated gelatin nanoparticles of cisplatin (Cis-GNs-FA) by two-step desolvation method with mean particle size of 210.6 ± 9.6 nm and 140.5 ± 10.9 nm for Cis-GNs to improve the drug delivery in cervical cancer, HeLa cells. FTIR and DSC spectra confirmed the presence and stability of cisplatin in gelatin matrix. Furthermore, amorphization of cisplatin in nanoparticles was ascertained by PXRD. Drug release followed a first-order release kinetic at both pH ∼ 5.6 (cervical cancer pH) and pH ∼ 7.4. In addition, a significant (P < 0.05) decrease in IC₅₀ value (8.3 μM) and enhanced apoptosis were observed in HeLa cells treated with Cis-GNs-FA as compared to Cis-GNs (15.1 μM) and cisplatin solution (40.2 μM). In contrast, A549 lung cancer cells did not discriminate between Cis-GNs-FA and Cis-GNs due to the absence of folate receptors-α (FR-α). Consistently, higher cellular uptake, 80.54 ± 7.60% was promoted by Cis-GNs-FA significantly (two-way ANOVA, P < 0.05) greater than 51.68 ± 9.78%, by Cis-GNs. This was also illustrated by CLSM images, which indicated that Cis-GNs-FA preferably accumulated in the cytoplasm of HeLa cells nearby nucleus by following receptor-mediated endocytosis pathway as compared to Cis-GNs.ConclusionTherefore, Cis-GNs-FA warrants further in-depth in vitro and in vivo investigations to scale up the technology for clinical translation.     

Diorganotin (IV) complexes with 4-nitro-N-phthaloyl-glycine: Synthesis,characterization, antitumor activity and DNA-binding studies

Two novel diorganotin (IV) complexes, based on 4-nitro-N-phthaloyl-glycine (HL), namely {4-NO₂C₆H₃(CO)₂NCH₂COO}₂Sn(n-Bu)₂ (1) and {4-NO₂C₆H₃(CO)₂NCH2COO}₂SnMe₂ (2), were synthesized and characterized by elemental analysis, FT-IR, ¹H- and ¹³C-NMR spectroscopic techniques. In vitro antitumor activities of both complexes were evaluated by the 3-(4,5-dimethylthiazoly-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay against three human cancer cell lines: HepG-2 (human liver carcinoma), SGC-7901 (human gastric carcinoma) and LS174T (human colon carcinoma). Complex 1 exhibited strong antitumor activity with IC₅₀ values of 1.51 ± 0.41, 1.80 ± 0.63, and 2.48 ± 0.96 μM, respectively; while complex 2 had no obvious effects on the three selected cancer cell lines at high concentrations up to 100 μM. Complex 1-induced apoptosis was further confirmed by morphological observations and annexin V-FITC/PI staining flow cytometry analysis in HepG-2 cells. Cell cycle analysis revealed that complex 1 caused cell cycle arrest at G2/M phase. Molecular mechanism studies suggested that the apoptosis was mediated through the mitochondrial pathway with intracellular reactive oxygen species (ROS) promotion and mitochondrial membrane potential (MMP) disruption by finally activating effector caspase-3/9 to trigger cell apoptosis. Moreover, the interactions of both complexes with calf thymus DNA (CT-DNA) were investigated by using UV-Vis titration and fluorometric competition measurements. The DNA-binding constants K_b (intrinsic binding constant) and K_sv (quenching constant) had been obtained in the order: 1 > 2, consisted with the antitumor activity results. Taken together, complex 1 exhibited excellent antitumor activity suggesting that it may be a potential candidate for further chemical optimization and cancer therapy.     

