Triacanthine enhances the sensitivity of colorectal cancer cells to 5-fluorouracil by regulating RRM2.

BACKGROUND: According to the literatures, triacanthine is isolated from the leaves of Gleditsia triacanthos L. and acts as an anti-hypertensive agent, also cardiotonic, antispasmodic and a respiratory analeptic. The 5-fluorouracil (5-FU) is widely used to treat the patients of colorectal cancer (CRC), but the resistance to 5-FU treatment restricts the therapeutic efficacy of CRC patients. PURPOSE: This study aims to explore a novel therapeutics regimen overcoming CRC resistance to 5-FU. METHODS: The cell proliferation of CRC cells was determined by SRB and colony formation assay. Transwell and wound-healing assay were applied to explore the potential metastatic abilities of CRC cells. qRT-PCR and Western blot were performed to evaluate the level of indicated mRNAs and proteins respectively. Xenograft assay was used to explore the anti-CRC effect of triacanthine. RESULTS: Triacanthine statistically restrained CRC proliferation both in vitro and in vivo. Triacanthine induced cell cycle G1/G0 phase arrest in CRC cells. Meanwhile, triacanthine also inhibited the migrative and invasive abilities of CRC cells. A Venn diagram was generated showing that O-6-Methylguanine-DNA Methyltransferase (MGMT) might be a molecular target of triacanthine in treating CRC. Furthermore, triacanthine plus 5-FU significantly suppressed the cell proliferation of CRC cells compared with single agent treatment alone, and highly synergistic anti-cancer effects were scored when 5-FU was combined with triacanthine in CRC cells. In addition, triacanthine sensitized the anti-cancer activity of 5-FU via regulating Ribonucleotide Reductase Regulatory Subunit M2 (RRM2). MGMT or RRM2 might be novel biomarkers for evaluating the therapeutical efficiency of 5-FU in CRC patients. CONCLUSION: We firstly demonstrated triacanthine suppressed cell proliferation and metastasis abilities and found the novel molecular targets of triacanthine in CRC cells. This is the first study to evaluate the anti-cancer efficiency of triacanthine plus 5-FU. Our study has revealed triacanthine as a pertinent sensitizer to 5-FU, and provided novel strategies for predicting outcomes and reversing resistance of 5-FU therapy.

Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/ß5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

Withanolides from Physalis angulata var. villosa and the Relative Configurational Revision of Some Known Analogs.

Physalis angulata var. villosa is a plant possessing abundant withanolides, but in-depth research is lacking. In our ongoing study of P. angulata var. villosa, 15 previously undescribed withanolides (1-15), along with 21 known analogs (16-36), were isolated from the whole plant. The structures of the withanolides (1-15) were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and ECD data. Additionally, the application of γ-gauche effects with the help of ROESY correlations led to the formulation of empirical rules for withanolides with 14-OH/15-OAc to rapidly determine the 14-OH orientations, making it possible to propose configurational revisions of 19 previously reported analogs (1'-19'). Withanolides 1, 4-6, and 10 showed potent cytotoxic activities against three human cancer cell lines (HCT-116, MDA-MB-231, and A549).

Effects and mechanisms of anti-diabetic dietary natural products: an updated review.

Diabetes is a global public health issue, characterized by an abnormal level of blood glucose. It can be classified into type 1, type 2, gestational, and other rare diabetes. Recent studies have reported that many dietary natural products exhibit anti-diabetic activity. In this narrative review, the effects and underlying mechanisms of dietary natural products on diabetes are summarized based on the results from epidemiological, experimental, and clinical studies. Some fruits (e.g., grape, blueberry, and cherry), vegetables (e.g., bitter melon and Lycium barbarum leaves), grains (e.g., oat, rye, and brown rice), legumes (e.g., soybean and black bean), spices (e.g., cinnamon and turmeric) and medicinal herbs (e.g., Aloe vera leaf and Nigella sativa), and vitamin C and carotenoids could play important roles in the prevention and management of diabetes. Their underlying mechanisms include exerting antioxidant, anti-inflammatory, and anti-glycation effects, inhibiting carbohydrate-hydrolyzing enzymes, enhancing insulin action, alleviating insulin resistance, modulating the gut microbiota, and so on. This review can provide people with a comprehensive knowledge of anti-diabetic dietary natural products, and support their further development into functional food to prevent and manage diabetes.

[A new allo-aromadendrane sesquiterpene from Dendrobium nobile].

