Context: The health benefits and medicinal properties of herbal food products are known since antiquity. Fenugreek [Trigonella foenum-graecum Linn. (Fabaceae)], a seed spice used to enhance flavor, color and texture of food, is employed for medicinal purposes in many traditional systems. A number of epidemiological studies and laboratory research have unraveled the biological actions of fenugreek. Objective: Research on fenugreek in recent years has identified a number of health benefits and physiological attributes in both experimental animals as well as clinical trials in humans. In this study we have reviewed the available scientific literature on fenugreek. Methods: This review article summarizes and reviews published experimental studies and scientific literature from the databases including PubMed, Google and local library searches. Results: The information available in the literature on the health benefits and pharmaceutical effects of Trigonella accounts for its known medicinal properties and adds new therapeutic effects in newer indications. Besides its known medicinal properties such as carminative, gastric stimulant, antidiabetic and galactogogue (lactation-inducer) effects, newer research has identified hypocholesterolemic, antilipidemia, antioxidant, hepatoprotective, anti-inflammatory, antibacterial, antifungal, antiulcer, antilithigenic, anticarcinogenic and other miscellaneous medicinal effects of fenugreek. Although most of these studies have used whole seed powder or different forms of extracts, some have identified active constituents from seeds and attributed them medicinal values for different indications. Conclusion: The resarch on Trigonella exhibits its health benefits and potential medicinal properties in various indications and has little or no side effects, suggesting its pharmaceutical, therapeutic and nutritional potential.

Oxidative stress-induced inflammation is a major contributor to several disease conditions including sepsis, carcinogenesis and metastasis, diabetic complications, allergic asthma, uveitis and after cataract surgery posterior capsular opacification. Since reactive oxygen species (ROS)-mediated activation of redox-sensitive transcription factors and subsequent expression of inflammatory cytokines, chemokines and growth factors are characteristics of inflammatory disorders, we envisioned that by blocking the molecular signals of ROS that activate redox-sensitive transcription factors, various inflammatory diseases could be ameliorated. We have indeed demonstrated that ROS –induced lipid peroxidation-derived lipid aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and their glutathione-conjugates (e.g. GS-HNE) are efficiently reduced by aldose reductase to corresponding alcohols which mediate the inflammatory signals. Our results showed that inhibition of aldose reductase (AKR1B1) significantly prevented the inflammatory signals induced by cytokines, growth factors, endotoxins, high glucose, allergens and auto-immune reactions in cellular as well as animal models. We have demonstrated that AKR1B1 inhibitor, fidarestat, significantly prevents tumor necrosis factor-alpha (TNF-α)-, growth factors-, lipopolysachharide (LPS)-, and environmental allergens-induced inflammatory signals that cause various inflammatory diseases. In animal models of inflammatory diseases such as diabetes, cardiovascular, uveitis, asthma, and cancer (colon, breast, prostate and lung) and metastasis, inhibition of AKR1B1 significantly ameliorated the disease. Our results from various cellular and animal models representing a number of inflammatory conditions suggest that ROS-induced inflammatory response could be reduced by inhibition of AKR1B1, thereby decreasing the progression of the disease and if the therapy is initiated early, the disease could be eliminated. Since fidarestat has already undergone phase III clinical trial for diabetic neuropathy and found to be safe, though clinically not very effective, our results indicate that it can be developed for the therapy of a number of inflammation- related diseases. Our results thus offer a novel therapeutic approach to treat a wide array of inflammatory diseases.