Directional modification of chrysin for exerting apoptosis and enhancing significantly anti-cancer effects of 10-hydroxy camptothecin

Chrysin, one of natural flavonoid compounds, has recently been found to possess anti-inflammatory, antiallergic and anticancer properties. To increase its anticancer effects, 5 chrysin derivates were synthesized on the base of DNA intercalator structure. The inhibiting effects of chrysin and its derivatives on cancer cells Hela, BGC823, MCF-7, HepG2, and normal cells HEK-293, were evaluated by MTT assays. 5-(2′-amino) phenyl-7-cyclohexanemethylchrysin (Ch-1), a unique chrysin derivate, killed all the cancer cells but kept above 60% survival rate in normal cells HEK-293 at 62.5 μM. Treated with chrysin from 250 μM to 500 μM, those cells were still maintained above 60% survival rate. The result of circular dichroism spectra showed that Ch-1 could intercalate DNA while chrysin had no effects on DNA. Interestingly, Hela cells survival rates were 95% and 10%, after treated with 20 μM and 30 μM of Ch-1, respectively. Both intrinsic and extrinsic apoptotic pathway were identified in regulating the cell death caused by Ch-1 in Hela cells. p53, the upstream regulator of apoptotic pathway were extremely significantly up-regulated in Hela cells treated with 25 μM Ch-1. Moreover, the inhibiting effects and apoptotic related proteins responses to Ch-1 on Hela cells were abolished after pre-treated with Pifithrin-α (Pft-α), a p53 inhibitor. So, p53-depedent apoptosis is the crucial factor governing the inhibiting effects of Ch-1 in Hela cells. Amazingly, Ch-1 at non-toxic concentration (2.5–10 μM) enhanced significantly anti-cancer effect of 10-hydroxy camptothecin (HCPT) on Hela, BGC823, and MCF-7 cells.     

Antiproliferation and induction of caspase-8-dependent mitochondria-mediated apoptosis by β-tocotrienol in human lung and brain cancer cell lines

The pure vitamin isomer, β-tocotrienol has the least abundance among the other vitamin E isomers that are present in numerous plants. Hence, it is very scarcely studied for its bioactivity. In this study, the antiproliferative effects and primary apoptotic mechanisms of β-tocotrienol on human lung adenocarcinoma A549 and glioblastoma U87MG cells were investigated. It was evidenced that β-tocotrienol had inhibited the growth of both A549 (GI₅₀ = 1.38 ± 0.334 μM) and U87MG (GI₅₀ = 2.53 ± 0.604 μM) cells at rather low concentrations. Cancer cells incubated with β-tocotrienol were also found to exhibit hallmarks of apoptotic morphologies including membrane blebbing, chromatin condensation and formation of apoptotic bodies. The apoptotic properties of β-tocotrienol in both A549 and U87MG cells were the results of its capability to induce significant (P < 0.05) double-strand DNA breaks (DSBs) without involving single-strand DNA breaks (SSBs). β-Tocotrienol is said to induce activation of caspase-8 in both A549 and U87MG cells guided by no activation when caspase-8 inhibitor, z-IETD-fmk was added. Besides, disruption on the mitochondrial membrane permeability of the cells in a concentration- and time-dependent manner had occurred. The induction of apoptosis by β-tocotrienol in A549 and U87MG cells was confirmed to involve both the death-receptor mediated and mitochondria-dependent apoptotic pathways. These findings could potentiate the palm oil derived β-tocotrienol to serve as a new anticancer agent for treating human lung and brain cancers.     

Antioxidant status and lipid peroxidation in the blood of breast cancer patients of different ages after chemotherapy with 5-fluorouracil,doxorubicin and cyclophosphamide

