Concurrent photothermal therapy and photodynamic therapy for cutaneous squamous cell carcinoma by gold nanoclusters under a single NIR laser irradiation.

Phototherapy, particularly photothermal therapy (PTT) and photodynamic therapy (PDT), has become a promising therapeutic technique for the treatment of skin cancers because of its minial invasiveness, high efficacy, and low side effects. Nevertheless, single modality therapy, either PTT or PDT, has limited clinical effectiveness in treating skin cancers. Thus, combined applications of PTT and PDT have been frequently reported; however, PTT and PDT often require their respective photoagents and excitation light sources, resulting in challenges in clinical transformation. In this study, to address these issues, we report the use of biocompatible gold nanoclusters Au25(Capt)18 for the concurrent PTT and PDT treatment of cutaneous squamous cell carcinoma (cSCC) using an 808 nm near-infrared (NIR) laser. Utilizing their high light-thermal conversion efficiency, potent generation of singlet oxygen, and strong photothermal stability, Au25(Capt)18 nanoclusters potentiated a significant proliferation suppression of cSCC XL50 cells in vitro and the inhibition of cSCC tumors on SKH-1 mice in vivo. In particular, under 808 nm light irradiation, the tumor-cell-killing contributions of PTT and PDT were estimated to be 28.86% and 71.14%, respectively, by using an ROS scavenger to quench the PDT effect. Tumor-infiltrating CD4+ T and CD8+ T cells were observed after one course of concurrent PTT and PDT. Preliminary toxicity studies indicated low adverse effects of the Au25(Capt)18 nanoclusters. Through this study, we report the use of a simple nanostructure for simultaneous PTT and PDT applications to effectively kill cSCC and to induce anti-tumor immune responses. Our study could lead to the development of effective photoagents for current, synergistic applications of different phototherapies with targeted immunological responses for the treatment of cancers.

Potential Angiotensin Converting Enzyme Inhibitors from Moringa oleifera.

BACKGROUND: Hypertension is the chronic medical condition and it affected billions of people worldwide. Natural medicines are the main alternatives to treatment for a majority of people suffering from hypertension. Niazicin-A, Niazimin-A, and Niaziminin-B compounds from Moringa oleifera ethanolic leave extract were reported to have potent antihypertensive activity. OBJECTIVE: These compounds were targeted with Angiotensin-converting enzyme [ACE] which is one of the main regulatory enzymes of the renin-angiotensin system. METHODS: Protein-ligand docking of these compounds with [ACE] [both domain N and C] was conceded out through Autodock vina and visualization was done by chimera. Pharmacokinetics study of these compounds was predicted by ADME-Toxicity Prediction. RESULTS: Niazicin-A, Niazimin-A, and Niaziminin-B showed high binding affinity with ACE and partially blocked the active sites of the enzyme. Niazicin-A, Niazimin-A and Niaziminin-B showed the estimated free binding energy of -7.6kcal/mol kcal/mol, -8.8kcal/mol and -8.0kcal/mol respectively with C-domain of ACE and -7.9kcal/mol, -8.5kcal/mol and -7.7kcal/mol respectively with N-domain of ACE. The compounds showed better binding energy with angiotensinconverting enzyme in comparison to Captopril -5.5kcal/mol and -5.6kcal/mol and Enalapril [standard] -8.4kcal/mol and -7.5kcal/mol with C and N domain, respectively. CONCLUSION: Computationally, the selected bioactive molecules have shown better binding energy to known standard drugs which have been already known for inhibition of ACE and can further act as a pharmacophore for in vitro and in vivo studies in the development of alternative medicine.

L-Captopril and its derivatives as potential inhibitors of microbial enzyme DapE: A combined approach of drug repurposing and similarity screening.

