Terpenoids and phenolics of Micromeria persica.

Phytochemical investigation of the aerial parts of Micromeria persica led to the isolation of a new oleane type triterpenoid ester (1), together with six known compounds 2-7), comprising one phenyl ethanoid ester, one glycosylated flavonoid, two triterpenoids, and two steroids. Their structures were elucidated by interpretation of their one-dimensional and two-dimensional NMR spectra and completed by the analysis of the HRESIMS data. Compounds 1 and 3 were evaluated for their cytotoxic feature against human breast adenocarcinoma cell line (MDA-MB231) and human prostate cancer cell line (DU145). However, they did not show positive effect (IC50 > 75µM).[Figure: see text].

Phosphodiesterase 4 and 7 inhibitors produce protective effects against high glucose-induced neurotoxicity in PC12 cells via modulation of the oxidative stress, apoptosis and inflammation pathways.

Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50-60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways. Phosphodiesterase 4 and 7 (PDE 4 and 7) regulate oxidative damage, neurodegenaration, and inflammatory responses through modulation of cyclic adenosine monophosphate (cAMP) level, and thus can be as important drug targets for regulating DN. The aim of this study was to evaluate the protective effects of inhibitors of PDE 4 and 7, named rolipram and BRL5048, on HG-induced neurotoxicity in PC12 cells as an in vitro cellular model for DN and determine the possible mechanisms for theirs effects. We report that the PC12 cells pre-treatment with rolipram (2 µM) and/or BRL5048 (0.2 µM) for 60 min and then exposing the cells to HG (4.5 g/L for 72 h) or normal glucose (NG) (1 g/L for 72 h) condition show: (1) significant attenuation in ROS, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, MMP and ATP levels. All these data together led us to propose PDE 4 and 7 inhibitors, and specifically, rolipram and BRL5048, as potential drugs candidate to be further studied for the prevention and treatment of DN.

Sildenafil protective effects on high glucose-induced neurotoxicity in PC12 cells: the role of oxidative stress, apoptosis, and inflammation pathways in an in vitro cellular model for diabetic neuropathy.

Objectives Diabetic neuropathy (DN) induces lifetime disability and there is currently no effective therapy to treat or to minimize patients suffering, so it is thereby imperative to develop therapeutic strategies for this disease. Since oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial mechanisms in development and progression of DN, it is important to explore tools by which one can reduce factors related to these pathways. Herein, the understandings of the sildenafil neuroprotective effect through increase of cGMP level and the mediation of oxidative stress, apoptosis, and inflammation pathways on neurotoxicity induced by high glucose (HG) in PC12 cells as an in vitro cellular model for DN were investigated. Methods We reported that the PC12 cells pre-treatment with sildenafil (0.008 µM) for 60 min and then exposing the cells to HG (25 mM for 72 h) or normal glucose (NG) (5 mM for 72 h) condition, show: Results (1) significant attenuation in reactive oxygen species, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, mitochondrial membrane potential, and ATP levels. Conclusion All these data together led us to propose neuroprotective effect of sildenafil is probably through its antioxidant, antiapoptotic, and anti-inflammatory activities. Of course, further studies are required to explain the underlying mechanism of the sildenafil effects.

Eupatorin and Salvigenin Potentiate Doxorubicin-Induced Apoptosis and Cell Cycle Arrest in HT-29 and SW948 Human Colon Cancer Cells

Background: Cancer persists as one of the world's most pressing maladies. Notable points about chemotherapy are drug side effects which are almost universally encountered. Emerging knowledge focusing on mechanisms of toxicity due to chemotherapy has led to characterization of novel methods, including the exploitation of natural compounds, in combination therapies. Flavonoids are natural polyphenolic compounds that play protective roles against tumor cell development. The focus of this study was apoptotic effects of two flavonoids, eupatorin and salvigenin, in combination with doxorubicin on a cellular model of colon cancer. Method: Upon establishing a non-effective dose of doxorubicin, and effective doses of eupatorin (100µM) and salvigenin (150µM) via MTT, morphological features of apoptosis were distinguished using DAPI staining and cell cycle blockage in the sub-G1 phase. Apoptosis was determined by annexin/ PI and western blotting. ROS levels and MMP were measured to show any role of mitochondria in apoptosis. Results: Co-administration of flavonoids with doxorubicin induced apoptosis via the mitochondrial pathway as mitochondrial membrane potential and ROS production were changed. Annexin/PI analysis demonstrated that apoptosis frequency was increased with the combination treatments in colon cancer cells. Finally, the combination of these flavonoids with doxorubicin increased the Bax/Bcl-2 ratio, caspase-3 expression and PARP cleavage. Conclusion: Combination of flavonoids with doxorubicin induces apoptosis and enhances effect on cancer cells which might allow amelioration of side effects by dose lowering.

Labdane Diterpenoids from Salvia leriifolia: Absolute Configuration, Antimicrobial and Cytotoxic Activities.

Fractionation of an n-hexane extract of the aerial parts of Salvia leriifolia led to the isolation of two new (1, 2) and two known (3, 4) labdane diterpenoids, together with three other known compounds. The structures were established by a combination of 1D and 2D NMR, and HRESIMS. The structures of 1 and 3 were confirmed by single-crystal X-ray analysis. The absolute configuration of 1-4 was established by electronic circular dichroism spectroscopy. Compounds 1-4 were evaluated for their cytotoxic activities against MCF-7 human breast cancer cells. Labdanes 3 and 4 were additionally tested against MDA-MB231 human breast cancer and DU-145 human prostate cancer cell lines. Compound 4 showed IC50 values of 25, 50, and 50 µM against MCF-7, MDA-MB231, and DU-145 cells, respectively. Compounds 1-4 were tested for activity against gram-positive (Staphylococcus aureus) and gram-negative (Escherichia coli) bacteria. Compound 3 showed an MIC of 213 µM against methicillin-resistant S. aureus.