BACKGROUND: Rosmarinus officinalis L. (Rosemary) is a popular herb with reported effectiveness against diarrhea, anxiety and constipation, albeit with limited pharmacological evidence.
OBJECTIVE: The current study was aimed at evaluating the therapeutic potential, possible pharmacological mechanisms of action and active constituents of hydro-ethanolic extract of rosemary (Rs.Cr), as potential anti-diarrheal, laxative and anxiolytic agent.
METHODS: Rs.Cr was analyzed through reverse-phase high pressure liquid chromatography (RP-HPLC). Laxative, antidiarrheal, and anxiolytic activities were assessed using in vivo models. Spasmogenic and spasmolytic mechanisms were studied on isolated guinea pig ileum and rabbit jejunum tissues, respectively. Possible role of diosmetin, one of the active constituents of Rs.Cr was also evaluated.
RESULTS: RP-HPLC analysis revealed presence of diosmetin, rutin and apigenin in Rs.Cr. Laxative effect was seen at low doses, which was partially reversed in atropinized mice. The spasmogenic mechanism was mediated by cholinergic and histaminergic receptors stimulation. At higher doses, antidiarrheal activity was evident, with reduction in gastrointestinal motility and secretions using charcoal meal and enteropooling assays, respectively. Rs.Cr also showed dose-dependent anxiolytic effect. The antispasmodic mechanisms were mediated by anti-muscarinic and K+ channel opening-like effect (predominant KATP-dependent). Diosmetin exhibited antidiarrheal and antispasmodic activities, but spasmogenic effect was not seen.
CONCLUSIONS: Rosemary leaves have dual antidiarrheal and laxative effects, and as well as anxiolytic activity. In addition, the possible modulation of muscarinic and histaminergic receptors, and KATP channels show it as potential herb to be explored for irritable bowel syndrome. Diosmetin is possibly one of its constituents that contributes to its antidiarrheal activity.

Constipation arising from the poor bowel movement is a rife enteric health problem. Shouhui Tongbian Capsule (SHTB) is a traditional Chinese medicine (TCM) which effectively improve the symptoms of constipation. However, the mechanism has not been fully evaluated. The purpose of this study was to evaluate the effect of SHTB on the symptoms and intestinal barrier of mice with constipation. Our data showed that SHTB effectively improved the constipation induced by diphenoxylate, which was confirmed by shorter first defecation time, higher internal propulsion rate and fecal water content. Additionally, SHTB improved the intestinal barrier function, which was manifested by inhibiting the leakage of Evans blue in intestinal tissues and increasing the expression of occludin and ZO-1. SHTB inhibited NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway, reduced the number of proinflammatory cell subsets and increased the number of immunosuppressive cell subsets to relieve inflammation. The photochemically induced reaction coupling system combined with cellular thermal shift assay and central carbon metabolomics technology confirmed that SHTB activated AMPKα through targeted binding to Prkaa1 to regulate Glycolysis/Gluconeogenesis and Pentose Phosphate Pathway, and finally inhibited intestinal inflammation. Finally, no obvious toxicity related to SHTB was found in a repeated drug administration toxicity test for consecutive 13 weeks. Collectively, we reported SHTB as a TCM targeting Prkaa1 for anti-inflammation to improve intestinal barrier in mice with constipation. These findings broaden our knowledge of Prkaa1 as a druggable target protein for inflammation inhibition, and open a new avenue to novel therapy strategy for constipation injury.

This study investigated the effects of the sugarcane flavones diosmin, diosmetin, luteolin, and tricin, and their interactions with sugarcane fiber on the modulation of gut microbiota using in vitro batch fermentation. The alteration of fecal fermentation bacterial profile was analyzed using 16S rRNA sequencing data, while the bioavailability of fiber was indicated by short-chain fatty acid (SCFA) production and metabolism of polyphenols was measured directly by phenolic metabolites. Application of diosmin, diosmetin, luteolin, and tricin without fiber had no significant effect on the overall microbiota profile after 24 h of fermentation. When fiber alone was added, total SCFA production increased, specifically that of propionic and valeric acids. However, when flavones were combined with fiber, synergistic effects on the modulation of relative abundances of different bacterial taxa was noted. In particular, the proportion of Prevotella spp. was significantly increased by the combinations of diosmin, luteolin, and tricin with fiber.