ObjectivesBreast carcinoma is related to the increase of lipid peroxidation in plasma with concomitant decrease of antioxidant (AO) defense capacity in blood cells, which becomes more pronounced during aging of the patients. This work evaluated the potential age-related effect of chemotherapy with 5-fluorouracil, doxorubicin and cyclophosphamide (FAC) on the level of lipid hydroperoxides (LP), glutathione (GSH), AO enzyme activities of copper, zinc superoxide dismutase (CuZnSOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR) in breast cancer patients. The level of CuZnSOD protein was assessed after the FAC therapy and radiotherapy of breast cancer.Design and methodsAO parameters were measured in the blood of 58 breast cancer patients and 60 healthy age-matched healthy subjects by biochemical and Western blot analyses.ResultsIncreased oxidative stress (LP: p < 0.05) and decreased AO enzyme activities (CuZnSOD: p < 0.01, GPx: p < 0.05, GR: p < 0.01) and GSH level (p < 0.01) in the blood of breast cancer patients in response to FAC chemotherapy seem not to be age-dependent. CuZnSOD enzyme expression decreased after the FAC chemotherapy (p < 0.05), while it increased after the radiotherapy of breast cancer (p < 0.05).ConclusionFAC chemotherapy and radiotherapy promote further oxidative shift, which potentiate already existing chronic oxidative stress linked to breast cancer. In these effects, impaired capacity for H₂O₂ detoxification (CAT, GPX and GSH) seems to have major contribution.     

Physalin F,a seco-steroid from Physalis angulata L., has immunosuppressive activity in peripheral blood mononuclear cells from patients with HTLV1-associated myelopathy

Human T-lymphotropic virus type 1 (HTLV-1) induces a strong activation of the immune system, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Physalin F is a secosteroid with potent anti-inflammatory and immunomodulatory activities. The present study aimed to investigate the effects of physalin F on peripheral blood mononuclear cells (PBMC) of HAM/TSP subjects. A concentration-dependent inhibition of spontaneous proliferation of PBMC from HAM/TSP subjects was observed in the presence of physalin F, as evaluated by ³H-thymidine uptake. The IC₅₀ for physalin F was 0.97 ± 0.11 μM. Flow cytometry analysis using Cytometric Bead Array (CBA) showed that physalin F (10 μM) significantly reduced the levels of IL-2, IL-6, IL-10, TNF-α and IFN-γ, but not IL-17A, in supernatants of PBMC cultures. Next, apoptosis induction was addressed by using flow cytometry to evaluate annexin V expression. Treatment with physalin F (10 μM) increased the apoptotic population of PBMC in HAM/TSP subjects. Transmission electron microscopy analysis of PBMC showed that physalin F induced ultrastructural changes, such as pyknotic nuclei, damaged mitochondria, enhanced autophagic vacuole formation, and the presence of myelin-like figures. In conclusion, physalin F induces apoptosis of PBMC, decreasing the spontaneous proliferation and cytokine production caused by HTLV-1 infection.     

Evaluation of anti-diabetic and anti-tumoral activities of bioactive compounds from Phoenix dactylifera L’s leaf: In vitro and in vivo approach

Among various chronic disorders, cancer and diabetes mellitus are the most common disorders. This study was designed to evaluate the effectiveness of hydroalcoholic extract of Phoenix dactylifera L. leaves (HEPdL) in animal models of type II diabetes in vitro/in vivo and in a human melanoma-derived cell line (IGR-39). A liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis was also performed to determine the amount of phenolic and flavonoid compounds in this plant. The physicochemical results by LC–MS/MS analysis of HEPdL showed the presence of 10 phenolic compounds. The in vitro study showed that the extract exhibited a more specific and potent inhibitor of α-glucosidase than α-amylase with an IC₅₀ value of 20 ± 1 μg/mL and 30 ± 0.8 μg/mL, respectively. More importantly, the in vivo study of the postprandial hyperglycemia activity with (20 mg/kg) of HEPdL showed a decrease in plasma glucose levels after 60 min in resemblance to the glucor (acarbose) (50 mg/kg) effect. The oral administration of HEPdL (20 mg/kg) in alloxan-induced diabetic mices for 28 days showed a more significant anti-diabetic activity than that of the drug (50 mg/kg). Moreover, cytotoxicity effects of HEPdL in IGR-39 cancer cell lines were tested by MTT assay. This extract was effective in inhibiting cancer cells growth (IGR-39) at dose 35 and 75 μg/mL. These results confirm ethnopharmacological significance of the plant and could be taken further for the development of an effective pharmaceutical drug against diabetes and cancer.     

