Methods are provided for inhibiting stenosis following vascular trauma or disease in a mammalian host, comprising administering to the host a therapeutically effective dosage of a therapeutic conjugate containing a vascular smooth muscle binding protein that associates in a specific manner with a cell surface of the vascular smooth muscle cell, coupled to a therapeutic agent dosage form that inhibits a cellular activity of the muscle cell. Methods are also provided for the direct and/or targeted delivery of therapeutic agents to vascular smooth muscle cells that cause a dilation and fixation of the vascular lumen by inhibiting smooth muscle cell contraction, thereby constituting a biological stent.

Therapeutic inhibitor of vascular smooth muscle cells

Onion (Allium cepa L.) is botanically included in the Liliaceae and species are found across a wide range of latitudes and altitudes in Europe, Asia, N. America and Africa. World onion production has increased by at least 25% over the past 10 years with current production being around 44 million tonnes making it the second most important horticultural crop after tomatoes. Because of their storage characteristics and durability for shipping, onions have always been traded more widely than most vegetables. Onions are versatile and are often used as an ingredient in many dishes and are accepted by almost all traditions and cultures. Onion consumption is increasing significantly, particularly in the USA and this is partly because of heavy promotion that links flavour and health. Onions are rich in two chemical groups that have perceived benefits to human health. These are the flavonoids and the alk(en)yl cysteine sulphoxides (ACSOs). Two flavonoid subgroups are found in onion, the anthocyanins, which impart a red/purple colour to some varieties and flavanols such as quercetin and its derivatives responsible for the yellow and brown skins of many other varieties. The ACSOs are the flavour precursors, which, when cleaved by the enzyme alliinase, generate the characteristic odour and taste of onion. The downstream products are a complex mixture of compounds which include thiosulphinates, thiosulphonates, mono-, di- and tri-sulphides. Compounds from onion have been reported to have a range of health benefits which include anticarcinogenic properties, antiplatelet activity, antithrombotic activity, antiasthmatic and antibiotic effects. Here we review the agronomy of the onion crop, the biochemistry of the health compounds and report on recent clinical data obtained using extracts from this species. Where appropriate we have compared the data with that obtained from garlic (Allium sativum L.) for which more information is widely available.

Onions—A global benefit to health

Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with a broad range of biological activities. Allicin is produced upon tissue damage from the non-proteinogenic amino acid alliin (S-allylcysteine sulfoxide) in a reaction that is catalyzed by the enzyme alliinase. Current understanding of the allicin biosynthetic pathway will be presented in this review. Being a thiosulfinate, allicin is a reactive sulfur species (RSS) and undergoes a redox-reaction with thiol groups in glutathione and proteins that is thought to be essential for its biological activity. Allicin is physiologically active in microbial, plant and mammalian cells. In a dose-dependent manner allicin can inhibit the proliferation of both bacteria and fungi or kill cells outright, including antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, in mammalian cell lines, including cancer cells, allicin induces cell-death and inhibits cell proliferation. In plants allicin inhibits seed germination and attenuates root-development. The majority of allicin's effects are believed to be mediated via redox-dependent mechanisms. In sub-lethal concentrations, allicin has a variety of health-promoting properties, for example cholesterol- and blood pressure-lowering effects that are advantageous for the cardio-vascular system. Clearly, allicin has wide-ranging and interesting applications in medicine and (green) agriculture, hence the detailed discussion of its enormous potential in this review. Taken together, allicin is a fascinating biologically active compound whose properties are a direct consequence of the molecule's chemistry.

