Nanoarchitectonics of Bimetallic Cu-/Co-Doped Nitrogen-Carbon Nanozyme-Functionalized Hydrogel with NIR-Responsive Phototherapy for Synergistic Mitigation of Drug-Resistant Bacterial Infections.

Superbug infections and transmission have become major challenges in the contemporary medical field. The development of novel antibacterial strategies to efficiently treat bacterial infections and conquer the problem of antimicrobial resistance (AMR) is extremely important. In this paper, a bimetallic CuCo-doped nitrogen-carbon nanozyme-functionalized hydrogel (CuCo/NC-HG) has been successfully constructed. It exhibits photoresponsive-enhanced enzymatic effects under near-infrared (NIR) irradiation (808 nm) with strong peroxidase (POD)-like and oxidase (OXD)-like activities. Upon NIR irradiation, CuCo/NC-HG possesses photodynamic activity for producing singlet oxygen(1O2), and it also has a high photothermal conversion effect, which not only facilitates the elimination of bacteria but also improves the efficiency of reactive oxygen species (ROS) production and accelerates the consumption of GSH. CuCo/NC-HG shows a lower hemolytic rate and better cytocompatibility than CuCo/NC and possesses a positive charge and macroporous skeleton for restricting negatively charged bacteria in the range of ROS destruction, strengthening the antibacterial efficiency. Comparatively, CuCo/NC and CuCo/NC-HG have stronger bactericidal ability against methicillin-resistant Staphylococcus aureus (MRSA) and ampicillin-resistant Escherichia coli (AmprE. coli) through destroying the cell membranes with a negligible occurrence of AMR. More importantly, CuCo/NC-HG plus NIR irradiation can exhibit satisfactory bactericidal performance in the absence of H2O2, avoiding the toxicity from high-concentration H2O2. In vivo evaluation has been conducted using a mouse wound infection model and histological analyses, and the results show that CuCo/NC-HG upon NIR irradiation can efficiently suppress bacterial infections and promote wound healing, without causing inflammation and tissue adhesions.

Electroacupuncture Alleviates LPS-Induced ARDS Through α7 Nicotinic Acetylcholine Receptor-Mediated Inhibition of Ferroptosis.

Acute respiratory distress syndrome (ARDS) is an uncontrollable, progressive pulmonary inflammatory disease, and as a common clinical critical disease, there is no effective treatment available. Electroacupuncture (EA) therapy is a type of traditional Chinese medicine physiotherapy that can alleviate the inflammatory response. However, the potential mechanism of EA in the treatment of ARDS is not yet clear. Ferroptosis is a new type of programmed cell death characterized by intracellular iron accumulation and lipid peroxidation. Recently, emerging evidence has shown that ferroptosis is closely related to the occurrence and development of ARDS caused by various pathological factors. Here, we further investigated whether EA-mediated inhibition of ferroptosis in lung tissue could attenuate lipopolysaccharide (LPS)-induced ARDS and explored its underlying mechanisms. In this study, mice were administered LPS intraperitoneally to establish a model of LPS-induced ARDS. We found that EA stimulation could not only reduce the exudation of inflammatory cells and proteins in the alveolar lumen but also significantly alleviate the pathological changes of lung tissue, inhibit the production of proinflammatory cytokines and improve the survival rate of mice. Concurrently, we also found that ferroptosis events occurred in the lung tissue of LPS-induced ARDS mice, manifested by elevated iron levels, ROS production and lipid peroxidation. Intriguingly, our results showed that EA stimulation at the Zusanli (ST36) acupoint activated α7 nicotinic acetylcholine receptor (α7nAchR) in lung tissue mainly through the sciatic nerve and cervical vagus nerve, thus exerting anti-ferroptosis and pulmonary protective effects. Additionally, these effects were eliminated by methyllycaconitine (MLA), a selective antagonist of α7nAchR. In vitro experiments, activation of α7nAchR protected alveolar epithelial cells from LPS-induced ferroptosis. Furthermore, our experiments showed that the pulmonary protective effects of EA stimulation were effectively reversed by erastin, a ferroptosis activator. Collectively, we demonstrated that EA stimulation could alleviate LPS-induced ARDS by activating α7nAchR to inhibit LPS-induced ferroptosis in alveolar epithelial cells. Targeting and regulating ferroptosis in alveolar epithelial cells may be a potential intervention approach for the treatment of LPS-induced ALI/ARDS in the future.