Among gynecologic malignancies, ovarian cancer is one of the most dangerous, with a high fatality rate and relapse due to the occurrence of chemoresistance. Many researchers demonstrated that oxidative stress is involved in tumor occurrence, development and procession. Nuclear factor erythroid 2-related factor 2 (NRF2) is an important transcription factor playing an important role in protecting against oxidative damage. Increased levels of Reactive Oxygen Species (ROS) activate NRF2 signaling inducing the expression of antioxidant enzymes such as heme oxygenase (HO-1), catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) that protect cells against oxidative stress. However, NRF2 activation in cancer cells is responsible for the development of chemoresistance inactivating drug-mediated oxidative stress that normally leads cancer cells to death. In this review we analyzed the current literature regarding the role of natural and synthetic compounds in modulating NRF2/KEAP1 (Kelch Like ECH Associated Protein 1) pathway in in vitro models of ovarian cancer. In particular, we reported how these compounds can modulate chemotherapy response.

With the coming of the era of the aging population, hypertension has become a global health burden to be dealt with. Although there are multiple drugs and procedures to control the symptoms of hypertension, the management of it is still a long-term process, and the side effects of conventional drugs pose a burden on patients. Flavonoids, common compounds found in fruits and vegetables as secondary metabolites, are active components in Chinese Herbal Medicine. The flavonoids are proved to have cardiovascular benefits based on a plethora of animal experiments over the last decade. Thus, the flavonoids or flavonoid-rich plant extracts endowed with anti-hypertension activities and probable mechanisms were reviewed. It has been found that flavonoids may affect blood pressure in various ways. Moreover, despite the substantial evidence of the potential for flavonoids in the control of hypertension, it is not sufficient to support the clinical application of flavonoids as an adjuvant or core drug. So the synergistic effects of flavonoids with other drugs, pharmacokinetic studies, clinical trials and the safety of flavonoids are also incorporated in the discussion. It is believed that more breakthrough studies are needed. Overall, this review may shed some new light on the explicit recognition of the mechanisms of anti-hypertension actions of flavonoids, pointing out the limitations of relevant research at the current stage and the aspects that should be strengthened in future researches.

There has always been a keen interest of basic and clinical researchers to search for cancer therapeutics having minimum off-target effects and maximum anticancer activities. In accordance with this approach, there has been an explosion in the field of natural products research in the past few decades because of extra-ordinary list of natural extracts and their biologically and pharmacologically active constituents having significant medicinal properties. Apparently, luteolin-mediated anticancer effects have been investigated in different cancers but there is superfluousness of superficial data. Generalized scientific evidence encompassing apoptosis, DNA damage and anti-inflammatory effects has been reported extensively. However, how luteolin modulates deregulated oncogenic pathways in different cancers has not been comprehensively uncovered. In this review we have attempted to focus on cutting-edge research which has unveiled remarkable abilities of luteolin to modulate deregulated oncogenic pathways in different cancers. We have partitioned the review into various sections to separately discuss advancements in therapeutic targeting of oncogenic protein networks. We have provided detailed mechanistic insights related to JAK-STAT signaling and summarized how luteolin inhibited STAT proteins to inhibit STAT-driven gene network. We have also individually analyzed Wnt/β-catenin and NOTCH pathway and how luteolin effectively targeted these pathways. Mapping of the signaling landscape has revealed that NOTCH pathway can be targeted therapeutically. NOTCH pathway was noted to be targeted by luteolin. We have also conceptually analyzed how luteolin restored TRAIL-induced apoptosis in resistant cancers. Luteolin induced an increase in pro-apoptotic proteins and efficiently inhibited anti-apoptotic proteins to induce apoptosis. Luteolin mediated regulation of non-coding RNAs is an exciting and emerging facet. Excitingly, there is sequential and systematic accumulation of clues which have started to shed light on intricate regulation of microRNAs by luteolin in different cancers. Collectively, sophisticated information will enable us to develop a refined understanding of the multi-layered regulation of signaling pathways and non-coding RNAs by luteolin in different cancers.

In this work, the phenolic composition of four rare cultivars grown under the same agronomical and environmental conditions was studied. This is to test the effects of cultivars and ripening index essentially on phenolic composition in olive oils as well as tocopherols composition, organoleptic profiling and oxidative properties. Furthermore, some agronomical traits were determined in which a general increase in the size of the fruit and oil contents were recorded for all cultivars. The phenolic fractions were identified and quantified using liquid chromatography coupled to diode array detection and electrospray ionization tandem mass spectrometry (LC-DAD-ESI-MS/MS) in multiple reaction monitoring mode (MRM). A total of 13 phenolic compounds belonging to different chemical families were determined. Qualitative and quantitative differences in phenolic composition were observed among cultivars and also among sampling times. On the contrary to the agronomical traits, a general decrease (p<0.05) of total phenolic compounds was observed during maturation. Likewise, a decrease in tocopherols concentrations and oxidative properties was observed.