Oxidative stress plays a critical role in the pathophysiology of a wide range of diseases including cancer. This view has broadened significantly with the recent discoveries that reactive oxygen species initiated lipid peroxidation leads to the formation of potentially toxic lipid aldehyde species such as 4-hydroxy-trans-2-nonenal (HNE), acrolein, and malondialdehyde which activate various signaling intermediates that regulate cellular activity and dysfunction via a process called redox signaling. The lipid aldehyde species formed during synchronized enzymatic pathways result in the posttranslational modification of proteins and DNA leading to cytotoxicity and genotoxicty. Among the lipid aldehyde species, HNE has been widely accepted as a most toxic and abundant lipid aldehyde generated during lipid peroxidation. HNE and its glutathione conjugates have been shown to regulate redox-sensitive transcription factors such as NF-κB and AP-1 via signaling through various protein kinase cascades. Activation of redox-sensitive transcription factors and their nuclear localization leads to transcriptional induction of several genes responsible for cell survival, differentiation, and death. In this review, we describe the mechanisms by which the lipid aldehydes transduce activation of NF-κB signaling pathways that may help to develop therapeutic strategies for the prevention of a number of inflammatory diseases.

The results indicate that AR inhibition suppresses the inflammation in EIU by blocking the expression and release of inflammatory markers in ocular tissues, along with the attenuation of NF-kappaB activation. This finding suggests that AR inhibition could be a novel therapeutic target for the treatment of uveitis and associated ocular inflammation.

Products of lipid peroxidation such as 4-hydroxy-trans-2-nonenal (HNE) trigger multiple signaling cascades that variably affect cell growth, differentiation, and apoptosis. Because glutathiolation is a significant metabolic fate of these aldehydes, we tested the possibility that the bioactivity of HNE depends upon its conjugation with glutathione. Addition of HNE or the cell-permeable esters of glutathionyl-4-hydroxynonenal (GS-HNE) or glutathionyl-1,4-dihydroxynonene (GS-DHN) to cultures of rat aortic smooth muscle cells stimulated protein kinase C, NF-B, and AP-1, and increased cell growth. The mitogenic effects of HNE, but not GS-HNE or GS-DHN, were abolished by glutathione depletion. Pharmacological inhibition or antisense ablation of aldose reductase (which catalyzes the reduction of GS-HNE to GS-DHN) prevented protein kinase C, NF-B, and AP-1 stimulation and the increase in cell growth caused by HNE and GS-HNE, but not GS-DHN. The growth stimulating effect of GS-DHN was enhanced in cells treated with antibodies directed against the glutathione conjugate transporters RLIP76 (Ral-binding protein) or the multidrug resistance protein-2. Overexpression of RLIP76 abolished the mitogenic effects of HNE and its glutathione conjugates, whereas ablation of RLIP76 using RNA interference promoted the mitogenic effects. Collectively, our findings suggest that the mitogenic effects of HNE are mediated by its glutathione conjugate, which has to be reduced by aldose reductase to stimulate cell growth. These results raise the possibility that the glutathione conjugates of lipid peroxidation products are novel mediators of cell signaling and growth.Incomplete reduction of oxygen leads to the generation of highly reactive species. When generated in high concentrations, the reactive oxygen species (ROS) 2 cause tissue injury and cell death. Excessive ROS production has been linked to a number of degenerative diseases including atherosclerosis (1-3), Alzheimer disease (4, 5), and heart failure (6 -8), as well as tissue injury and dysfunction associated with myocardial ischemia and reperfusion (9, 10) and diabetes (11,12). Additionally, recent evidence suggests that ROS are physiological regulators and mediators of cell signaling due to cytokines and growth factors (13-16). Under physiological conditions, the biological effects of ROS are tightly regulated by chemical and enzymatic antioxidant defenses. However, when these defenses are overwhelmed by disease or injury, ROS attack many cell constituents, with unsaturated lipids being the main target. Unsaturated lipids provide a readily extractable proton to oxygen-free radicals. The resultant lipid radical is stabilized by the bis-allylic double bond system and rapidly accepts molecular oxygen to form peroxyl radicals. This initiates a series of complex, autocatalytic reactions that generate a variety of carbonyl compounds as their end products (17). Of these, aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE) are the most abundant and hence of greater biological significance (...