Unveiling Anthraquinones: Diverse Health Benefits of an Essential Secondary Metabolite.

Since ancient times, plants have been used as a remedy for numerous diseases. The pharmacological properties of plants are due to the presence of secondary metabolites like terpenoids, flavonoids, alkaloids, etc. Anthraquinones represent a group of naturally occurring quinones found generously across various plant species. Anthraquinones attract a significant amount of attention due to their reported efficacy in treating a wide range of diseases. Their complex chemical structures, combined with inherent medicinal properties, underscore their potential as agents for therapy. They demonstrate several therapeutic properties such as laxative, antitumor, antimalarial, antibacterial, antifungal, antioxidant, etc. Anthraquinones are found in different forms (derivatives) in plants, and they exhibit various medicinal properties due to their structure and chemical nature. The precursors for the biosynthesis of anthraquinones in higher plants are provided by different pathways such as plastidic hemiterpenoid 2-C-methyl-D-erthriol4-phosphate (MEP), mevalonate (MVA), isochorismate synthase and polyketide. By conducting a thorough analysis of scientific literature, this review provides insights into the intricate interplay between anthraquinone biosynthesis and its broad-ranging contributions to human health.

Carbendazim Modulates the Metabolically Active Bacterial Populations in Soil and Rhizosphere.

The impact of fungicide residues on non-target soil bacterial communities is relatively unexplained. We hypothesize that the persistence of fungicide residues in the soil will affect the soil bacterial populations. Persistence depends on biotic and abiotic factors, primarily determined by agricultural activities. Activities such as fallow soil (F), farmyard manure (FYM) amendment, rice straw (RS) mulching, and cultivation of maize (Zea mays) and clover (Trifolium alexandrinum) were used as treatments. The soil CO2 efflux showed no effect of Carbendazim on dormant bacteria (unwatered condition). However, in irrigated condition, Carbendazim enhanced the CO2 efflux by 8, 164, 131, 249, and 182% in fallow, FYM, RS, maize, and Trifolium treatments, respectively. However, 16S rRNA metagenome study after 30 days of carbendazim treatment showed that maize rhizosphere microflora was most susceptible, decreasing the Shannon diversity index from 0.321 to 0.165. Diversity indices generally increased in maize and RS treatments, and Proteobacteria was the most prominent bacterial phyla in the maize rhizosphere. The microbial communities separated into distinct groups on the Principal Co-ordinate analysis (PCoA) plot. The separation on scale 1 (35%) and scale 2 (13%) was based, respectively, on microbial activity and carbendazim treatments. Functionally Maize+Carbendazim treatment showed the highest enzyme activities dehydrogenase (82.25%), acid phosphatase (78.10%), alkaline phosphatase (48.26%), ß-glucosidase (59.99%), protease (126.65%), and urease (50.66%) compared to fallow soil. Overall, Carbendazim enhanced non-target bacterial activity in metabolically active niches, while it did not affect the dormant microflora. Thus, organic amendments and cultivation of fungicide-contaminated soil may help render the contaminant through bacterial activity.

Heat shock proteins: a therapeutic target worth to consider.

Heat shock proteins (HSPs) are the molecular chaperones, that are not only expressed during the normal growth process of cell cycle consecutively, but also get induced in cells during various stress conditions produced by cellular insult, environmental changes, temperature, infections, tumors etc. According to their molecular weight and functions, HSPs are divided into five major families. HSP90, HSP70, HSP60 and HSP100 are the most studied members of the family. Experimental studies have proved that overexpression and/or inhibition of HSPs play an important role in maintaining the tolerance and cell viability under above-described stress conditions. HSP90 is found to be a promising the candidate for the diagnosis, prognosis and treatment of cancer. Similarly, HSP70, HSP60 and small HSPs experimentally and clinically have potential for the treatment of neurodegenerative disease, ischemia, cell death, autoimmunity, graft rejection, etc. In a way, exploring, the cytoprotective and immunoregulatory role of HSPs can open a new avenue for the drug discovery and treatment of critical diseases.

Treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates ischemic acute kidney injury.