To study the chemical constituents in the non-alkaloid part of stems of Dendrobium nobile. The macroporous adsorption resin, MCI, silica gel, RP-C_(18), and Sephadex LH-20 gel, preparative thin layer chromatography, and preparative high-performance liquid chromatography(HPLC) were used to isolate and purify the compounds. The structures of the compound were determined according to the spectra data, physicochemical properties, and relevant references. A total of 8 compounds were isolated from D. nobile, which were soltorvum F(1), p-hydroxyphenylpropionic acid(2), vanillic acid(3), p-hydroxybenzoic acid(4), N-trans-cinnamic acid acyl-p-hydroxybenzene ethylamine(5),(+)-(1R,2S,3R,4S,5R,6S,9R)-2,11,12-trihydroxypicrotoxane-3(15)-lactone(6), dendronobilin H(7), soltorvum E(8). Compound 1 was a novel compound, named as soltorvum F. Compound 8 was isolated from Dendrobium species for the first time.

[Muscone inhibits opening of mPTP to alleviate OGD/R-induced injury of HT22 cells].

This study aims to investigate the mechanism of muscone in inhibiting the opening of mitochondrial permeability transition pore(mPTP) to alleviate the oxygen and glucose deprivation/reoxygenation(OGD/R)-induced injury of mouse hippocampal neurons(HT22). An in vitro model of HT22 cells injured by OGD/R was established. CCK-8 assay was employed to examine the viability of HT22 cells, fluorescence microscopy to measure the mitochondrial membrane potential, the content of reactive oxygen species(ROS), and the opening of mPTP in HT22 cells. Enzyme-linked immunosorbent assay was employed to determine the level of ATP and the content of cytochrome C(Cyt C) in mitochondria of HT22 cells. Flow cytometry was employed to determine the Ca~(2+) content and apoptosis of HT22 cells. The expression of Bcl-2(B-cell lymphoma-2) and Bcl-2-associated X protein(Bax) was measured by Western blot. Molecular docking and Western blot were employed to examine the binding between muscone and methyl ethyl ketone(MEK) after pronase hydrolysis of HT22 cell proteins. After the HT22 cells were treated with U0126, an inhibitor of MEK, the expression levels of MEK, p-ERK, and CypD were measured by Western blot. The results showed that compared with the OGD/R model group, muscone significantly increased the viability, mitochondrial ATP activity, and mitochondrial membrane potential, lowered the levels of ROS, Cyt C, and Ca~(2+), and reduced mPTP opening to inhibit the apoptosis of HT22 cells. In addition, muscone up-regulated the expression of MEK, p-ERK, and down-regulated that of CypD. Molecular docking showed strong binding activity between muscone and MEK. In conclusion, muscone inhibits the opening of mPTP to inhibit apoptosis, thus exerting a protective effect on OGD/R-injured HT22 cells, which is associated with the activation of MEK/ERK/CypD signaling pathway.

Dendrobium huoshanense Polysaccharide Improves High-Fat Diet Induced Liver Injury by Regulating the Gut-Liver Axis.

Dendrobium huoshanense is an important Traditional Chinese medicine that thickens the stomach and intestines. Its active ingredient Dendrobium huoshanense polysaccharide (DHP), was revealed to relieve the symptoms of liver injury. However, its mechanism of action remains poorly understood. This study aimed to investigate the mechanism of DHP in protecting the liver. The effects of DHP on lipid levels, liver function, and intestinal barrier function were investigated in mice with high-fat diet-induced liver damage. Changes in the gut flora and their metabolites were analyzed using 16S rRNA sequencing and metabolomics. The results showed that DHP reduced lipid levels, liver injury, and intestinal permeability. DHP altered the intestinal flora structure and increased the relative abundance of Bifidobacterium animalis and Clostridium disporicum. Furthermore, fecal metabolomics revealed that DHP altered fecal metabolites and significantly increased levels of gut-derived metabolites, spermidine, and indole, which have been reported to inhibit liver injury and improve lipid metabolism and the intestinal barrier. Correlation analysis showed that spermidine and indole levels were significantly negatively correlated with liver injury-related parameters and positively correlated with the intestinal species B. animalis enriched by DHP. Overall, this study confirmed that DHP prevented liver injury by regulating intestinal microbiota dysbiosis and fecal metabolites.

The Role of Gut Microbiota in Anxiety, Depression, and Other Mental Disorders as Well as the Protective Effects of Dietary Components.

