Advanced researches of traditional uses, phytochemistry, pharmacology, and toxicology of medical Uncariae Ramulus Cum Uncis.

ETHNOPHARMACOLOGICAL RELEVANCE: Medical Uncariae Ramulus Cum Uncis consists of Uncaria rhynchophylla (Miq.) Miq. ex Havil, Uncaria macrophylla Wall, Uncaria sinensis (Oliv.) Havil, Uncaria hirsuta Havil, and Uncaria sessilifructus Roxb, which belongs to the species widely used in the genus Uncaria. These species resource widely distributed in China and abroad, and the hook-bearing stem is the primary constituent enrichment site. There are many different forms and architectures of chemicals, depending on the extraction site. Traditional remedies employing URCU had been used widely in antiquity and were first compiled in renowned ancient masterpiece 'Mingyi Bielu ()' written by Hongjing Tao. In modern pharmacological studies, both the total extracts and the phytoconstituents isolated from URCU have been shown to have neuroprotective, antioxidant, anti-inflammatory, anticancer, antibacterial, and autophagy-enhancer properties. AIM OF THE STUDY: This review concentrates on the traditional uses, phytochemistry, pharmacology, toxicology, and nanomaterials studies of URCU, with a perspective to assist with further research and advance. MATERIAL AND METHODS: The Chinese and English literature studies of this review are based on these database searches including Science Direct, CNKI, Wiley online library, Spring Link, Web of Science, PubMed, Medalink, Google scholar, Elsevier, ACS Publications, iPlant, Missouri Botanical Garden, Plant of the World Online. The pertinent data on URCU was gathered. RESULTS: Based on the examination of the genus Uncaria, 107 newly marked chemical compositions have been identified from URCU from 2015 to present, including alkaloids, terpenoids, flavonoids, steroids, and others. Pharmacological studies have demonstrated that URCU has a variety of benefits in diseases such as neurodegenerative diseases, cancer, cardiovascular diseases, diabetes, and migraine, due to its neuroprotective, anti-inflammatory, antioxidant, anti-tumor, anti-bacterial and anti-viral properties. According to metabolic and toxicological studies, the dosage, frequency, and interactions of the drugs that occur in vivo are of great significance for determining whether the organic bodies can perform efficacy or produce toxicity. The research on URCU-mediated nanomaterials is expanding and increasing in order to address the inadequacies of conventional Chinese medicine. The alkaloids in URCU have the capability to self-assemble with other classes of components in addition to being biologically active. CONCLUSION: URCU plants are widely distributed, abundant in chemical constituents, and widely used in both traditional and modern medicine for a variety of pharmacological effects. The utilization of herbal medicines can be raised by assessing the pharmacological distinctions among several species within the same genus and may accelerate the modernization of traditional Chinese medicine. Controlling the concentration of drug administration, monitoring metabolic markers, and inventing novel nanotechnologies are effective strategies for synergistic influence and detoxification to alleviate the main obstacles that toxicity, low bioavailability, and poor permeability. This review can assist further research and advances.

Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms.

The resistance and immune escape of methicillin-resistant Staphylococcus aureus (MRSA) biofilms cause recalcitrant infections. Here, we design a targeting and synergizing cascade PDT with nutritional immunotherapy nanosystems (Arg-PCN@Gel) containing PCN-224 as PDT platform for providing reactive oxygen species (ROS), incorporating arginine (Arg) as nitric oxide (NO) donor to cascade with ROS to produce more lethal ONOO- and promote immune response, and coating with gelatin as targeting agent and persistent Arg provider. The nanosystems adhered to the autolysin of MRSA and inhibited Arg metabolism by down-regulating icdA and icaA. It suppressed polysaccharide intercellular adhesin and extracellular DNA synthesis to prevent biofilm formation. The NO broke mature biofilms and helped ROS and ONOO- penetrate into biofilms to inactivate internal MRSA. Arg-PCN@Gel drove Arg to enhance immunity via inducible NO synthase/NO axis and arginase/polyamine axis and achieve efficient target treatment in MRSA biofilm infections. The targeting and cascading PDT synergized with nutritional immunotherapy provide an effective promising strategy for biofilm-associated infections.