[Fruit variation and geographical distribution of citron].

The ripe dried fruit of citron(Citrus medica) is one of the important sources of Chinese herb Citri Fructus. At the same time, it is also grown for edible and ornamental uses. There are many species and abundant genetic variation. To clarify the intraspecific variation and resource distribution of citron, this study investigated the variation in 11 citron fruits, basically covering the main species in China, including Xiaoguo citron(C. medica var. ethrog), Goucheng(C. medica var. yunnanensis), Muli citron(C.medica var. muliensis), Dehong citron(C.medica×Citrus spp.), Fuzhou citron(C.medica×C.grandis?), Mawu(C.medica×C.grandis?), Cangyuan citron, Binchuan citron, Sweet citron, Big citron, and Small citron. The natural communities of citron were proved to be mainly distributed in the southwestern and western Yunnan and southeastern Tibet of China, with Yunnan, Sichuan, Guangxi, Chongqing, Hubei, and Zhejiang identified as the main production areas. Citron has also been widely grown in India, the Mediterranean region, and the Caribbean coast countries. The field investigation revealed the large-scale intraspecific variation of citron fruits. Most of the fruits are oval-like or sphere-like in shape. The fruits are green when raw and yellow when ripe, with oil cell dots on the skin, stripe-likes running from top to bottom, and bulge at the top. Usually, in the smaller citron fruits, the pulp and juice vesicles are better developed and the central columella is tighter. By contrast, the juice vesicles and central columella in larger fruits became more vacant, with carpels visible, and the apex segregation and development of the carpels is one of the reasons for variation. These variations should be given top priority in the future variety selection and breeding, and the quality differences of different citron species and their mechanisms should be further studied. In particular, variety selection and classification management according to their medicinal or edible purposes will provide scientific and technological supports for the orderly, safe, and effective production of citron products consumed as food and medicine.

Valtrate as a novel therapeutic agent exhibits potent anti-pancreatic cancer activity by inhibiting Stat3 signaling.

BACKGROUND: Valtrate is a novel epoxy iridoid ester isolated from Chinese herbal medicine Valeriana jatamansi Jones with anti-proliferative activity against various human cancer cell lines. However, its efficacy and molecular mechanisms against pancreatic cancer (PC) cells are largely unclear. PURPOSE: To investigate the anti-cancer effects of valtrate on PC cell lines and its underlying mechanisms. METHODS: MTT assay was first performed to detect the effect of valtrate on cell viability in human PC cell lines and normal pancreatic epithelial cells HPDE. Cell apoptosis and cycle phase assay were detected by flow cytometry. The relative mRNA expressions of Bax, Bcl-2, c-Myc, and CyclinB1 were tested by quantitative PCR (qPCR) assay. The expression of relative proteins was detected by Western blotting (WB). A PANC-1luc cells xenograft mouse model in nu/nu female mice was used to elucidate the effect of valtrate on tumor growth in vivo. RESULTS: Valtrate significantly inhibited the growth of PC cells without affecting the growth of normal pancreatic epithelial cells HPDE, induced significant apoptosis and cell cycle arrest in G2/M phase. Moreover, valtrate inhibited the tumor growth of PC cell PANC-1 in xenograft mice by 61%. Further mechanism study demonstrated that valtrate could increase the expression level of Bax, suppress Bcl-2 as well as c-Myc and Cyclin B1, inhibit the transcriptional activity of Stat3, while valtrate decreased the expression level of Stat3 and phosphated-Stat3 (Tyr705) and induced the high molecular aggregation of Stat3. Molecular docking analysis predicted that valtrate might interact with Cys712 of Stat3 protein. Valtrate could also induce a transient depleted intracellular glutathione (GSH) level and increased reactive oxygen species (ROS). NAC (N-acetylcysteine), a reducer reversed valtrate-induced the depletion of Stat3, p-Stat3, c-Myc, and Cyclin B1. CONCLUSION: Valtrate exerts anti-cancer activity against PC cells by directly targeting Stat3 through a covalent linkage to inhibit Stat3 activity, which causes apoptosis and cell cycle arrest.

