Potential Involvement of Organic Anion Transporters in Drug Interactions with Shuganning Injection, a Traditional Chinese Patent Medicine.

Traditional Chinese medicine injections have been widely used in China for the treatment of various diseases. Transporter-mediated drug-drug interactions are a major contributor to adverse drug reactions. However, the research on transporter-mediated Traditional Chinese medicine injection-drug interactions is limited. Shuganning injection is a widely used Traditional Chinese medicine injection for treating various liver diseases. In this study, we investigated the inhibitory effect of Shuganning injection and its four main ingredients (baicalin, geniposide, chlorogenic acid, and oroxylin A) on 9 drug transporters. Shuganning injection strongly inhibited organic anion transporter 1 and organic anion transporter 3 with IC50 values < 0.1% (v/v), and moderately inhibited organic anion transporter 2, organic anion transporting-polypeptide 1B1, and organic anion transporting-polypeptide 1B3 with IC50 values < 1.0%. Baicalin, the most abundant bioactive ingredient in the Shuganning injection, was identified as both an inhibitor and substrate of organic anion transporter 1, organic anion transporter 3, and organic anion transporting-polypeptide 1B3. Oroxylin A had the potential to act as both an inhibitor and substrate of organic anion transporting-polypeptide 1B1 and organic anion transporting-polypeptide 1B3. In contrast, geniposide and chlorogenic acid had no significant inhibitory effect on drug transporters. Notably, Shuganning injection markedly altered the pharmacokinetics of furosemide and atorvastatin in rats. Using Shuganning injection as an example, our findings support the implementation of transporter-mediated Traditional Chinese medicine injection-drug interactions in the development of Traditional Chinese medicine injection standards.

Sub-lethal Camphor Exposure Triggers Oxidative Stress, Cardiotoxicity, and Cardiac Physiology Alterations in Zebrafish Embryos.

Camphor is a terpene ketone with aromatic and volatile properties in nature derived from the bark of Cinnamomum camphora or synthesized from turpentine. Camphor exhibits various biological properties such as anti-microbial, anti-viral, anti-coccidial, and anti-cancer. It is also used as a form of topical medication for skin irritation, joint pain, and as a relief for itching from insect bites. However, even though the high dose of camphor has been documented to be toxic/lethal in humans in different studies, camphor's developmental toxicity has not yet been explored, and its extensive mechanism of action is still unclear. In the present study, we aimed to assess the toxic effects of camphor in zebrafish embryos in the initial developmental stages. The obtained results demonstrated that a sub-lethal dose of camphor caused a decrease in hatching rate, body length, and substantial elevation in malformation rate on zebrafish embryos. On further observation, in the following time frame, curved body and pericardial edema of zebrafish were also observed. Furthermore, exposure to a sub-lethal dose of camphor was also able to trigger cardiotoxicity in zebrafish larvae. Later, on subsequent biochemical analysis, it was found that the antioxidant capacity inhibition and oxidative stress elevation that occurred after camphor exposure might be associated with the inhibition of total superoxide dismutase (SOD) activity and an increase in reactive oxygen species (ROS) and malondialdehyde (MDA) concentration. In addition, compared to the control group, several apoptotic cells in treated zebrafish were also found to be elevated. Finally, after further investigation on marker gene expressions, we conclude that the developmental toxicity of camphor exposure might be associated with apoptosis elevation and oxidative stress. Taken together, the current study provides a better understanding of the developmental toxicity of camphor on zebrafish, a promising alternative animal model to assess the developmental toxicity of chemical compounds.

Cardiotoxicity induced by Cochinchina momordica seed extract in zebrafish.

Momordica cochinchinensis (Lour.) Spreng is an indigenous South Asian edible fruit, and seeds of Momordica cochinchinensis have been used therapeutically in traditional Chinese medicine. Previous studies have shown that M. cochinchinensis seed (Momordicae Semen) has various pharmaceutical properties such as antioxidant and anti-ulcer effects as well as contains secondary metabolites with potential anticancer activities such as triterpenoids and saponins. Recent studies reported that water extract and ethanol extract of M. cochinchinensi seed were tested on mammals using an acute toxic classic method as OECD guidelines 420. No matter injected intravenously or intramuscularly, animals died within several days. In this study, zebrafish embryos were exposed to various doses of Cochinchina momordica seed extract (CMSE) from 2 dpf (days post fertilization, dpf) to 3 dpf. CMSE-induced cardiotoxicity such as pericardial edema, cardiac apoptosis, increased ROS production, cardiac neutrophil infiltration, decreased blood flow velocity, and reduced expression of three marker genes of cardiac functions were found in zebrafish roughly in a dose-dependent manner. These results suggest that CMSE may induce cardiotoxicity through pathways involved in inflammation, oxidative stress, and apoptosis.

Roots and stems of Kadsura coccinea extract induced developmental toxicity in zebrafish embryos/larvae through apoptosis and oxidative stress.