Mitochondria-anchoring self-assembled nanoparticles for multi-path energy depletion: A "nano bomb" in chemo-co-starvation therapy.

As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid BLG@TPGS NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that Nanobomb-BLG@TPGS NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the "energy factory" mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a "three-prone strategy" to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.

Enhanced Anti-Rheumatoid Arthritis Activity of Total Alkaloids from Picrasma Quassioides in Collagen-Induced Arthritis Rats by a Targeted Drug Delivery System.

New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including ß-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC50= 8.088±0.903 µg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.

Taking glucose as intermediate bridge-signal-molecule for on-site and convenient detection of ochratoxin A in rice with portable glucose meter.

On-site screening of biotoxins is of great importance for food safety. A new electrochemical-biosensing strategy was constructed for ochratoxin A (OTA) detection by direct using ready-made commercial portable-glucose-meter (PGM). Aptamer against OTA was adopted as the recognition probe and pre-immobilized onto the sensing interface. The complementary biotin-modified probe was further decorated by hybridization. Biotinylated invertase was further introduced onto the sensing system with streptavidin, which also acted as the signal amplification unit. The invertase, which was depended on the amount of OTA, produced the glucose from sucrose in the sensing solution. The glucose could be directly and conveniently measured with PGM. Quantitative analysis of OTA was achieved with a linear range from 0.5 ng/mL to 10 ng/mL and detection limit of 0.45 ng/mL. Of significance, it has been successfully applied for OTA analysis in rice with satisfied recoveries. This unique PGM-based electrochemical platform reveals prospective potential in food safety monitoring.

Saikosaponin a promotes sleep by decreasing neuronal activities in the lateral hypothalamus.

Insomnia is one of the most prevalent sleep disorders, which imparts tremendous societal and economic impact. However, the present pharmacotherapy is greatly limited by adverse effects, so it is necessary to explore new drugs for the treatment of insomnia. Radix Bupleuri (RB) has been widely used in traditional Chinese medicine for >2000 years; it has many pharmacological effects, including sedation and anticonvulsant properties. The present study investigated the effects of saikosaponin a (SSa), an active component of RB, on sleep and locomotion. Male C57BL/6j mice received intraperitoneal injections of SSa at three different dosages (0.625, 1.25, and 2.5 mg/kg). Sleep parameters were analysed by electroencephalography and electromyography. The open-field test was used to measure locomotor activities. Our present results showed that SSa treatment significantly increased the duration of non-rapid eye movement sleep and shortened sleep latency in a dose-dependent manner. A high dose of SSa (2.5 mg/kg) also decreased locomotor activities. Moreover, by measuring c-Fos expression and the calcium signal in the lateral hypothalamus (LH), we found that SSa treatment decreased neuronal activity in the LH. In conclusion, SSa might be the sleep-promoting component in RB and its mechanism may be related to the modulation of neuronal activity in the LH.

[Transcutaneous electrical acupoint stimulation improves pregnancy outcomes of in vitro fertilization- embryo transfer : A meta-analysis of randomized controlled trials].

OBJECTIVE: To evaluate the effect of transcutaneous electrical acupoint stimulation (TEAS) on the pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET) based on the available clinical evidence. METHODS: We searched PubMed, MEDLINE, EMBASE, Cochrane Library, CNKI, VIP, CBM and Wanfang Database up to February 2021 for published randomized controlled trials (RCT) relevant to TEAS for the improvement of the pregnancy outcomes of IVF-ET. We performed literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria, followed by a meta-analysis with the RevMan 5.3 software. RESULTS: A total of 2 206 cases of IVF-ET from 9 RCTs were included, 1 018 in the TEAS group and 1 188 in the control. The clinical pregnancy rate was significantly higher in the TEAS than in the mock TEAS and non-TEAS control groups (RR = 1.85, 95% CI: 1.42－2.42, P < 0.001; RR = 1.23, 95% CI: 1.10－1.39, P = 0.0004), and so was it before and after oocyte retrieval (RR = 1.50, 95% CI: 1.03－2.17, P = 0.03; RR = 1.47, 95% CI: 1.12－1.92, P = 0.005). The TEAS group also showed dramatically improved embryo implantation rate (RR = 1.49, 95% CI: 1.24－1.79, P < 0.0001) and live birth rate (RR = 1.44, 95% CI: 1.04－1.98, P = 0.03) compared with the control. CONCLUSIONS: As a safe and non-invasive treatment, TEAS can significantly improve the pregnancy outcomes of IVF-ET, with definite effectiveness. /.