Comparative effects of catechin,epicatechin and N-Ω-nitroarginine on quinolinic acid-induced oxidative stress in rat striatum slices

The aim of this work was to compare the effects of catechin (CAT), epicatechin (EPI) and N-ω-l-nitroarginine (L-NARG) on different endpoints of oxidative stress induced by quinolinic acid (QUIN) in a simple tissue preparation, rat striatal slices – with particular emphasis in the glutathione system – in order to provide revealing information on the antioxidant efficacy of these agents in an excitotoxic model.MethodsRat striatal slices were incubated for 1 h in the presence of 100 μM QUIN and/or 85 μM CAT or EPI, or 100 μM L-NARG. Lipid peroxidation (LP) and the levels of reduced and oxidized glutathione (GSH and GSSG) were determined.ResultsThe three agents tested completely blocked the QUIN-induced lipid peroxidation and recovered the QUIN-induced altered GSH/GSSG balance. No statistical differences were detected among the protective effects exerted by these antioxidants, suggesting similar efficacy and common antioxidant mechanisms. The antioxidant properties exhibited by these molecules on the excitotoxic model tested herein support an active role of glutathione and prompt their use as therapeutic tools in models of neurodegenerative disorders.     

Clinical significance of serum M30 and M65 levels in patients with breast cancer

M30 and M65 are relatively new assays that detect different circulating forms of the epithelial cell structural protein cytokeratin18. The objective of this study was to determine the clinical significance of the serum levels of M30 and M65 in patients with breast cancer. A total of 80 patients with a pathologically confirmed diagnosis of breast cancer were enrolled into the study. Serum M30 and M65 concentrations were determined by the solid-phase sandwich ELISA method. Serum samples were obtained on first admission before any type of treatment. The median age at diagnosis was 52 years, range 30 to 81 years. The baseline serum M30 and M65 levels in patients with metastatic disease were significantly higher than those in the non-metastatic patients (P = 0.017 and P = 0.003, respectively). Moreover, serum M65 level was also elevated in patients with large tumor size (P = 0.02). No correlation was found between these serum assay levels and response to chemotherapy (P > 0.05). However, the significant relationship was found between the serum levels of M30 and M65 (r_s = 0.96, P < 0.001). Neither serum M30 nor serum M65 had significantly effect on survival (P = 0.50, and P = 0.52, respectively). In conclusion, although both serum M30 and M65 levels are elevated in metastatic disease, no predictive and prognostic roles on survival were found in patients with breast cancer.     

Biological activities of skin and parotoid gland secretions of bufonid toads (Bufo bufo,Bufo verrucosissimus and Bufotes variabilis) from Turkey

Toad glandular secretions and skin extractions contain numerous natural agents which may provide unique resources for novel drug development. Especially the skin-parotoid gland secretions of toads from genus Bufo contain as many as 86 different types of active compounds, each with the potential of becoming a potent drug. In the present study, crude skin-parotoid gland secretions from Bufo bufo, Bufo verrucosissimus and Bufotes variabilis from Turkey were screened against various cancer cells together with normal cells using MTT assay. Furthermore, the antimicrobial properties of skin secretions were tested on selected bacterial and fungal species for assessing the possible medical applications. Antimicrobial activity of skin secretions was studied by determining minimal inhibitory concentration (MIC) in broth dilution method. Hemolytic activity of each skin-secretion was also estimated for evaluating pharmaceutical potential. Both skin-parotoid gland secretions showed high cytotoxic effect on all cancerous and non-cancerous cell lines with IC₅₀ values varying between <0.1 μg/ml and 6.02 μg/ml. MIC results of antimicrobial activity tests were found to be between 3.9 μg/ml and 250 μg/ml. No hemolytic activities on rabbit red blood cells at concentrations between 0.5 μg/ml and 50 μg/ml were observed. In conclusion, skin-parotoid secretions of bufonid toads might be remarkable candidates for anti-cancer and antimicrobial agents without hemolytic activities.     