Electroacupuncture Pretreatment Alleviates LPS-Induced Acute Respiratory Distress Syndrome via Regulating the PPAR Gamma/NF-Kappa B Signaling Pathway.

Electroacupuncture (EA) is reported to possess anti-inflammatory properties and has beneficial effects on acute respiratory distress syndrome (ARDS). However, the underlying mechanisms of the effects of EA on ARDS remain unclear. This study aims to investigate the protective effect of EA on LPS-induced ARDS. In this study, Sprague-Dawley male rats were treated with EA at Hegu (LI4) for 45 minutes before LPS instillation (0.4 mg/kg, 100 ul). H&E staining, wet-to-dry weight (W/D) ratio, PaO2, and protein content in BALF were employed to determine the function of lung tissues. Inflammatory cytokines in serum and BALF were detected by enzyme-linked immunoassay assay (ELISA). The levels of oxidative stress markers were detected to determine the oxidative stress status. Cell apoptosis was observed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining and western blot. Here, we found that EA pretreatment effectively alleviated lung pathological damage. Moreover, EA suppressed the oxidative stress damage by upregulating glutathione and superoxide dismutase and downregulating malondialdehyde. EA pretreatment also regulated apoptosis-related proteins, such as Bax and Bcl-2. We found that peroxisome proliferators-activated receptors γ (PPARγ) play a critical role during ARDS, EA up-regulated the expression of PPARγ, which inhibited the activation of nuclear factor-kappa B (NF-κB) and decreased the inflammatory cytokines (interleukin-1ß, interleukin-6, and tumor necrosis factor-α). When rats were treated with GW9662, a selective PPARγ antagonist, these effects of EA were reversed. Our study demonstrated that EA pretreatment had a beneficial effect on LPS-induced ARDS in rats by anti-inflammatory, antioxidative, and antiapoptotic properties which was regulated via PPARγ/NF-κB signaling pathway.

Coix Seed Extract Enhances the Anti-Pancreatic Cancer Efficacy of Gemcitabine through Regulating ABCB1- and ABCG2-Mediated Drug Efflux: A Bioluminescent Pharmacokinetic and Pharmacodynamic Study.

A deep insight into the function and kinetics of ATP-binding cassette (ABC) transporters may aid in the development of pharmaceutics that can minimize the particular facet of chemo-resistance. We utilized bioluminescence imaging to monitor the ABC transporter mediated intracellular drug efflux function. We also investigated the potential association between the intracellular bioluminescent pharmacokinetic profiles and the anti-tumor efficacy of the coix seed extract and gemcitabine against pancreatic cancer cells in vitro and in vivo. The bioluminescent pharmacokinetic parameters and pharmacodynamic index (IC50 and TGI) were determined. The expression levels ABCB1 and ABCG2 were assessed. Results showed that coix seed extract could synergistically enhance the anti-cancer efficacy of gemcitabine (p < 0.05). Meanwhile coix seed extract alone or in combination with gemcitabine could significantly increase the AUCluc while decreasing the Kluc (p < 0.01). Western blot and immunohistochemistry assay demonstrated that coix seed extract could significantly mitigate gemcitabine-induced upregulation of ABCB1 and ABCG2 protein. The Pearson correlation analysis demonstrated that the bioluminescent pharmacokinetic parameters and pharmacodynamic index have strong association in vitro and in vivo. In conclusion coix seed extract could augment the efficacy of gemcitabine therapy in pancreatic cancer cells may at least partly due to the alteration of ABC transporter-mediated drug efflux function.