The perils of antimicrobial drug resistance can be overcome by finding novel antibiotic targets and corresponding small molecule inhibitors. Microbial enzyme DapE is a promising antibiotic target due to its importance to the bacterial survival. The potency of L-Captopril, a well known angiotensin-converting enzyme inhibitor, as an inhibitor of DapE enzyme has been evaluated by analyzing its binding modes and binding affinity towards DapE enzyme. L-Captopril is found to bind the metal centers of DapE enzyme either via its thiolate group or through its carboxylate group. While the latter binding mode is found to be thermodynamically favorable, the former binding mode, also seen in the crystal structure, is kinetically favored. To optimize the binding affinity of the inhibitor towards DapE enzyme, a series of L-Captopril-based inhibitors have been modelled by changing the side groups of L-Captopril. The introduction of a bipolar functional group at the C4 position of the pyrrolidine ring of L-Captopril and the substitution of the thiol group with a carboxylate group, have been shown to provide excellent enzyme affinity that supersedes the binding affinity of DapE enzyme towards its natural substrate, thus making this molecule a potential inhibitor with great promise.

Novel Antihypertensive Prodrug from Grape Seed Proanthocyanidin Extract via Acid-Mediated Depolymerization in the Presence of Captopril: Synthesis, Process Optimization, and Metabolism in Rats.

Grape seed extract contains a high content of proanthocyanidins that can be depolymerized into C-4-substituted (epi)catechin derivatives in the presence of nucleophiles. However, the biological and medicinal values of depolymerization products have been rarely investigated. Recently, we developed a novel depolymerization product (-)-epicatechin-4ß- S-captopril methyl ester (ECC) derived from the reaction of grape seed proanthocyanidin extract with captopril in the presence of acidified methanol. A central composite design was employed to select the most appropriate depolymerization temperature and time to obtain the target product ECC with a high yield. A total of 16 metabolites of ECC in rat urine, feces, and plasma were identified using liquid chromatography quadrupole time-of-flight tandem mass spectrometry. The in vivo results suggested that ECC could release captopril methyl ester and epicatechin, followed by the generation of further metabolites captopril and epicatechin sulfate conjugates. Therefore, ECC may be used as a potential prodrug with synergistic or additive hypotensive effects.

Bioactivity-Guided Fractionation of Pine Needle Reveals Catechin as an Anti-hypertension Agent via Inhibiting Angiotensin-Converting Enzyme.

Hypertension has been recognized as one of the highest risk factors for cardiovascular diseases. Anti-hypertension agent screening and development has been recognized as a pharmaceutical therapy approach for the cardiovascular diseases treatment. Many kinds of traditional Chinese medicines, such as pine needle, have been used for the treatment of hypertension for a long time, but the bioactive ingredients which responsible for their therapeutic effectiveness are remain unclear. Therefore, screening bioactive chemicals in natural sources is still the most straightforward strategy for novel Angiotensin-converting enzyme inhibitor (ACEi)-based anti-hypertension agents discovery. In this study, we demonstrated a bioactivity-guided fractionation strategy for identifying bioactive fractions and chemicals from pine needle based on LC/MS assay as well as elucidating their mechanisms of pharmacological activity. And we found out the compound in pine needle extracts being ACE-inhibitory active is catechin. When ACE activity was assayed in rat tissue membranes, it was observed that catechin demonstrate ACE inhibition in kidney, lung and testes tissue. All these presents catechin in pine needle could be a potential cardiovascular medicine.

Endothelin A receptor blocker atrasentan lowers blood pressure by the reduction of nifedipine-sensitive calcium influx in Ren-2 transgenic rats fed a high-salt diet.

