Xianglian Pill combined with 5-fluorouracil enhances antitumor activity and reduces gastrointestinal toxicity in gastric cancer by regulating the p38 MAPK/NF-κB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. AIM OF THE STUDY: To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. MATERIALS AND METHODS: XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. RESULTS: The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. CONCLUSIONS: XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway.

Antimicrobial activity of natural products against MDR bacteria: A scientometric visualization analysis.

Objective: A growing number of studies have demonstrated the antimicrobial activity of natural products against multidrug-resistant bacteria. This study aimed to apply scientometric method to explore the current status and future trends in this field. Methods: All relevant original articles and reviews for the period 1997-2021 were retrieved from the Web of Science Core Collection database. VOSviewer, a scientometric software, and an online bibliometric analysis platform were used to conduct visualization study. Results: A total of 1,267 papers were included, including 1,005 original articles and 262 reviews. The United States and India made the largest contribution in this field. The University of Dschang from Cameroon produced the most publications. Coutinho HDM, Kuete V, and Gibbons S were key researchers, as they published a great many articles and were co-cited in numerous publications. Frontiers in Microbiology and Antimicrobial Agents and Chemotherapy were the most influential journals with the highest number of publications and co-citations, respectively. "Medicinal plants", "methicillin-resistant Staphylococcus aureus", "biofilm", "minimum inhibitory concentration", and "efflux pumps" were the most frequently used keywords, so these terms are presumed to be the current hot topics. All the included keywords could be roughly divided into four major themes, of which the theme of "natural product development approach" had attracted much attention in recent years. Furthermore, "Pseudomonas aeruginosa", "nanoparticles", "green synthesis", "antimicrobial peptides", "antibiofilm", "biosynthetic gene clusters", and "molecular dynamics simulation" had the latest average appearance year, indicating that these topics may become the research hot spots in the coming years. Conclusion: This study performed a scientometric analysis of the antibacterial activity of natural products against multidrug-resistant bacteria from a holistic perspective. It is hoped to provide novel and useful data for scientific research, and help researchers to explore this field more intuitively and effectively.

[Research progress on mechanism of Carthamus tinctorius in ischemic stroke therapy].

Carthamus tinctorius is proved potent in treating ischemic stroke. Flavonoids, such as safflower yellow, hydroxysafflor yellow A(HSYA), nicotiflorin, safflower yellow B, and kaempferol-3-O-rutinoside, are the main substance basis of C. tinctorius in the treatment of ischemic stroke, and HSYA is the research hotspot. Current studies have shown that C. tinctorius can prevent and treat ischemic stroke by reducing inflammation, oxidative stress, and endoplasmic reticulum stress, inhibiting neuronal apoptosis and platelet aggregation, as well as increasing blood flow. C. tinctorius can regulate the pathways including nuclear factor(NF)-κB, mitogen-activated protein kinase(MAPK), signal transducer and activator of transcription protein 3(STAT3), and NF-κB/NLR family pyrin domain containing 3(NLRP3), and inhibit the activation of cyclooxygenase-2(COX-2)/prostaglandin D2/D prostanoid receptor pathway to alleviate the inflammatory development during ischemic stroke. Additionally, C. tinctorius can relieve oxidative stress injury by inhibiting oxidation and nitrification, regulating free radicals, and mediating nitric oxide(NO)/inducible nitric oxide synthase(iNOS) signals. Furthermore, mediating the activation of Janus kinase 2(JAK2)/STAT3/suppressor of cytokine signaling 3(SOCS3) signaling pathway and phosphoinositide 3-kinase(PI3 K)/protein kinase B(Akt)/glycogen synthase kinase-3ß(GSK3ß) signaling pathway and regulating the release of matrix metalloproteinase(MMP) inhibitor/MMP are main ways that C. tinctorius inhibits neuronal apoptosis. In addition, C. tinctorius exerts the therapeutic effect on ischemic stroke by regulating autophagy and endoplasmic reticulum stress. The present study reviewed the molecular mechanisms of C. tinctorius in the treatment of ischemic stroke to provide references for the clinical application of C. tinctorius.

Rhein activated Fas-induced apoptosis pathway causing cardiotoxicity in vitro and in vivo.