The number of individuals experiencing mental disorders (e.g., anxiety and depression) has significantly risen in recent years. Therefore, it is essential to seek prevention and treatment strategies for mental disorders. Several gut microbiota, especially Firmicutes and Bacteroidetes, are demonstrated to affect mental health through microbiota-gut-brain axis, and the gut microbiota dysbiosis can be related to mental disorders, such as anxiety, depression, and other mental disorders. On the other hand, dietary components, including probiotics (e.g., Lactobacillus and Bifidobacterium), prebiotics (e.g., dietary fiber and alpha-lactalbumin), synbiotics, postbiotics (e.g., short-chain fatty acids), dairy products, spices (e.g., Zanthoxylum bungeanum, curcumin, and capsaicin), fruits, vegetables, medicinal herbs, and so on, could exert protective effects against mental disorders by enhancing beneficial gut microbiota while suppressing harmful ones. In this paper, the mental disorder-associated gut microbiota are summarized. In addition, the protective effects of dietary components on mental health through targeting the gut microbiota are discussed. This paper can be helpful to develop some dietary natural products into pharmaceuticals and functional foods to prevent and treat mental disorders.

New N-oxide alkaloids from the stems of Sinomenium acutum.

Six new alkaloids (1-6) and six known alkaloids (7-12) were obtained from the stems of Sinomenium acutum. Among them, compounds 1-3 and 6 were four N-oxide alkaloids. The structures and absolute configurations of these new alkaloids were elucidated through comprehensive data of 1D and 2D NMR, HRESIMS and ECD spectra. All isolated compounds were evaluated in vitro for their inhibitory activities against nitric oxide (NO) production and inhibitory effects on AChE. Among them, the sinomenine N-oxide (9) was the most potent NO production inhibitor, with an IC50 value of 23.04 µM.

A Study on the Potential Mechanism of Shujin Dingtong Recipe against Osteoarthritis Based on Network Pharmacology and Molecular Docking.

Background: With the aging of the social population, Osteoarthritis (OA) has already become a vital health and economic problem globally. Shujin Dingtong recipe (SJDTR) is an effective formula to treat OA in China. Although studies have shown that SJDTR can significantly alleviate OA symptoms, its mechanism still remains unclear. Purpose: This study is aimed at investigating the potential mechanism of SJDTR for the treatment of OA based on network pharmacology and molecular docking. Methods: Main ingredients of SJDTR were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. OA disease targets were obtained from the Gene Expression Omnibus (GEO) database. The overlapped targets and signaling pathways were explored using Protein-Protein Interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Following this, the core targets were employed to dock with corresponding components via molecular docking in order to further explore the mechanism of SJDTR in the treatment of OA. Results: From network pharmacology, we found 100 active components of SJDTR, 31 drug and OA-related targets, 1161 GO items, and 91 signaling pathways. Based on the analysis with PPI network and molecular docking, TP53, CCNB1, and MMP-2 were selected for the core targets of SJDTR against OA. Molecular docking demonstrated that Quercetin, Baicalein, and Luteolin, had good binding with the TP53, CCNB1, and MMP-2 protein, respectively. Conclusion: To conclude, our study suggested the main ingredients of SJDTR might alleviate the progression of OA through multiple targets and pathways. Additionally, network pharmacology and molecular docking, as new approaches, were adopted for systematically exploring the potential mechanism of SJDTR for the treatment of OA.

Amphiphilic Metallodrug Assemblies with Red-Light-Enhanced Cellular Internalization and Tumor Penetration for Anticancer Phototherapy.

Metallodrugs are widely used in cancer treatment. The modification of metallodrugs with polyethylene glycol (PEGylation) prolongs blood circulation and improves drug accumulation in tumors; it represents a general strategy for drug delivery. However, PEGylation hinders cellular internalization and tumor penetration, which reduce therapeutic efficacy. Herein, the red-light-enhanced cellular internalization and tumor penetration of a PEGylated anticancer agent, PEGylated Ru complex (Ru-PEG), are reported upon. Ru-PEG contains a red-light-cleavable PEG ligand, anticancer Ru complex moiety, and fluorescent pyrene group for imaging and self-assembly. Ru-PEG self-assembles into vesicles that circulate in the bloodstream and accumulate in the tumors. Red-light irradiation induces dePEGylation and changes the Ru-PEG vesicles to large compound micelles with smaller diameters and higher zeta potentials, which enhance tumor penetration and cellular internalization. Red-light irradiation also generates intracellular 1 O2 , which induces the death of cancer cells. This work presents a new strategy to enhance the cellular internalization and tumor penetration of anticancer agents for efficient phototherapy.