BACKGROUND: Our previous experiments demonstrated that selective endothelin A (ETA) receptor blockade had antihypertensive effects in Ren-2 transgenic rats (TGRs), but the mechanisms responsible for this change of blood pressure (BP) have not been explored yet. METHOD: Four-week-old male heterozygous TGRs and their normotensive controls--Hannover Sprague-Dawley (HanSD) rats--were fed high-salt diet (2% NaCl) and were treated with selective ETA receptor blocker atrasentan (5 mg/kg per day) for 8 weeks. At the end of the study, the contribution of principle vasoactive systems was evaluated by the sequential blockade of the renin-angiotensin system (captopril), sympathetic nervous system (pentolinium) and nitric oxide synthase [N-nitro-L-arginine methyl ester (L-NAME)]. The role of calcium influx through L-type voltage-dependent calcium channels in BP maintenance was evaluated using nifedipine. In a separate group of animals, the efficiency of distinct vasodilator systems--prostanoids (blocked by nonselective cyclooxygenase inhibitor indomethacin) and Ca-activated K channels (inhibited by tetraethylammonium)--was also analyzed. RESULTS: Atrasentan attenuated the development of hypertension in heterozygous TGRs, but had no effects in Hannover Sprague-Dawley rats. Moreover, atrasentan moderately attenuated renin-angiotensin system-dependent vasoconstriction, whereas it had no effect on sympathetic vasoconstriction. The nifedipine-sensitive BP component was markedly decreased by atrasentan treatment. In contrast, vasodilatation mediated by nitric oxide, endogenous prostanoids or Ca-activated K channels was reduced in atrasentan-treated TGRs, indicating the absence of compensatory augmentation of endothelin B receptor-mediated vasodilation in these animals. CONCLUSION: BP-lowering effect of chronic atrasentan treatment in TGRs was mainly caused by reduced Ca influx through L-type voltage-dependent calcium channels due to missing ETA receptor-dependent vasoconstriction and attenuated angiotensin II-dependent vasoconstriction.

Assay of angiotensin I-converting enzyme-inhibiting activity based on the detection of 3-hydroxybutyric acid.

Hypertension and related diseases afflict millions of individuals worldwide, and many investigations of angiotensin I-converting enzyme (ACE) activity have been carried out. Most of these have used hippuryl-histidyl-leucine (HHL) as a substrate for ACE reaction with considerable interferences. Here we propose the use of a new substrate, 3-hydroxybutyrylglycyl-glycyl-glycine (3HB-GGG) for the screening of ACE inhibitors. Under the actions of ACE and aminoacylase, 3HB-GGG is cleaved into amino acids (Gly and Gly-Gly) and 3-hydroxybutyric acid (3HB). The assay conditions were optimized and applied to monitor the ACE inhibitory activity in terms of 3HB measured using an F-kit. Under the optimum assay parameters-ACE (0.2 U/ml) and aminoacylase (172 kU/ml) incubated with 3HB-GGG (3.4 mg/ml) at 37 degrees C for 30 min-the Gly-Gly and Gly cleaved from 3HB-GGG by enzymes was able to be identified, affirming the feasibility of substituting 3HB-GGG for the conventional substrate HHL. In addition, the current method was more sensitive, accurate, rapid, and convenient than the conventional method.

In vitro interactions of captopril with NSAID's.

Captopril is effective in the treatment of hypertension of all grades of severity. Present paper deals with the in vitro availability studies of captopril in presence and absence of commonly used NSAID's likes diclofenac sodium, flurbiprofen, mefenamic acid, meloxicam and tiaprofenic acid. Since it had been established that simultaneous administration of both drugs may alter the antihypertensive effect of captopril. In order to find out the kinetics and energitics of captopril in presence of NSAID's, these studies were carried out in buffers of pH 4, 7.4 and 9 at 37 degrees C and at elevated temperatures. These studies clearly indicate that most of the NSAID's bind to captopril, forming charge-transfer complexes revealing that the availability of captopril can be affected by the concurrent administration of NSAID's. Accordingly coadministration of both the drugs should be avoided.

Antioxidant properties of captopril in vitro.

This paper reports on the effect of captopril on the stability of unsaturated fatty acids in the evening primrose oil. The experiment was performed for captopril at concentrations of 0.05%, 0.1% and 0.2% in the samples of evening primrose oil at temperatures of 20 degrees, 40 degrees and 60 degrees C. The determination was performed on the 10th day of incubation. The results were compared to those obtained for analogous samples with octyl gallate, an antioxidant commonly used in oil systems, taken at the same concentrations and at the same temperatures. The changes in concentrations of the substances studied with time were monitored by gas chromatography. The results have shown captopril to be a stronger antioxidant than octyl gallate at all concentrations and temperatures used.