Effect of vitamin D on musculoskeletal pain and headache: A randomized,double-blind,placebo-controlled trial among adult ethnic minorities in Norway

Immigrants from South Asia, the Middle East, and Africa living in Northern Europe frequently have low vitamin D levels and more pain compared to the native Western population. The aim of this study was to examine whether daily vitamin D₃ (25 μg/d or 10 μg/d) supplementation for 16 weeks would improve musculoskeletal pain or headache compared to placebo. This randomized, double-blind, placebo-controlled, parallel-group trial recruited 251 participants aged 18 to 50 years, and 215 (86%) attended the follow-up visit. The pain measures were occurrence, anatomical localization, and degree of musculoskeletal pain, as measured by visual analogue scale (VAS) score during the past 2 weeks. Headache was measured with VAS and the Headache Impact Test (HIT-6) questionnaire. At baseline, females reported more pain sites (4.7) than males (3.4), and only 7% reported no pain in the past 2 weeks. During the past 4 weeks, 63% reported headache with a high mean HIT-6 score of 60 (SD 7). At follow-up, vitamin D level, measured as serum 25(OH)D₃, increased from 27 nmol/L to 52 nmol/L and from 27 nmol/L to 43 nmol/L in the 25-μg and 10-μg supplementation groups, respectively, whereas serum 25(OH)D₃ did not change in the placebo group. Pain scores and headache scores were improved at follow-up compared with baseline. The use of vitamin D supplements, however, showed no significant effect on the occurrence, anatomical localization, and degree of pain or headache compared to placebo.     

Vitamin E (α-tocopherol) enhances the PDT action of hematoporphyrin derivatives on cervical cancer cells

ObjectiveThe effect of antioxidant vitamin E (VE) on PDT (a mainly reactive oxygen species-driven process) has in the past shown contradicting results. Hence, we studied the effect of different concentrations and different incubation periods of VE on the PDT cytotoxicity of the cervical adenocarcinoma HeLa cell line.Materials and methodsHeLa cells were incubated with 25 μg/ml of hematoporphyrin derivatives (HpD) for 25 min (1st PDT regimen) or 24 h (2nd PDT regimen), then irradiated with visible light (total light dose of 10 J/cm²) either with or without different concentrations of VE (1–1000 μM) which had been incubated with the cells for 1 h or 24 h prior to PDT. After irradiation, viability was measured using MTT assay.ResultsThe results obtained showed that PDT is effective against cervical cancer cells. Incubation of HpD for 24 h leads to improved PDT action. Higher concentrations of VE incubated in HeLa cells for 1 h before the 2nd PDT regimen significantly enhanced cytotoxicity of PDT and the maximal enhancement was at 1000 μM of VE. The cytotoxic effect of VE on HeLa cells after incubation for 24 h before PDT is enhanced by the PDT action.ConclusionIn conclusion 1000 μM of VE can be used 1 h before PDT to enhance its effect on cervical adenocarcinoma, a disease which is steadily increasing in young women. It is well-known that the cervical adenocarcinoma is resistant to anticancer agents and radiotherapy and it was previously considered to be HpD-PDT resistant.     

Role of NF-E2-related factor 2 in neuroprotective effect of l-carnitine against high glucose-induced oxidative stress in the retinal ganglion cells