Evaluation of the efficacy and safety of intradermal needle therapy on the sleep quality of patients following laparoscopic hysterectomy: study protocol for a randomized controlled trial.

Background: Sleep disorder is a commonly reported complication in patients who have undergone a hysterectomy, which increases perioperative complications and delays patient recovery. Several pharmacological and non-pharmacological approaches have been employed to improve the quality of sleep of patients during the postoperative period, but these strategies have certain limitations. Intradermal needle therapy is now among the most common treatments for insomnia in traditional Chinese medicine (TCM). The present study was developed to explore the effects of intradermal needle therapy (as an adjunct to physiotherapy-based treatments for postoperative sleep impairment) on the postoperative sleep quality of patients who have undergone a laparoscopic hysterectomy. Methods: This is a prospective, single-center, single-blind, randomized controlled trial. In total, 80 eligible patients will be randomly allocated to the control and experimental groups at a 1:1 ratio. Random numbers and grouping schemes will be generated using the SPSS 25.0 software package. Following the completion of the laparoscopic hysterectomy procedure, the patients will be returned to the medical ward and undergo authentic or sham intradermal needle therapy as appropriate. For patients in the experimental group, following sterilization, intradermal needles will be inserted into the bilaterally "Shenmen" (HT36) and "Sanyinjiao" (SP6) acupoints; the needles will be replaced after 24 h. False intradermal needles that exhibit similar surface characteristics but lack needles will be employed in the control group. Patients will undergo a single 3-day treatment course. The primary outcome is the Pittsburgh Sleep Quality Index. The secondary outcomes are the 10-Item Short-Form Identity-Consequence Fatigue Scale, the Hospital Anxiety and Depression Scale-Anxiety, and postoperative pain scores, which will be rated using a visual analog scale. Time to postoperative defecation and the duration of hospitalization will also be recorded. Discussion: The present study seeks to examine the efficacy of the intradermal needle as a therapeutic tool for improving the sleep quality of patients after surgery who have undergone a laparoscopic hysterectomy to provide a foundation for future large-scale clinical studies. Trial Registration: Chinese Clinical Trial Registry (identifier: ChiCTR2200056890).

Phenylpropanoids from Brachybotrys paridiformis maxim. Ex oliv. And their anti-HBV activities (II).

Five undescribed phenylpropanoids, one undescribed phenolic glucoside, and sixteen known compounds were isolated from Brachybotrys paridiformis Maxim. Ex Oliv. The undescribed compounds were named brachoside B-C, brach acid A-B, brachnan A, and brachin D, respectively. Additionally, the anti-hepatitis B virus activities of all isolated compounds were studied. Among them, brachnan A, brach acid A, globoidnan A, 3-carboxy-6,7-dihydroxy-1-(3',4'-dihydroxy-phenyl)-naphthalene, and 3,4-dihydroxybenzaldehyde showed significant anti-hepatitis B virus activities.

Anticancer Effects and Mechanisms of Berberine from Medicinal Herbs: An Update Review.

Cancer has been a serious public health problem. Berberine is a famous natural compound from medicinal herbs and shows many bioactivities, such as antioxidant, anti-inflammatory, antidiabetic, anti-obesity, and antimicrobial activities. In addition, berberine shows anticancer effects on a variety of cancers, such as breast, lung, gastric, liver, colorectal, ovarian, cervical, and prostate cancers. The underlying mechanisms of action include inhibiting cancer cell proliferation, suppressing metastasis, inducing apoptosis, activating autophagy, regulating gut microbiota, and improving the effects of anticancer drugs. This paper summarizes effectiveness and mechanisms of berberine on different cancers and highlights the mechanisms of action. In addition, the nanotechnologies to improve bioavailability of berberine are included. Moreover, the side effects of berberine are also discussed. This paper is helpful for the prevention and treatment of cancers using berberine.

Effects and mechanisms of resveratrol for prevention and management of cancers: An updated review.