https://www.mdpi.com/1420-3049/19/8/12591/pdf

Allicin: Chemistry and Biological Properties

Context—Garlic-containing drugs have been used in the treatment of hypercholesterolemia
even though their efficacy is not generally established Little is known about
the mechanisms of action of the possible effects on cholesterol in humansObjective—To estimate the hypocholesterolemic effect of garlic oil and to investigate
the possible mechanism of actionDesign—Double-blind, randomized, placebo-controlled trialSetting—Outpatient lipid clinicPatients—We investigated 25 patients (mean age, 58 years) with moderate hypercholesterolemiaIntervention—Steam-distilled garlic oil preparation (5 mg twice a day) vs placebo
each for 12 weeks with wash-out periods of 4 weeksMain Outcome Measures—Serum lipoprotein concentrations, cholesterol absorption, and cholesterol
synthesisResults—Baseline lipoprotein profiles were (mean [SD]): total cholesterol, 753
(075) mmol/L (291 [29] mg/dL); low-density lipoprotein cholesterol (LDL-C),
535 (078) mmol/L (207 [30] mg/dL); high-density lipoprotein cholesterol
(HDL-C), 150 (041) mmol/L (58 [16] mg/dL); and triglycerides, 145 (073)
mmol/L (127 [64] mg/dL) Lipoprotein levels were virtually unchanged at the
end of both treatment periods (mean difference [95% confidence interval]):
total cholesterol, 0085 (−0201 to 0372) mmol/L (33 [−78 to
144] mg/dL), P=54; LDL-C, 0001 (−0242 to
0245) mmol/L (004 [−94 to 95] mg/dL), P=99;
HDL-C, 0050 (−0028 to 0128) mmol/L (19 [−11 to 49] mg/dL), P=20; triclycerides, 0047 (−0229 to 0135) mmol/L
(42 [−203 to 120]) mg/dL, P=60 Cholesterol
absorption (375% [105%] vs 383% [107%], P=58),
cholesterol synthesis (127 [65] vs 134 [66] mg/kg of body weight per day, P=64), mevalonic acid excretion (192 [66] vs 187 [66]
µg/d, P=78), and changes in the ratio of lathosterol
to cholesterol in serum (44% [243%] vs 106% [211%], P=62) were not different in garlic and placebo treatmentConclusions—The commercial garlic oil preparation investigated had no influence
on serum lipoproteins, cholesterol absorption, or cholesterol synthesis Garlic
therapy for treatment of hypercholesterolemia cannot be recommended on the
basis of this study

Effect of a Garlic Oil Preparation on Serum Lipoproteins and Cholesterol Metabolism: A Randomized Controlled Trial

Using primary rat hepatocyte cultures, the potency of several garlic-derived organosulfur compounds to inhibit cholesterol biosynthesisin toto as well as at early and late steps of this metabolic pathway was compared. Concerning early steps, allicin significantly inhibited incorporation of [14C]acetate into nonsaponifiable neutral lipids already at concentrations as low as 10 µM, while diallyl disulfide and allyl mercaptan were effective above 100 µM only. Likewise, inhibition in response to the two vinyl-dithiins started at 500 µM. If [14C]acetate was replaced by [14C]mevalonate, inhibition due to allicin, diallyl disulfide, and allyl mercaptan disappeared suggesting that HMGCoA-reductase was the target of inhibition. In contrast, for the vinyl-dithiins a stimulation of mevalonate incorporation was found. Concerning the late step, the potency to exert accumulation of lanosterol presumably by inhibiting lanosterol 14α-demethylase decreased in the order allicin>diallyl disulfide>allyl mercaptan=1,3-vinyl-dithiin≫1,2-vinyldithiin, the effect of the latter compound being close to zero. With respect to the total inhibition of [14C]acetate labeling of cholesterol, the half-maximal effective concentration-value of allicin was determined to be 17±2 µM compared to 64±7 µM for diallyl disulfide and to 450±20 µM for allyl mercaptan. Cytotoxicity as determined by the lactate dehydrogenase leakage assay was slightly higher for the two vinyl-dithiins than for diallyl disulfide and allyl mercaptan, but was apparent only at concentrations higher than 10 mM and, consequently, was irrelevant for the effects described. These results demonstrate that different garlic-derived organosulfur compounds interfere differently with cholesterol biosynthesis and, thus, may provoke multiple inhibition of this metabolic pathway in response to garlic consumption. The fact that allicin was the most effective inhibitor argues against the possibility that its degradation products, namely diallyl disulfide or allyl mercapatan, might mediate its effects, a possibility that might be true, however, in the case of the vinyl-dithiins.

Karl G. Wagner

Papers

Inhibition of cholesterol biosynthesis by allicin and ajoene in rat hepatocytes and HepG2 cells