CONTEXT: Although the roots and stems of Kadsura coccinea (Lem.) A. C. Smith. [Schisandraceae] are herbs and traditional foods in Li nationality, its toxicity remains unclear. OBJECTIVE: To study developmental toxicity of K. coccinea consumption and explain underlying mechanisms. MATERIALS AND METHODS: Zebrafish were applied to assess LC50 values of hydroethanol extract (KCH) and water extract (KCW) of Kadsura coccinea. In further study, three concentrations groups of KCH (3.75, 7.5 and 15 µg/mL for embryo, 7.5, 15 and 30 µg/mL for larvae) and control group (n = 30) were administered. At specific stages of zebrafish development, spontaneous movement, hatching rate, etc., were measured. Gene expressions related to developmental toxicity were examined. RESULTS: The LC50 value of KCH (24 or 45 µg/mL) was lower than KCW (1447 or 2011 µg/mL) in embryos or larvae. The inhibited spontaneous movement (20%), hatching rate (20%), body length (12%) and eye area (30%) were observed after KCH treatment. Moreover, the decreased liver areas (25%) and fluorescence intensity (33%), increased ALT (37%) and AST levels (42%) were found in larvae treated with KCH (30 µg/mL). The increased ROS (89%), MDA concentrations (30%), apoptosis generation (62%) and decreased T-SOD activity (16%) were also observed. The represented genes of developmental hepatotoxicity, oxidative stress and apoptosis in zebrafish were activated after KCH (15 or 30 µg/mL) treatment. DISCUSSION AND CONCLUSIONS: These results demonstrate that KCH has developmental toxicity on zebrafish. Our study provides a scientific basis for further research on the toxicity of Kadsura coccinea.

Hyperbaric-Oxygen Therapy Improves Survival and Functional Outcome of Acute Severe Intracerebral Hemorrhage.

BACKGROUND: Prognosis of spontaneous intracerebral hemorrhage (ICH) remains poor worldwide. AIMS OF THE STUDY: To investigate the effect and optimal protocol for hyperbaric-oxygen therapy (HBOT), and reduce incidence of upper gastrointestinal bleeding (UGIB) in ICH. METHODS: This prospective, randomized, controlled trial included 565 patients with acute severe ICH. Participants were randomly assigned to a sham-control group (Group A) and four intervention groups: Groups B and C with 2.0 atmospheres absolute (ATA) pressure and HBOT exposure for 60 or 90 sessions, respectively; and Groups D and E with 1.5 ATA for 60 or 90 sessions, respectively. All patients received emergency craniotomy with hematoma evacuation. Outcome measures were modified Barthel Index (MBI) and modified Rankin Scale (mRS) scores, mortality rates at follow-up six months. UGIB rates were assessed as potential side effect. RESULTS: In four intervention groups, MBI and mRS scores were all significantly improved, and mortality rates were all significantly decreased compared with Group A (all p < 0.005). UGIB rates were 39.25, 60.00, 64.49, 36.79, and 34.26% in Groups A, B, C, D, and E, respectively. UGIB rates in Groups B and C were significantly increased compared with Groups A, D and E (all p < 0.005). None of UGIB were clinically significant. CONCLUSIONS: HBOT significantly improves survival and functional outcomes of ICH. HBOT at 1.5 and 2.0 ATA had the same beneficial effect. A pressure of 1.5 ATA and 60 HBOT exposures represents an optimal protocol for HBOT. Further studies are needed to optimize the protocol per specific patient.

A translationally controlled tumor protein gene Rpf41 is required for the nodulation of Robinia pseudoacacia.

Translationally controlled tumor protein (TCTP) is fundamental for the regulation of development and general growth in eukaryotes. Its multiple functions have been deduced from its involvement in several cell pathways, but its potential involvement in symbiotic nodulation of legumes cannot be suggested a priori. In the present work, we identified and characterized from the woody leguminous tree Robinia pseudoacacia a homolog of TCTP, Rpf41, which was up-regulated in the infected roots at 15 days post-inoculation but decreased in the matured nodules. Subcellular location assay showed that Rpf41 protein was located in the plasma membrane, cytoplasm, nucleus, and also maybe in cytoskeleton. Knockdown of Rpf41 via RNA interference (RNAi) resulted in the impaired development of both nodule and root hair. Compared with wild plants, the root and stem length, fresh weight and nodule number per plant was decreased dramatically in Rpf41 RNAi plants. The number of ITs or nodule primordia was also significantly reduced in the Rpf41 RNAi roots. The analyses of nodule ultrastructure showed that the infected cell development in Rpf41 RNAi nodules remained in zone II, which had fewer infected cells. Furthermore, the symbiosomes displayed noticeable shrinkage of bacteroid and peribacteroid space enlargement in the infected cells of Rpf41 RNAi nodules. In the deeper cell layers, a more remarkable aberration of the infected cell ultrastructure was observed, and electron-transparent lesions in the bacteroid cytoplasm were detected. These results identify TCTP as an important regulator of symbiotic nodulation in legume for the first time, and it may be involved in symbiotic cell differentiation and preventing premature aging of the young nodules in R. pseudoacacia.

CdO nanosheet film with a (200)-preferred orientation with sensitivity to liquefied petroleum gas (LPG) at low-temperatures.

CdO nanosheet film can be synthesized by electrochemical deposition in an ultra-thin liquid layer by using Cd(NO(3))(2) and HNO(3) as source materials for Cd and oxygen respectively. HNO(3) is also used to adjust the pH of the electrolyte. Studies on the detailed structure indicate that the synthesized CdO nanosheet film has a face-centered cubic structure with (200)-preferred orientation. The response of the CdO nanosheet film to liquefied petroleum gas (LPG) at low temperature has been significantly improved by the novel structure of film. It has exhibited excellent sensitivity and selectivity to LPG at low temperature. A new growth mechanism of electrochemical deposition has been proposed to elaborate the formation of nanosheet in an ultra-thin liquid layer. The self-oscillation of potential in the growth interface and intermediate hydroxide are responsible for the formation of nanosheets.