l-Carnitine (LC) has protective effects on high glucose-induced oxidative stress in the retinal ganglion cells (RGCs). The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2), Kelch like-ECH-associated protein 1 (Keap1), haemoxygenase-1 (HO-1) and γ-glutamyl cysteine synthetase (γ-GCS) in the protective effect of LC on RGCs. RGCs were first processed with high concentrations of glucose. LC treatment at three concentrations (50 μM, 100 μM and 200 μM) was applied to high glucose stimulated RGCs. The expression of Nrf2, Keap1, haemoxygenase-1 (HO-1) and γ-glutamyl cysteine synthetase (γ-GCS) was quantified by Western blot in the treatment and control (high glucose stimulation) groups. In the three LC groups (50 μM, 100 μM and 200 μM), Nrf-2 (0.71 ± 0.04, 0.89 ± 0.05, 1.24 ± 0.05 vs 0.56 ± 0.03, p < 0.05), HO-1 (0.58 ± 0.04, 0.76 ± 0.06, 0.89 ± 0.07 vs 0.25 ± 0.03, p < 0.01), and γ-GCS protein expression (0.66 ± 0.03, 0.79 ± 0.05, 0.84 ± 0.08 vs 0.84 ± 0.08, p < 0.01) was higher than in the control group. The levels of Keap1 protein were in the LC groups were lower than in the control group (0.50 ± 0.03, 0.45 ± 0.02, 0.53 ± 0.03 vs 0.86 ± 0.05, p < 0.01). In conclusion, in high glucose stimulated RGCs, LC treatment was associated with an increased level of Nrf2, HO-1and γ-GCS. LC treatment was also associated with a reduced expression of Keap1 protein. These results suggest that the protective effect of LC treatment on RGCs may be related to Nrf2-Keap1 pathway.     

Enhancement of orofacial antinociceptive effect of carvacrol,a monoterpene present in oregano and thyme oils,by β-cyclodextrin inclusion complex in mice

Orofacial pain is associated with diagnosis of chronic pain of head, face, mouth, neck and all the intraoral structures. Carvacrol, a naturally occurring isoprenoid with diverse class of biological activities including anti-inflammatory, analgesic, antitumor and antioxidant properties. Now, the antinociceptive effect was studied in mice pretreatment with carvacrol (CARV) and β-cyclodextrin complex containing carvacrol (CARV-βCD) in formalin-, capsaicin-, and glutamate- induced orofacial nociception. Mice were pretreated with vehicle (0.9% Nacl, p.o.), CARV (10 and 20 mg/kg, p.o.), CARV-βCD (10 and 20 mg/kg, p.o.) or MOR (10 mg/kg, i.p.) before the nociceptive behavior induced by subcutaneous injections (s.c.) of formalin (20 μl, 2%), capsaicin (20 μl, 2.5 μg) or glutamate (20 μl, 25 μM) into the upper lip respectively. The interference on motor coordination was determined using rotarod and grip strength meter apparatus. CARV-βCD reduced the nociceptive during the two phases of the formalin test, whereas CARV did not produced the reduction in face-rubbing behavior in the initial phase. CARV-βCD (20 mg/kg, p.o.) produced 49.3% behavior pain while CARV alone at 20 mg/kg, p.o, produced 28.7% of analgesic inhibition in the second phase of formalin test. CARV, CARV-βCD and Morphine (MOR) showed a significant reduction against nociception caused by capsaicin or glutamate injection. Thus the encapsulation of carvacrol in β-cyclodextrin can acts as a considerable therapeutic agent with pharmacological interest for the orofacial pain management.     

Therapeutic efficacy of Traditional Chinese medicine, “Kuan-Sin-Yin”, in patients undergoing chemotherapy for advanced colon cancer – A controlled trial