Cancer is a severe public health problem. Resveratrol is a famous natural compound that has various bioactivities, such as antioxidant, anti-inflammatory, antidiabetic and antiaging activities. Especially, resveratrol could prevent and treat various cancers, such as oral, thyroid, breast, lung, liver, pancreatic, gastric, colorectal, bladder, prostate and ovarian cancers. The underlying mechanisms have been widely studied, such as inhibiting cell proliferation, suppressing metastasis, inducing apoptosis, stimulating autophagy, modulating immune system, attenuating inflammation, regulating gut microbiota and enhancing effects of other anticancer drugs. In this review, we summarize effects and mechanisms of resveratrol on different cancers. This paper is helpful to develop resveratrol, crude extract containing resveratrol, or foods containing resveratrol into functional food, dietary supplements or auxiliary agents for prevention and management of cancers.

Red-Light-Responsive Metallopolymer Nanocarriers with Conjugated and Encapsulated Drugs for Phototherapy Against Multidrug-Resistant Tumors.

It is challenging to treat multidrug-resistant tumors because such tumors are resistant to a broad spectrum of structurally and functionally unrelated drugs. Herein, treatment of multidrug-resistant tumors using red-light-responsive metallopolymer nanocarriers that are conjugated with the anticancer drug chlorambucil (CHL) and encapsulated with the anticancer drug doxorubicin (DOX) is reported. An amphiphilic metallopolymer PolyRuCHL that contains a poly(ethylene glycol) (PEG) block and a red-light-responsive ruthenium (Ru)-containing block is synthesized. Chlorambucil is covalently conjugated to the Ru moieties of PolyRuCHL. Encapsulation of DOX into PolyRuCHL in an aqueous solution results in DOX@PolyRuCHL micelles. The DOX@PolyRuCHL micelles are efficiently taken up by the multidrug-resistant breast cancer cell line MCF-7R and which carries DOX into the cells. Free DOX, without the nanocarriers, is not taken up by MCF-7R or pumped out of MCF-7R via P-glycoproteins. Red light irradiation of DOX@PolyRuCHL micelles triggers the release of chlorambucil-conjugated Ru moieties and DOX. Both act synergistically to inhibit the growth of multidrug-resistant cancer cells. Furthermore, the inhibition of the growth of multidrug-resistant tumors in a mouse model using DOX@PolyRuCHL micelles is demonstrated. The design of red-light-responsive metallopolymer nanocarriers with both conjugated and encapsulated drugs opens up an avenue for photoactivated chemotherapy against multidrug-resistant tumors.

Supervised Graph Clustering for Cancer Subtyping Based on Survival Analysis and Integration of Multi-Omic Tumor Data.

Identifying cancer subtypes by integration of multi-omic data is beneficial to improve the understanding of disease progression, and provides more precise treatment for patients. Cancer subtypes identification is usually accomplished by clustering patients with unsupervised learning approaches. Thus, most existing integrative cancer subtyping methods are performed in an entirely unsupervised way. An integrative cancer subtyping approach can be improved to discover clinically more relevant cancer subtypes when considering the clinical survival response variables. In this study, we propose a Survival Supervised Graph Clustering (S2GC)for cancer subtyping by taking into consideration survival information. Specifically, we use a graph to represent similarity of patients, and develop a multi-omic survival analysis embedding with patient-to-patient similarity graph learning for cancer subtype identification. The multi-view (omic)survival analysis model and graph of patients are jointly learned in a unified way. The learned optimal graph can be unitized to cluster cancer subtypes directly. In the proposed model, the survival analysis model and adaptive graph learning could positively reinforce each other. Consequently, the survival time can be considered as supervised information to improve the quality of the similarity graph and explore clinically more relevant subgroups of patients. Experiments on several representative multi-omic cancer datasets demonstrate that the proposed method achieves better results than a number of state-of-the-art methods. The results also suggest that our method is able to identify biologically meaningful subgroups for different cancer types. (Our Matlab source code is available online at github: https://github.com/CLiu272/S2GC).

Slow development allows redundant genes to restore the fertility of rpg1, a TGMS line in Arabidopsis.

