Effect of Pterostilbene, a Natural Derivative of Resveratrol, in the Treatment of Colorectal Cancer through Top1/Tdp1-Mediated DNA Repair Pathway

Topoisomerase 1 (Top1) inhibitor is an effective anticancer drug, but several factors limit its clinical application such as drug inactivation, tyrosyl-DNA phosphodiesterase 1 (Tdp1)-mediated tumor drug resistance, and its toxicity. Our previous study identified pterostilbene (PTE) and resveratrol (RE) to suppress these two proteins by binding to their active center. PTE and RE could inhibit the proliferation of various colorectal cancer cells, induce cell apoptosis, and make cell cycle stay in G2/M phase in vitro. PTE and RE could decrease Top1 and Tdp1 contents and mRNA expression in wild-type, constructed Tdp1 overexpressing CL187, Top1- or Tdp1- silenced CL187 cell lines. PTE exhibited excellent antitumor activity in subcutaneous CL187 transplantation model (TGI = 79.14 ± 2.85%, 200 mg/kg, i.p.) and orthotopic transplantation model (TGI = 76.57 ± 6.34%, 100 mg/kg, i.p.; TGI = 72.79 ± 4.06%, 500 mg/kg, i.g.) without significant toxicity. PTE had no significant inhibitory effect on non-tumor cell proliferation in vitro and would not induce damage to liver, kidney, and other major organs. Overall, PTE and RE can inhibit the activity of Top1 enzyme and inhibit the DNA damage repair pathway mediated by Top1/Tdp1, and can effectively inhibit colorectal cancer development with low toxicity, thus they have great potential to be developed into a new generation of anti-tumor drugs.

In Vitro and In Vivo Antifibrotic Effects of Fraxetin on Renal Interstitial Fibrosis via the ERK Signaling Pathway

Fraxetin, a natural derivative of coumarin, is known to have anti-inflammatory, anti-oxidant, and hepatoprotective effects in multiple diseases and in liver fibrosis. Whether fraxetin exerts similar effects against renal fibrosis is unknown. In a Unilateral Ureteral Obstruction (UUO) mouse model of renal fibrosis, fraxetin decreased UUO-induced renal dysfunction with a marked reduction in renal interstitial collagen fibers as detected by Masson’s Trichrome staining. Fraxetin treatment also inhibited the expression of α-SMA, Collagen I, Collagen IV, fibronectin, N-cadherin, vimentin, phosphorylated-ERK, and increased the expression of E-cadherin in UUO mice, as shown by immunohistochemical staining and western blot analysis. In vitro studies showed that fraxetin and indoxyl sulfate had no cytotoxic effects on MES13 kidney cells, but that fraxetin significantly decreased IS-induced cell motility and decreased protein expression of α-SMA, N-cadherin, vimentin, and Collagen IV via the ERK-mediated signaling pathway. These findings provide insight into the mechanism underlying fraxetin-induced inhibition of fibrogenesis in renal tissue and suggest that fraxetin treatment may be beneficial for slowing CKD progression.

Isolating an active and inactive CACTA transposon from lettuce color mutants and characterizing their family

Dietary flavonoids play an important role in human nutrition and health. Flavonoid biosynthesis genes have recently been identified in lettuce (Lactuca sativa); however, few mutants have been characterized. We now report the causative mutations in Green Super Lettuce (GSL), a natural light green mutant derived from red cultivar NAR; and GSL-Dark Green (GSL-DG), an olive-green natural derivative of GSL. GSL harbors CACTA 1 (LsC1), a 3.9-kb active nonautonomous CACTA superfamily transposon inserted in the 5′ untranslated region of anthocyanidin synthase (ANS), a gene coding for a key enzyme in anthocyanin biosynthesis. Both terminal inverted repeats (TIRs) of this transposon were intact, enabling somatic excision of the mobile element, which led to the restoration of ANS expression and the accumulation of red anthocyanins in sectors on otherwise green leaves. GSL-DG harbors CACTA 2 (LsC2), a 1.1-kb truncated copy of LsC1 that lacks one of the TIRs, rendering the transposon inactive. RNA-sequencing and reverse transcription quantitative PCR of NAR, GSL, and GSL-DG indicated the relative expression level of ANS was strongly influenced by the transposon insertions. Analysis of flavonoid content indicated leaf cyanidin levels correlated positively with ANS expression. Bioinformatic analysis of the cv Salinas lettuce reference genome led to the discovery and characterization of an LsC1 transposon family with a putative transposon copy number greater than 1,700. Homologs of tnpA and tnpD, the genes encoding two proteins necessary for activation of transposition of CACTA elements, were also identified in the lettuce genome.

Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources

Species of the Celastraceae family are traditionally consumed in different world regions for their stimulating properties. Celastrol, a triterpene methylene quinone isolated from plants of celastraceas, specifically activates satiety centers in the brain that play an important role in controlling body weight. In this work, the antimicrobial activity and mechanism of action of celastrol and a natural derivative, pristimerin, were investigated in Bacillus subtilis. Celastrol showed a higher antimicrobial activity compared with pristimerin, being active against Gram-positive bacteria with minimum inhibitory concentrations (MICs) that ranged between 0.16 and 2.5 µg/mL. Killing curves displayed a bactericidal effect that was dependent on the inoculum size. Monitoring of macromolecular synthesis in bacterial populations treated with these compounds revealed inhibition in the incorporation of all radiolabeled precursors, but not simultaneously. Celastrol at 3 µg/mL and pristimerin at 10 µg/mL affected DNA and RNA synthesis first, followed by protein synthesis, although the inhibitory action on the uptake of radiolabeled precursors was more dramatic with celastrol. This compound also caused cytoplasmic membrane disruption observed by potassium leakage and formation of mesosome-like structures. The inhibition of oxygen consumption of whole and disrupted cells after treatments with both quinones indicates damage in the cellular structure, suggesting the cytoplasmic membrane as a potential target. These findings indicate that celastrol could be considered as an interesting alternative to control outbreaks caused by spore-forming bacteria.