Formulation of a rational dosage regimen of ceftiofur hydrochloride oily suspension by pharmacokinetic-pharmacodynamic (PK-PD) model for treatment of swine Streptococcus suis infection.

BACKGROUND: Our previously prepared ceftiofur (CEF) hydrochloride oily suspension shows potential wide applications for controlling swine Streptococcus suis infections, while the irrational dose has not been formulated. OBJECTIVES: The rational dose regimens of CEF oily suspension against S. suis were systematically studied using a pharmacokinetic-pharmacodynamic model method. METHODS: The healthy and infected pigs were intramuscularly administered CEF hydrochloride oily suspension at a single dose of 5 mg/kg, and then the plasma and pulmonary epithelial lining fluid (PELF) were collected at different times. The minimum inhibitory concentration (MIC), minimal bactericidal concentration, mutant prevention concentration (MPC), post-antibiotic effect (PAE), and time-killing curves were determined. Subsequently, the area under the curve by the MIC (AUC0-24h/MIC) values of desfuroylceftiofur (DFC) in the PELF was obtained by integrating in vivo pharmacokinetic data of the infected pigs and ex vivo pharmacodynamic data using the sigmoid Emax (Hill) equation. The dose was calculated based on the AUC0-24h/MIC values for bacteriostatic action, bactericidal action, and bacterial elimination. RESULTS: The peak concentration, the area under the concentration-time curve, and the time to peak for PELF's DFC were 24.76 ± 0.92 µg/mL, 811.99 ± 54.70 µg·h/mL, and 8.00 h in healthy pigs, and 33.04 ± 0.99 µg/mL, 735.85 ± 26.20 µg·h/mL, and 8.00 h in infected pigs, respectively. The MIC of PELF's DFC against S. suis strain was 0.25 µg/mL. There was strong concentration-dependent activity as determined by MPC, PAE, and the time-killing curves. The AUC0-24h/MIC values of PELF's DFC for bacteriostatic activity, bactericidal activity, and virtual eradication of bacteria were 6.54 h, 9.69 h, and 11.49 h, respectively. Thus, a dosage regimen of 1.94 mg/kg every 72 h could be sufficient to reach bactericidal activity. CONCLUSIONS: A rational dosage regimen was recommended, and it could assist in increasing the treatment effectiveness of CEF hydrochloride oily suspension against S. Suis infections.

Melatonin supplementation in the subacute phase after ischemia alleviates postischemic sleep disturbances in rats.

BACKGROUND: Sleep disorders are highly prevalent among stroke survivors and impede stroke recovery. It is well established that melatonin has neuroprotective effects in animal models of ischemic stroke. However, as a modulator of endogenous physiological circadian rhythms, the effects of melatonin on poststroke sleep disorders remain unclear. In the present study, we investigated how melatonin delivered intraperitoneally once daily in the subacute phase after stroke onset, influencing neuronal survival, motor recovery, and sleep-wake profiles in rats. METHODS: Transient ischemic stroke in male Sprague-Dawley rats was induced with 30 min occlusion of the middle cerebral artery. Melatonin or vehicle was delivered intraperitoneally once daily in the subacute phase, from 2 to 7 days after stroke. Electroencephalogram and electromyogram recordings were obtained simultaneously. RESULTS: Compared to the effects observed in the vehicle-treated ischemic group, after 6 daily consecutive treatment of melatonin at 10 mg/kg starting at ischemic/reperfusion day 2, the infarct volume was significantly decreased (from 39.6 to 26.2%), and the degeneration of axons in the ipsilateral striatum and the contralateral corpus callosum were significantly alleviated. Sensorimotor performances were obviously improved as evidenced by significant increases in the latency to falling off the wire and in the use of the impaired forelimb. In addition to those predictable results of reducing brain tissue damage and mitigating behavioral deficits, repeated melatonin treatment during the subacute phase of stroke also alleviated sleep fragmentation through reducing sleep-wake stage transitions and stage bouts, together with increasing stage durations. Furthermore, daily administration of melatonin at 9 a.m. significantly increased the nonrapid eye movement sleep delta power during both the light and dark periods and decreased the degree of reduction of the circadian index. CONCLUSIONS: Melatonin promptly reversed ischemia-induced sleep disturbances. The neuroprotective effects of melatonin on ischemic injury may be partially associated with its role in sleep modulation.