Slow development has been shown to be a general mechanism to restore the fertility of thermo-sensitive and photoperiod-sensitive genic male sterile (TGMS and PGMS) lines in Arabidopsis. rpg1 is a TGMS line defective in primexine, which is essential for pollen wall pattern formation. Here, we showed that RPG1-GFP was highly expressed in microsporocytes, microspores, and pollen grains but not in the tapetum in the complemented transgenic line, suggesting that microsporocytes are the main sporophytic cells for primexine formation. Further cytological observations showed that primexine formation in rpg1 was partially restored under slow growth conditions, leading to its fertility restoration. RPG2 is the homolog of RPG1 in Arabidopsis. We revealed that the fertility recovery of rpg1 rpg2 was significantly reduced compared with that of rpg1 under low temperature. The RPG2-GFP protein was also expressed in microsporocytes in the RPG2-GFP (WT) transgenic line. These results suggest that RPG2 plays a redundant role in rpg1 fertility restoration. rpg1 plants were male sterile at the early growth stage, while their fertility was partially restored at the late developmental stage. The fertility of the rpg1 lateral branches was also partially restored. Further growth analysis showed that slow growth at the late reproductive stage or on the lateral branches led to fertility restoration. This work reveals the importance of gene redundancy in fertility restoration for TGMS lines and provides further insight into pollen wall pattern formation.

[Pharmacokinetic characteristics of psoralen,isopsoralen,psoralenoside and isopsoralenoside in rats after oral administration of Psoraleae Fructus extract].

Coumarins are the main active components in Psoraleae Fructus. To study the multi-component pharmacokinetics of Psoraleae Fructus, this study established a sensitive and rapid ultra-pressure liquid chromatography coupled to tandem mass spectrometry(UPLC-MS/MS) method for simultaneous determination of psoralen, isopsoralen, psoralenoside, and isopsoralenoside in rat plasma. After validation, the method was applied to the investigation of pharmacokinetics of psoralen, isopsoralen, psoralenoside, and isopso-ralenoside in rats after single and multiple administration of Psoraleae Fructus extract. The results revealed that the exposure of psoralen and isopsoralen in rat plasma was high after a single intragastric administration of Psoraleae Fructus extract, with an AUC_(0-∞) of 443 619-582 680 and 167 314-276 903 ng·mL~(-1)·h~(-1), respectively. Compared with these two compounds, the exposure of psoralenoside and isopsoralenoside was lower with marked gender difference. After 7-day administration of Psoraleae Fructus extract to rats, the AUC_(0-∞) of psoralen and isopsoralen was 29 701-81 783 and 39 234-89 914 ng·mL~(-1)·h~(-1), respectively, which was significantly lower than that at the first day(P<0.05), and that of psoralenoside and isopsoralenoside was 7 360-19 342 and 8 823-45 501 ng·mL~(-1)·h~(-1), respectively. There was no significant gender difference in exposure of psoralenoside and isopsoralenoside in male and female rats. However, the exposure of psoralenoside and isopsoralenoside in male rats was reduced(P<0.05), and the t_(1/2) and mean residence time(MRT) were shortened, suggesting that the removal of these two compounds from the body was accelerated.

Analysis based on Monte Carlo simulation: How effective is tigecycline in routine antimicrobial therapy?

OBJECTIVE: This paper aims to assess the efficacy of tigecycline in the treatment of several different infections from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. MATERIALS AND METHODS: The minimum inhibitory concentration (MIC) test strip test was used to determine the MICs of clinical isolates of tigecycline. A 5,000-subjects simulation was performed by Crystal Ball software to calculate the probability of achieving the required PK/PD exposure. RESULTS: The use of standard tigecycline dosing is predicted to have a good clinical outcome for patients suffering from complicated skin and skin structure infection (cSSSI) with MICs ≤ 0.25 mg×L-1, patients suffering from complicated intra-abdominal infection (cIAI) with MICs ≤ 1 mg×L-1, and patients suffering from hospital-acquired pneumonia (HAP) with MICs ≤ 0.5 mg×L-1. Generally, Gram-positive bacteria are highly sensitive to tigecycline, while Gram-negative bacteria are less sensitive: for patients with HAP and cIAI, the tolerable outcome was achieved using the standard regimen for most Gram-negative pathogens; the desired outcomes could be obtained for the increased-dose treatment; with increasing dose (100 mg every 12 hours), the average cumulative fractions of response (CFRs) markedly increased from 38.18 to 56.21% for cSSSI patients. When tigecycline, a standard regimen, was used to treat carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Enterobacter spp. (CRE) infections, the cumulative response scores were 4.96 - 66.39% and 13.14 - 95.18%, respectively, and the CFRs of the increased dose also increased correspondingly. CONCLUSION: Currently, the standard dose of tigecycline is feasible in the treatment of common bacterial infections, and PK/PD indexes are needed to optimize the regimens for refractory carbapenem-resistant bacterial infections.