BACKGROUND: Hypoxia-inducible factor (HIF) transcriptional system plays a central role in cellular adaptation to low oxygen levels. Preconditional activation of HIF and/or expression of its individual target gene products leading to cytoprotection have been well established in hypoxic/ischemic renal injury. Increasing evidence indicate HIF activation is involved in hypoxic/ischemic postconditioning of heart, brain and kidney. Very few studies evaluated the potential benefits of postischemia HIF activation in renal injury employing a pharmacological agent. We hypothesized that postischemia augmentation of HIF activation with a pharmacological agent would protect renal ischemia/reperfusion injury. For this, TRC160334, a novel HIF hydroxylase inhibitor, was used. METHODS: TRC160334, a novel HIF hydroxylase inhibitor, was synthesized. Ability of TRC160334 for stabilization of HIF-α and consequent HIF activation was evaluated in Hep3B cells. Efficacy of TRC160334 was evaluated in a rat model of ischemia/reperfusion-induced AKI. Two different treatment protocols were employed, one involved treatment with TRC160334 before onset of ischemia, the other involved treatment after the reperfusion of kidneys. RESULTS: TRC160334 treatment results in stabilization of HIF-α leading to HIF activation in Hep3B cells. Significant reduction in renal injury was observed by both treatment protocols and remarkable reduction in serum creatinine (23 and 71% at 24 and 48 h, respectively, p < 0.01) was observed with TRC160334 treatment applied after reperfusion. Urine output was significantly improved up to 24 h by both treatment protocols. CONCLUSION: The data presented here provide pharmacologic evidence for postischemia augmentation of HIF activation by TRC160334 as a promising and clinically feasible strategy for the treatment of renal ischemia/reperfusion injury.

TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats.

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components.

TRC120038, a Novel Dual AT(1)/ET(A) Receptor Blocker for Control of Hypertension, Diabetic Nephropathy, and Cardiomyopathy in ob-ZSF1 Rats.

In hypertensive subjects, angiotensin II and endothelin participate in a manner involving closely interwoven pathways in increasing blood pressure (BP) and inducing end organ damage. The primary objective of this study was to determine the effect of TRC120038, a novel dual AT(1)/ET(A) receptor blocker on BP, in obese Zucker spontaneously hypertensive fatty rats (ob-ZSF1), an animal model of moderate hypertension, diabetes with progressive renal and cardiac dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC120038 (11.8 mg/kg bid.) or candesartan cilexetil (0.3 mg/kg od.) or vehicle control. Blood pressure (by radio-telemetry) and renal functional markers were monitored throughout the study. Cardiac function was assessed terminally by pressure volume catheter. Markers for renal dysfunction were measured and changes were evaluated histopathologically. TRC120038 showed greater fall in both systolic and diastolic BP in comparison to candesartan at its maximum antihypertensive dose. TRC120038 also reduced the severity of renal dysfunction and preserved cardiac function in ob-ZSF1 rat.

TRC4186, a novel AGE-breaker, improves diabetic cardiomyopathy and nephropathy in Ob-ZSF1 model of type 2 diabetes.

Advanced glycation end products (AGEs) contribute significantly to diabetic complications, both macro- and microvascular. TRC4186 is an AGE-breaker that has been evaluated in vitro and in vivo and shown to reduce AGE burden. The aim of this study was to determine the effect of TRC4186 on diabetic cardiomyopathy and nephropathy in obese Zucker spontaneously hypertensive fatty rats (Ob-ZSF1), an animal model of diabetes with progressive cardiac and renal dysfunction. Ob-ZSF1 rats loaded with 0.5% salt were treated with TRC4186, 9 or 27 mg/kg twice daily intraperitoneally or vehicle control and monitored telemetrically throughout the study. Cardiac function was assessed terminally by Millar catheter. Markers of cardiac and renal dysfunction were measured and changes evaluated histopathologically. TRC4186 at 27 mg/kg prevented rise in blood pressure (BP) and also improved cardiac output (CO) secondary to better diastolic relaxation as well as systolic emptying in association with the reduction in afterload. At 9 mg/kg, CO was improved by compensatory increase in pre-load however afterload reduction was not adequate to allow efficient systolic emptying. Brain natriuretic peptide (BNP) and interleukin-6 (IL-6) expression was reduced with treatment. Deterioration in renal function was retarded as evident from albumin to creatinine ratio and renal histopathology. TRC4186, an AGE-breaker, clearly preserved cardiac function and reduced the severity of renal dysfunction in Ob-ZSF1, an animal model with persistent severe hyperglycemia leading to diabetic heart failure and renal failure.