UHPLC-Q-TOF MS-Based Metabolic Analysis for the Therapeutic Efficacy of "Xuebijing Injection" against Sepsis-Induced Acute Lung Injury.

"Xuebijing Injection" (XBJ) is a traditional Chinese medicine and has been wildly used in the treatment of sepsis in China. However, few studies have reported the use of XBJ in sepsis with acute lung injury (ALI). This study aimed to investigate the therapeutic efficacy of XBJ against sepsis-induced ALI. Generally a total of 27 mice were equally randomized into three groups: a sham group was given saline before sham operation. A sepsis group received the cecal ligation and puncture (CLP) operation only. A sepsis+XBJ group, XBJ, was injected at 72, 48, and 24 h before CLP operation. The lung tissue was collected for UHPLC-Q-TOF/MS profiling analysis, biomarker identification, and pathway analysis. With the analysis of principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA), forty-five purine, amino acid, and sphingolipid metabolites in lung tissues were identified as potential biomarkers of sepsis-induced ALI, among which 22 were reversed in the sepsis+XBJ group significantly. Conclusively, our results suggest that purine metabolic pathway, glutathione metabolic pathway, sphingomyelin metabolic pathway, arachidonic acid metabolic pathway, and phospholipid metabolic pathway may be the potential therapeutic pathways to overcome sepsis-induced acute lung injury and we provided the potential mechanisms of protective effects of XBJ against ALI.

Brief history of pharmaceutical standard system in China / 中国中药杂志

Pharmaceutical standard system which belongs to an important part of national drug policies is an inevitable result of the development of pharmacy. There was a long standing of pharmaceutical standard system in China whose germination could be traced back to Qin and Han dynasties, and it had laid a solid foundation for the establishment and improvement of modern pharmaceutical standard system by continual accumulation from the past dynasties. Since the founding of new China, distinguished achievements had been obtained on pharmaceutical standardization working,and currently it is in a new developing stage. There was a brief description in this paper on the development history of pharmaceutical standard system in China.

Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia.

Alzheimer's disease (AD), characterized by accumulation of amyloid-beta protein (Abeta) in brain parenchyma, is closely associated with brain ischemia. Decreased clearance of Abeta from brain is the main cause of Abeta accumulation in sporadic AD. However, the mechanisms underlying ischemia-mediated AD pathogenesis remain unclear. The receptor for advanced end glycation products (RAGE) and low-density lipoprotein receptor-related protein-1 (LRP-1) expressed at blood brain barrier (BBB) are actively involved in Abeta clearance. RAGE is thought to be a primary transporter of Abeta across BBB into the brain from the systemic circulation, while LRP-1 mediates the transport of Abeta out of the brain. Ginkgo biloba extract EGb761, a traditional Chinese medicine, has been widely used in the treatment of AD. To investigate the effects of EGb761 on the expression of RAGE and LRP-1 in endothelial cells in response to ischemic injury, we cultured bEnd.3 cells, an immortalized mouse cerebral microvessel endothelial cell line, under a chronic hypoxic and hypoglycemic condition (CHH) to mimic ischemic injury of BBB, and then treated with EGb 761. We found that EGb 761 markedly ameliorated the damage (evaluated by MTT assay) from CHH. Moreover, we demonstrated that CHH led to a significant increase in the expression of RAGE both at the mRNA and protein levels at all times (24, 36, and 48 h), conversely; CHH induced a dramatic decrease in LRP-1 mRNA and protein expression at both 36 and 48 h. The results indicated that CHH has differential effects on the expression of RAGE and LRP-1. Furthermore, EGb761 significantly reversed CHH-induced upregulation of RAGE expression and downregulation of LRP-1 expression. Our findings suggest that EGb761 favor clearance of Abeta via regulating the expression of RAGE and LRP-1 during brain ischemia. This may provide a new insight into a possible molecular mechanism underlying brain ischemia-mediated AD pathogenesis, and potential therapeutic application of EGb 761 in treatment of AD.