Rhein, one of the main active components of rhubarb (Dahuang) and Polygonum multiflorum (Heshouwu), has a wide range of effective pharmacological effects. Recently, increasing studies have focused on its potential hepatorenal toxicity, but the cardiotoxicity is unknown. In this study, we found that the IC50 of rhein to H9c2 cells at 24 h and 48 h were 94.5 and 45.9µmol/L, respectively, with positive correlation of dose-toxicity and time-toxicity. After the treatment of rhein (106, 124 and 132µmol/L), the number of H9c2 cells decreased significantly, and the morphology of H9c2 cells showed atrophy, round shape and wall detachment. Moreover, the proportion of apoptotic cells in H9c2 cells treated with rhein was significantly increased in a dose-dependent manner. And rhein induced S phase arrest of H9c2 cells and inhibited cell proliferation. Rhein up-regulated ROS, LDH levels and low MMP but down-regulated SOD content in H9c2 cells. Additionally, the results showed that the cardiac function LVEF and LVFS of rhein high-medium-low dose groups (350, 175, 87.5 mg/kg) were significantly reduced. And the contents of Ca2+, cTnT, CK and LDH in serum of KM mice were significantly up-regulated by rhein. Furthermore, western blot results suggested that rhein the above effects via promoting Fas-induced apoptosis pathway in vitro and in vivo. In general, rhein may cause cardiotoxicity via Fas-induced apoptosis pathway in vivo and in vitro, which provides reference for the safe use of medicinal plant containing rhein and its preparations.

Update on Pharmacological Activities, Security, and Pharmacokinetics of Rhein.

Rhein, belonging to anthraquinone compounds, is one of the main active components of rhubarb and Polygonum multiflorum. Rhein has a variety of pharmacological effects, such as cardiocerebral protective effect, hepatoprotective effect, nephroprotective effect, anti-inflammation effect, antitumor effect, antidiabetic effect, and others. The mechanism is interrelated and complex, referring to NF-κB, PI3K/Akt/MAPK, p53, mitochondrial-mediated signaling pathway, oxidative stress signaling pathway, and so on. However, to some extent, its clinical application is limited by its poor water solubility and low bioavailability. Even more, rhein has potential liver and kidney toxicity. Therefore, in this paper, the pharmacological effects of rhein and its mechanism, pharmacokinetics, and safety studies were reviewed, in order to provide reference for the development and application of rhein.

Chemical composition and uterine smooth muscle relaxant activity of essential oils from 10 kinds of blood-activating and stasis-resolving Chinese medicinal herbs.

ETHNOPHARMACOLOGICAL RELEVANCE: Dysmenorrhea is one of the most common gynecological problems among menstruating females. Blood-activating and stasis-resolving herbs (BASRHs) have been employed to be the first choice for treating dysmenorrhea in China. Especially, the essential oils of some BASRHs have been confirmed to play important roles in the treatment of dysmenorrhea, but the constituents and uterine smooth muscle relaxant activity of some commonly used BASRH essential oils have not been fully assessed, and whether there are differences in the constituents and anti-dysmenorrhea effect among BASRH essential oils has not been evaluated. AIM OF THE STUDY: This study aims to systematically investigate the chemical constituents of 10 BASRH essential oils and assess their uterine smooth muscle relaxant activity and the preliminary mechanism of the most effective essential oil. MATERIALS AND METHODS: The chemical constituents of 10 BASRH essential oils were analyzed by Gas Chromatography-Mass Spectrometer. A rat model of dysmenorrhea in vitro was established to investigate the uterine smooth muscle relaxant activity of 10 kinds of essential oils. Rat isolated uterus strips were given different dose of 10 kinds of essential oils (0.04, 0.08, 0.16 mg/mL). The contractile responses were recorded with Power Lab recording system, and contractile tension, contractile frequency, and contractile activity were evaluated. The preliminary mechanism of the essential oil of the rhizomes of Curcuma phaeocaulis Valeton (CPEO) was assessed using a rat model of dysmenorrhea in vivo and in vitro, and rats were given the CPEO (15, 30, and 60 mg/kg) by gavage. The level of Ca2+ in uterine tissue of rats was determined by methyl thyme phenol blue colorimetric and Bradford methods. The effects of CPEO on extracellular Ca2+ influx and intracellular Ca2+ release were evaluated using the isolated uterus. RESULTS: The results of Gas Chromatography-Mass Spectrometer analysis showed that more than 81 components (content: 1% max appearance) were identified. The main components of the 10 BASRH essential oils were found to be monoterpenoids, sesquiterpenoids, diterpenoids, aromatics, aliphatics, and phthalides. The study of in vitro smooth muscle relaxant activity demonstrated that all the essential oils except the essential oil of the roots of Cyathula officinalis K.C.Kuan markedly decrease the contractile activity, tension, and frequency (P < 0.05 or P < 0.01). Among these oils, CPEO has the most pronounced effect. Further in vivo studies indicated that CPEO can significantly decrease the level of Ca2+ in uterine tissue when compared with the model group (P < 0.05 or P < 0.01). In vitro studies indicated that CPEO can inhibit the extracellular Ca2+ influx and intracellular Ca2+ release in favor of uterine relaxation. CONCLUSIONS: BASRH essential oils play an important role in inhibiting uterine smooth muscle contractions, and sesquiterpenoids and phthalides in BASRH essential oils are important active compounds for relaxing uterine smooth muscle. CPEO is a favorable candidate for developing anti-dysmenorrhea drugs.