Dual Targeting of Autophagy and NF-κB Pathway by PPARγ Contributes to the Inhibitory Effect of Demethoxycurcumin on NLRP3 Inflammasome Priming

Background: Demethoxycurcumin (DMC), a natural derivative of curcumin, has anti-inflammatory activities. However, the mechanism has not been fully elucidated. Objective: The aim of the current study was to investigate the role of DMC on NLRP3 inflammasome priming. Methods: Protein expression was quantified by western blotting. Inflammatory cytokines were measured by ELISA. Autophagosomes were evaluated by transmission electron microscopy. Results: DMC inhibited LPS-stimulated NLRP3, pro-caspase-1, and pro-IL-1β expression. Meanwhile, DMC diminished NLRP3-dependent IL-1β maturation, caspase-1 activation, IL-1β and IL-18 production caused by LPS plus ATP. Moreover, DMC induced autophagy and autophagy inhibitor 3-MA abrogated the role of DMC on NLRP3 inflammasome priming and subsequent activation. DMC also inhibited LPS-stimulated phosphorylation and nuclear translocation of p65 NF-κB. Additionally, DMC significantly increased the PPARγ expression and the effects of DMC in NF-κB inhibition, autophagy, and NLRP3 inflammasome priming were abrogated by specific PPARγ antagonist T0070907. Conclusion: The evidence presented here has confirmed that DMC increases PPARγ expression, resulting in autophagy and NF-κB inhibition, and subsequently inhibits LPS-induced NLRP3 inflammasome priming and subsequent activation.

Differential relieving effects of shikonin and its derivatives on inflammation and mucosal barrier damage caused by ulcerative colitis

Background Ulcerative colitis (UC) is one of the most challenging human diseases. Natural shikonin (SK) and its derivatives (with have higher accumulation) isolated from the root of Lithospermum erythrorhizon have numerous beneficial effects, such as wound healing and anti-inflammatory activities. Some researchers have reported that hydroxynaphthoquinone mixture (HM) and SK attenuate the acute UC induced by dextran sulfate sodium (DSS). However, no existing study has systemically investigated the effectiveness of SK and other hydroxynaphthoquinone natural derivative monomers on UC. Methods In this study, mice were treated with SK and its derivatives (25 mg/kg) and mesalazine (200 mg/kg) after DSS administration daily for one week. Disease progression was monitored daily by observing the changes in clinical signs and body weight. Results Intragastric administration natural single naphthoquinone attenuated the malignant symptoms induced by DSS. SK or its derivatives remarkably suppressed the serum levels of pro-inflammatory cytokines while increasing the inflammatory cytokine interleukin (IL)-10 . Additionally, both SK and alkanin restrained the activities of cyclooxygenase-2 (COX-2), myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) in serum and colonic tissues. SK and its derivatives inhibited the activation of nucleotide binding oligomerization domain-like receptors (NLRP3) inflammasome and NF-κB signaling pathway, thereby relieving the DSS-induced disruption of epithelial tight junction (TJ) in colonic tissues. Conclusions Our findings shed more lights on the pharmacological efficacy of SK and its derivatives in UC against inflammation and mucosal barrier damage.

ANTICANCER ACTIVITY OF UPAVISHA ARKA: AN OVERVIEW

Cancer is one amongst the dreadful diseases of present century. The incidence of cancer is increasing worldwide. Every year about 8,00,000 new cancer patients get registered with the national cancer registry program in India. Ayurveda an ancient Indian medicine science describes many useful herbal drugs for such types of advanced diseases. Upavisha the plant poisons of low potency are mentioned in Agadtantra. Arka (Calotropis procera/ Calotropis gigantea) is one among these Upavisha is emerging as an effective anticancer drug. It shows various pharmacological activities such as Anticancer, Antimicrobial, Antiimplantation etc. Different parts of Arka are used to treat cancer. In current scenario number of synthetic anticancer drugs are used to treat cancer. These synthetic anticancer drugs are expensive and shows harmful adverse effects. Upavisha like Arka which is natural derivative may be cost effective & less harmful as Anticancer drug. Anticancer activity of Calotropis procera/Calotropis gigantea is reported in scientific journals. This review summarizes various In Vitro and In Vivo studies of anticancer activity of Upavisha Arka.

1H NMR study of the interaction of trans-resveratrol with soybean phosphatidylcholine liposomes

Resveratrol (RSV) is a well-known natural derivative with a wide range of biological and pharmacological activities. Despite of these demonstrated properties, it exhibits low both aqueous solubility and chemical stability and therefore low bioavailability. Consequently, the major concern of the technological research is to exploit delivery systems able to overcome bioavailability problems. In the recent past liposomes have been successfully studied for these purposes. In this paper, 1H-NMR spectroscopy, Nuclear Overhauser Spectroscopy (NOESY) as well as Paramagnetic Relaxation Enhancements (PRE) experiments have been carried out to quantitatively investigate the incorporation of resveratrol, at both the liposome preparation stage and by preformed liposomes, also with the aim to characterize resveratrol- soybean phosphatidylcholine (P90G) lipid bilayer interactions. Overall results of 1H NMR spectroscopy analysis suggest that RSV is located nearby the phosphocholine headgroups and also provide quantitative data on the incorporation of RSV (5% w/w), which corresponds to a 150-fold increase with respect to the solubility of RSV in water. Beside, considering that the same level of RSV incorporation was obtained via spontaneous uptake by preformed P90G liposomes, it can be concluded that RSV easily diffuses through the lipid bilayer.