BackgroundTraditional Chinese Medicine (TCM) has been used increasingly as complementary medicine in cancer care. Kuan-Sin-Yin (KSY) is a TCM decoction containing seven herbs known to cause immunomodulation or anticancer activity, and which are associated with the TCM concept of Qi and energy supply. Kuan-Sin-Yin has cytostatic effects on cancer cells in animal models.ObjectiveThe aim of this study is to evaluate the level of improvement in meridian energy and heart-rate variability (HRV) and to assess whether these observations are compatible with TCM theory.MethodA non-randomized controlled trial was designed with monitoring of the meridian electro-conductivity and heart-rate variability (HRV) to compare the efficacy of Kuan-Sin-Yin in the control and experimental groups. 52 patients were enrolled in this study. We also measured cancer-related symptoms and quality of life as secondary outcomes.ResultsWe found that colon cancer patients who received KSY as complementary therapy benefitted with enhancement of meridian energy (Yin meridian: 27.90:35.45 μA; p = 0.014; Yang meridian: 27.09:33.55 μA; p = 0.024) and increases in HRV activity (78.40:129.04 ms; SDNN: p = 0.001) and parasympathetic tone(HF:1644.80:3217.92 ms²; p = 0.003; RMMSD:99.76:164.52 ms; p = 0.002). Cancer-related symptoms decreased (ECOG > 1:46.2:7.7%; p = 0.0001), and quality of life (KSY group: PCS 35.46:42.12, p = 0.0001; MCS: 44.50:47.55, p = 0.209) was improved with statistical significance.ConclusionsThe correlation of positive results reflected in meridian energy and HRV activity confirms the positive role of complementary medicine of Kuan-Sin-Yin in cancer care.     

Antileishmanial,antioxidant, and cytotoxic activities of Quercus infectoria Olivier extract

Currently, there is no effective vaccine available, and chemotherapy is the main approach for treatment of cutaneous leishmaniasis (CL). During recent decades, studies have demonstrated that a number of plant-derived compounds may act as new therapeutic tools against leishmaniasis. This study was evaluated the antileishmanial, antioxidant, and cytotoxic activities of Quercus infectoria Olivier (oak) extract. The total amount of phenolic and flavonoid compounds was measured in oak extract. High performance liquid chromatography (HPLC) analysis was also performed to determine the amount of quercetin and gallic acid in this plant. This extract (0–80 g/mL) was evaluated in vitro against promastigote and intracellular amastigote forms of Leishmania major (MRHO/IR/75/ER) using MTT assay and in a macro-phage model, respectively. Then oak extract was tested on CL in infected male BALB/c mice with L. major in order to evaluate the antileishmanial activity topically. Moreover, cytotoxicity effects of oak in murine macrophage cells were tested by MTT assay. Antioxidative activity of oak was also determined by the 2,2-diphenyl-1,1-picrylhydrazyl (DPPH) scavenging test. The amount of phenolic and flavonoid compounds in the oak extract was 57.50 and 1.86%, respectively. The amount of quercetin and gallic acid in the oak extract was 0.0064 and 0.22%, respectively. The findings revealed that oak significantly (P < 0.05) inhibited the growth rate of promastigote of (IC₅₀ 12.65 μg/mL) and amastigotes (IC₅₀ 10.31 μg/mL) as a dose-dependent response. In the in vivo assay, after 4 weeks of treatment, 91.6, 66.66, and 50% recovery was observed in the infected mice treated with 20, 10, and 5 mg/kg of oak extract, respectively. After treatment of the infected mice with the concentration of 10 and 20 mg/kg of oak, the mean diameter of lesions, parasite load and mean number of parasites was significantly (P < 0.05) reduced. Selectivity index of greater than 10 for oak revealed that oak extract had no cytotoxic effects on macrophage cells. Moreover, DPPH test demonstrated that radical inhibition occurred at greater power with increasing the concentration of oak. To conclude, the present study showed potent antileishmanial and antioxidant activity of oak extract; whereas this plant had no toxic effect on mammalian cells.     

Exenatide suppresses 1,2-dimethylhydrazine-induced colon cancer in diabetic mice: Effect on tumor angiogenesis and cell proliferation