Patchouli alcohol isolated from Pogostemon cablin mediates endothelium-independent vasorelaxation by blockade of Ca2+ channels in rat isolated thoracic aorta.

ETHNOPHARMACOLOGICAL RELEVANCE: The aerial parts of Pogostemon cablin (Blanco) Benth. for the treatment of cardiodynia have been documented in Mingyi Bielu of late Han Dynasty, in addition to that the Ca2+ antagonized activities of P. cablin and its critically pharmacological ingredient patchouli alcohol (PA) were reported previously. AIM OF THE STUDY: To investigate the relaxant effects of PA on rat isolated thoracic aortas and further explore its potential mechanisms of actions. MATERIALS AND METHODS: The aortas with endothelium and without endothelium were prepared and suspended in the organ bath for isometric tension recordings. The responses to accumulative concentrations of PA in endothelium-intact (E + ) aortas with basal tension and in different treated aortas pre-contracted with potassium chloride (KCl) or phenylephrine (PHE) were observed; the effects of L-NAME and indomethacin in aortas with intact endothelium, and of L-NAME, propranolol, tetraethtylamine (TEA), 4-aminopyridine (4-AP), barium chloride (BaCl2), glyburide in aortas with endothelial denudation on PA-produced vasorelaxation were assessed; the influences of PA on extracellular Ca2+ influx and intracellular Ca2+ release were measured in Ca2+-free medium. Finally, the abilities of PA to inhibit KCl- and PHE-induced contractions were compared to that of verapamil in E- aortas. RESULTS: PA produced vasorelaxant effects in KCl- and PHE-precontracted E + aortas in a concentration-dependent manner, which had no statistically different from that in KCl- and PHE-precontracted E- aortas. PA (10 µM) significantly reduced KCl-induced contractions while PHE-induced contractions were significantly reduced by 100 µM of PA instead of 10 µM and 30 µM in aortas with endothelium. Pre-incubation of E + aortas with L-NAME as well as indomethacin and of E- aortas with L-NAME, propranolol, TEA, 4-AP, BaCl2 and glyburide had no obvious effects on vasorelaxation of PA. In endothelium-removed aortas around Ca2+-free solution, PA remarkably lowered the contractions stimulated with Ca2+ and PHE, and application of ruthenium red and heparin further enhanced the abilities of PA to reduce PHE-caused contractions. In aortas without endothelium, 100 µM of PA markedly attenuated KCl-induced contractions but not affect PHE-induced contractions. Verapamil at the equal dose markedly attenuated KCl- and PHE-induced contractions, and the inhibitory effects on KCl-induced contractions were more forceful than that on PHE-induced contractions. In combined usage, the inhibitory effects on the contractions elicited by KCl were evidently weaker than that of verapamil alone and indifferently stronger than that of PA alone, and the inhibitory effects on the contractions elicited by PHE were evidently weaker than that of single verapamil but stronger than that of single PA. CONCLUSION: PA may act as a Ca2+ antagonist to exert an intensively vasorelaxant effects through endothelium-independent pathway, and its mechanisms underlying the vasoactivities seem to be associated with the blockade of extracellular Ca2+ influx through VDCCs and ROCCs in vascular smooth muscle cells (VSMCs) membrane and intracellular Ca2+ releases through IP3R- and RYR-mediated Ca2+ channels in sarcolemma.