[Determination of organochlorine pesticide residues in nine herbs by solid-phase extraction and capillary gas chromatography].

The solid-phase extraction and capillary gas chromatography was introduced for determining 13 organochlorine pesticide residues including alpha-benzene hexachloride (BHC), betaBHC, gamma-BHC, delta-BHC, p,p'-dichloro-diphenyl-dichloroethylene (pp'-DDE), p,p'-dichloro-di-phenyl-dichloroethane (pp'-DDD), o,p'-dichloro-diphenyl-trichloroethane (op'-DDT), pp'-DDT, heptachlor (HEPT), aldrin, heptachlor epoxide (HCE), dieldrin and endrin in Scutellaria baicalensis, Salvia miltiorrhiza, Belamcanda chinensis, Paeoniae lactiflora, Angelica dahurica, Arisaema erubescens, Fructus arctii, Anemarrhena asphodeloides and Platycodon grandiflorum. The organochlorine pesticides were extracted from herbs with mixed solvents of acetone and n-hexane by ultrasonic and cleaned up by Florisil solid-phase extraction column. Then, the extract was separated by capillary column (30 m x 0.25 mm i.d. x 0.25 microm) and detected by electrochemical detector. The carrier gas was N2 (99.999%) with the flow rate of 1.4 mL/min. The split ratio was 1:2.2. The injector temperature was 220 degrees C and the detector temperature was 330 degrees C. The column temperature was increased by the rate of 20 degrees C/min from 100 degrees C to 190 degrees C (hold for 1. 0 min), then to 235 degrees C by the rate of 4 degrees C/min and hold for 7 min at 235 degrees C. The good linearities were obtained for 13 organochlorine pesticides. The detection limits were between 0.064-0.61 microg/L. The average recoveries were between 87.3%-102.3% and relative standard deviations of 1.3%-6.8%. The method is effective, fast and accurate.

Small nonphosphorylated Grb2-SH2 domain antagonists evaluated by surface plasmon resonance technology.

The growth factor receptor-binding protein-Src homology 2 (Grb2-SH2) domain plays an important role in the oncogenic Ras signal transduction pathway, which involves cell proliferation and differentiation. Therefore, the Grb2-SH2 domain has been chosen as our target for development of potential antiproliferative agents. Herein, we report the study of the inhibitory effects of small nonphosphorylated peptide analogs interacting with the Grb2-SH2 domain protein by surface plasmon resonance (SPR) technology. A set of 8 related peptide analogs were synthesized, purified, and characterized. Their inhibitory effects on Grb2-SH2 were evaluated by the SPR technology developed with the BIACORE X instrument. The lead peptide, Fmoc-Glu-Tyr-Aib-Asn-NH2 (Fmoc-E-Y-Aib-N; Fmoc: 9-fluorenylmethyoxycarbonyl; Aib=alpha-amino isobutyric acid) inhibited Grb2-SH2 domain function with an IC50 value of 8.7 microM. A molecular modeling study of the lead peptide indicated that the glutamate in the Fmoc peptide is ideally positioned to form a strong salt bridge to Arg 67 in the Grb2-SH2 domain, using both its backbone carbonyl and its acidic group. Residue Glu 89 in Grb2-SH2 flips inward to fill the binding site and partially replace the phosphate group as a hydrogen-bond acceptor. Results of these studies provide important information for further development of potent nonphosphorylated peptide inhibitors of the Grb2-SH2 domain.