Colon cancer is the third leading cause of cancer mortality worldwide, which results from interactions of different factors. It is frequently a pathological consequence of persistent inflammation. Diabetes affects several cancers and is positively correlated with the incidence of colon cancer. This study aimed to study the effect of exenatide in ameliorating inflammation, angiogenesis and cell proliferation in 1,2-dimethyl hydrazine (DMH) induced colorectal carcinoma in diabetic mice. Mice were randomly allocated into six groups, 8 mice each. Group 1: vehicle control group. Group 2: diabetic control group. Group 3: DMH control group: diabetic mice treated with DMH (20 mg/kg/week, s.c.) for 15 week. Group 4: DMH-cisplatin group: mice received cisplatin (4 mg/kg/week, i.p.). Groups 5 & 6: DMH-exenatide (10 and 20 μg/kg) group: mice received exenatide (10 or 20 μg/kg/day, s.c.), respectively. The present results highlighted an increase in angiogenic markers and cell proliferation in the DMH-diabetic group in comparison with the control group with greater expression of endothelial marker (CD₃₄) and Ki-67 in colon tissue. Monotherapy with cisplatin or exenatide (10 and 20 μg/kg) downregulated these markers to different extents. The current results provided evidence that exenatide represents a promising chemopreventive effect against DMH-induced colon carcinogenesis in diabetic mice, at least in part, attributed to its anti-angiogenic and anti-proliferative mechanisms.     

Nitric oxide levels in HIV-infected,untreated patients and HIV-infected patients receiving antiretroviral therapy

The role of nitric oxide (NO) in HIV infection is ambiguous; controversy exists around whether the levels of serum NO are increased or decreased in HIV-infected patients. Thus, it is necessary to reassess NO levels in HIV-infected patients. The aim of this study was to investigate the nitrite/nitrate metabolite (NOx) levels in HIV-infected untreated patients and in HIV-infected patients receiving highly active antiretroviral therapy (HAART), compared with HIV-uninfected individuals (control group). The HIV-infected patients enrolled in this study had been receiving HAART for at least 6 months (HIV-treated) or had not received HAART for at least 6 months (HIV-untreated group). New recommendations encourage initiating treatment in HIV-infected adults at a CD4 cell count of 500 cells/mm³ or less. We also investigated whether levels of NOx were associated with immunophenotypic characteristic of HIV-infected patients. Our results showed a statistically significant increase in NOx levels in the HIV-untreated group (164.0 ± 166.6 μmol/L), compared with both the control (98.9 ± 59.4 μmol/L) and HIV-treated group (71.7 ± 53.3 μmol/L). Multiple regression analysis showed that the differences in NOx level were independent of gender, liver enzyme level, lipid measurement, and hematological parameters. In addition, a lower CD4/CD8 ratio was associated with higher NOx levels in HIV-infected patients. The results further revealed that NOx levels were increased in HIV infection, and that derangement of immune system function was associated with increased NO levels. The levels of NOx were found to decline with the use of HAART, which may contribute to cardiovascular disease in HIV-infected patients.     

Presurgery Psychological Factors Predict Pain,Nausea, and Fatigue One Week After Breast Cancer Surgery

Before scheduled surgery, breast cancer surgical patients frequently experience high levels of distress and expect a variety of postsurgery symptoms. Previous literature has supported the view that presurgery distress and response expectancies are predictive of postsurgery outcomes. However, the contributions of distress and response expectancies to postsurgical side effect outcomes have rarely been examined together within the same study. Furthermore, studies on the effects of response expectancies in the surgical setting have typically focused on the immediate postsurgical setting rather than the longer-term setting. The purpose of the present study was to test the contribution of presurgery distress and response expectancies to common postsurgery side effects (pain, nausea, and fatigue). Female patients (n = 101) undergoing breast cancer surgery were recruited to a prospective study. Results indicated that presurgery distress uniquely contributed to patients' postsurgery pain severity (P < 0.05) and fatigue (P < 0.003) one week after surgery. Response expectancies uniquely contributed to pain severity (P < 0.001), nausea (P < 0.012), and fatigue (P < 0.010) one week after surgery. Sobel tests indicated that response expectancies partially mediated the effects of distress on pain severity (P < 0.03) and fatigue (P < 0.03). Response expectancies also mediated the effects of age on pain severity, nausea, and fatigue. Results highlight the contribution of presurgery psychological factors to postsurgery side effects, the importance of including both emotional and cognitive factors within studies as predictors of postsurgery side effects, and suggest presurgical clinical targets for improving patients' postoperative experiences of side effects.