Discovery of novel nitrogenous heterocyclic-containing quinoxaline-1,4-di-N-oxides as potent activator of autophagy in M.tb-infected macrophages.

As a continuation of our research on antimycobacterial agents, a series of novel quinoxaline-1,4-di-N-oxides (QdNOs) containing various nitrogenous heterocyclic moieties at the R6 position were designed and synthesized. Antimycobacterial activities, as well as the cytotoxic effects, of the compounds were assayed. Four compounds (6b, 6f, 6n, and 6o), characterized by 2-carboxylate ethyl or benzyl ester, 6-imidazolyl or 1,2,4-triazolyl, and a 7-fluorine group, exhibited the most potent antimycobacterial activity against M.tb strain H37Rv (MIC ≤ 0.25 µg/mL) with low toxicity in VERO cells (SI = 169.3-412.1). Compound 6o also exhibited excellent antimycobacterial activity in an M.tb-infected macrophage model and was selected for further exploration of the mode of antimycobacterial action of QdNOs. The results showed that compound 6o was capable of disrupting membrane integrity and disturbing energy homeostasis in M.tb. Furthermore, compound 6o noticeably increased cellular ROS levels and, subsequently, induced autophagy in M.tb-infected macrophages, possibly indicating the pathways of QdNOs-mediated inhibition of intracellular M.tb replication. The in vivo pharmacokinetic (PK) profiles indicated that compounds 6o was acceptably safe and possesses favorable PK properties. Altogether, these findings suggest that compound 6o is a promising antimycobacterial candidate for further research.

Digestive promoting effect and mechanism of Jiao Sanxian in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiao Sanxian, a customary term for the three Traditional Chinese Medicines of charred hawthorn (Crataegi Fructus), charred malt (Hordei Fructus Germinatus) and Liu Shenqu (Massa Medicata Fermentata), is a classic prescription for the treatment of functional dyspepsia (FD). This prescription is called "Jiao Sanxian" in China because people believe that it is a miracle medicine for enhancing digestion and improving stagnation of digestive system. Even though Jiao Sanxian is widely used in clinical treatment, the underlying mechanism has not been clarified to date. AIM OF THE STUDY: The present study is aimed to explore the efficacy and mechanism of Jiao Sanxian in improving the symptoms of FD in rats by using multiple pharmacological methods. MATERIALS AND METHODS: The Sprague Dawley (SD) rats were divided into control, model, Jiao Sanxian decoction low-dosage (JSXD LD), Jiao Sanxian decoction medium-dosage (JSXD MD), and Jiao Sanxian decoction high-dosage (JSXD HD) group at random. A FD model was established with reserpine, and animals were given intragastric administration. During this period, weight and food intake of animals were recorded. Samples of rat gastric antrum, spleen, and duodenum were collected for pathological staining and immunohistochemical determination of Ghrelin protein expression after 19 days of treatment. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentration of related brain gut peptides in serum. Moreover, 16S rRNA sequencing was used to valuate the influence of intestinal flora structure of the cecal contents of experimental rats. And plasma metabolomics by Ultra Performance Liquid Chromatography coupled with Quadrupole-Time-of-Flight mass spectrometry (UPLC-Q/TOF-MS) were performed to further reveal the mechanism of action. RESULTS: Jiao Sanxian decoction (JSXD) group with different dosage could increase body weight and food intake, improve histopathological changes, and alter disordered brain gut peptides in FD rats. 16S rRNA sequencing results described that JSXD improved the disorder of structural composition, biodiversity and function of gut microbiota in FD rats. Metabolomics illustrated 26 metabolites with JSXD treatment underwent continuous changes, which revealed JSXD might exert digestive effect by ameliorating abnormal metabolic pathways. The most relevant metabolic pathways were arachidonic acid metabolism, pyruvate metabolism, glycerophospholipid metabolism, alanine, aspartate and glutamate metabolism. CONCLUSIONS: JSXD can improve functional dyspepsia in rats and the mechanism is related to regulate secretion of brain gut peptides, significantly improve the disorder of intestinal flora and ameliorated multi-metabolic pathways.