Citrus flavonoids are acknowledged for numerous pharmacological activities, including the myorelaxant effect on various smooth muscles. However, there is no data on their effect on jejunum contractility. Therefore, the aim of the study at hand was to evaluate the impact of hesperetin and diosmetin along with their glycosides on the motoric activity of intestine and to verify the possible mechanism of hesperetin-induced effect. The experiments were performed on rat isolated jejunum strips and were conducted under isometric conditions. Hesperetin and diosmetin, but not hesperidin and diosmin, dose-dependently (10-100µM) and reversibly inhibited acetylcholine (1µM) and KCl (80mM) induced contractile activity. The antispasmodic effect of hesperetin was partially blocked by 4-aminopyridine (100µM), glibenclamide (100µM) and NG-nitro-L-arginine methyl ester (L-NAME, 100µM). By contrast, apamin (0.1µM), tetraethylammonium (500µM) and methylene blue (10µM) did not affect the magnitude of hesperetin-induced myorelaxant effect. Indomethacin (10µM) increased the force of hesperetin-evoked reaction. In conclusion, hesperetin and diosmetin are potent myorelaxant agents. The antispasmodic effect of hesperetin is partially mediated by fast current low-voltage activated K+ channels, voltage-independent K+ channels and involves the nitric oxide pathway. Finally, hesperetin shows a synergistic effect with indomethacin towards jejunal KCl-precontracted smooth muscle.

BACKGROUND: Maydis stigma (corn silk) has a long history of use as a traditional herbal medicine or functional food in China and many other countries and has been listed in the Chinese Pharmacopea. However, little data about its potential toxicity is available.
OBJECTIVE: In this study, we evaluated the subchronic toxicity and genotoxicity of the flavonoid-rich extract from Maydis stigma (FMS) in mice.
METHODS: In the subchronic toxicity study, the FMS was administered orally to mice at doses of 2.50, 5.00 and 10.00g/kg/day for 28 consecutive days. At the end of experiment, general clinical signs, mortality, haematological, biochemical and histopathological parameters were examined. The genotoxicity of FMS was also evaluated by the micronucleus assay and the sperm malformation assay.
RESULTS: All animals survived until the scheduled necropsy, and no statistically significant or toxicologically relevant differences were observed in any of the FMS-treatment groups, compared with the control group. The no-observed-adverse-effect level (NOAEL) was determined as 10.00g/kg/day. Based on the results of the micronucleus assay and the sperm malformation assay, no evidence of genotoxicity was found either in somatic cells or germ cells even at an experimental upper limit dose (10.00g/kg/day).
CONCLUSIONS: The results of the present studies might support the safe use of FMS as a functional food, food additive and natural remedy.

A new monoterpene-flavonoid, saturejin (3\'-(2,5-dihydroxy-p-cymene) 5,7,4\'-trihydroxy flavone) (4), together with twelve known flavonoids consist of two flavanonols (aromadendrin (8) and taxifolin (12)), two flavanones (naringenin (3) and 5,7,3\',5\'-tetrahydroxy flavanone (9)) and eight flavones (xanthomicrol (1), acacetin (2), cirsimaritin (5), 7-methoxy luteolin (6), apigenin (7), cirsilineol (10), diosmetin (11) and 6-hydroxyluteolin 7,3\'-dimethyl ether (13)), were isolated from an ethyl acetate extract and identified for the first time in the dried aerial parts of Satureja khuzistanica Jamzad, an endemic medicinal plant traditionally used as dental anesthetic, oral antiseptic and anti-inflammatory among the nomadic inhabitants of southwestern Iran. The structures of these compounds were determined using the usual spectroscopic methods including 2D-NMR and MS analyses. Saturejin showed a significant β-glucosidase inhibitory activity at concentration of 10 μg as well as positive antioxidant activity at the amount of 1 μg. These results could be correlated with the in vitro and in vivo anti-inflammatory, anti-oxidant and anti-diabetic properties reported from this medicinal plant. Similar activities were also described for some of the other isolated compounds.