Efficacy and safety of traditional Chinese patent medicine on carotid artery atherosclerosis in adults: A network meta-analysis protocol.

BACKGROUND: Atherosclerosis (AS), the predominant pathological basis of ischemic cardiovascular and cerebrovascular diseases, remains a common and severe clinical problem. The experiments in vitro and in vivo indicate that Traditional Chinese patent medicine (TCPM) shows beneficial efficacy against AS through a variety of mechanisms. However, the existing therapeutic TCPM for the treatment of AS are diverse, and it is still significant to evaluate the pros and cons of a certain TCPM. Therefore, the study aims to compare the efficacy and outcomes of different anti-atherosclerotic TCPM in adults with the hope of providing references for clinical decision making. METHODS: Cochrane Library, PubMed, Embase, Web of Science, China National Knowledge Infrastructure Database, Wanfang Database, Chinese BioMedical Literature Database, and China Science and Technology Journal Database will be searched. Randomized controlled trials (RCTs) of TCPM for aortic AS in adults will be included in this study if they meet the Population/Intervention/Comparison/Outcomes/Study Design (PICOS) criteria. Two reviewers will independently perform citations screening, data extraction and risk of bias assessment. STATA 15.0 and WinBUGS 1.4.3 will be employed to conduct statistical analyses under the Bayesian framework. RESULTS: The efficacy and safety of various TCPM strategies on aortic AS in adults will be compared. CONCLUSION: The study will expand the range of options for anti-atherosclerotic therapeutic strategies and encourages further clinical research in traditional Chinese medicine. INPLASY REGISTRATION NUMBER: INPLASY2020120036.

Effects of calcium treatment on malate metabolism and γ-aminobutyric acid (GABA) pathway in postharvest apple fruit.

Calcium treatment effects on malate metabolism and the GABA pathway in 'Cripps Pink' apple fruit during storage were investigated. Postharvest apple fruit treated with 1% and 4% calcium chloride solutions were stored at 25 ± 1 °C. The 4% calcium treatment suppressed declines in titratable acidity and malate content and increased succinate and oxalate concentrations. Calcium treatment also reduced the respiration rate and decreased ethylene production peak during storage. Moreover, 4% calcium treatment significantly enhanced cyNAD-MDH and PEPC activities and upregulated MdMDH1, MdMDH2, MdPEPC1 and MdPEPC2 expression while inhibiting cyNADP-ME and PEPCK activities and downregulating MdME1, MdME4 and MdPEPCK2 expression. Surprisingly, calcium treatment changed the content of some free amino acids (GABA, proline, alanine, aspartic acid and glutamate), two of which (glutamate and GABA) are primary metabolites of the GABA pathway. Furthermore, calcium application enhanced GABA pathway activity by increasing MdGAD1, MdGAD2, MdGABA-T1/2 and MdSSADH transcript levels.

Hypnotic activities of Zao Ren An Shen capsule, a traditional Chinese medicine, in an anxiety-like mouse model.

PURPOSE: Zao Ren An Shen capsule (ZRASC) which is composed of three kinds of traditional Chinese herbs is a popular Chinese medicine for the treatment of insomnia. This study investigated the hypnotic effect of ZRASC in an anxiety-like mouse model. METHODS: We determined the role of ZRASC in anxiety and co-morbid insomnia using electroencephalogram and electromyogram recordings. Anxiety-like behaviors were tested by using the open-field, light/dark box, or elevated plus-maze in mice. Immunohistochemical techniques were employed to reveal the mechanism by which ZRASC regulated anxiety and insomnia. RESULTS: ZRASC at 680 mg/kg prolonged the time spent in the central area, open arms area, and light box by 1.9, 2.3, and 1.7-fold respectively, compared with the vehicle control group in immobilization stress (IMS) mice. ZRASC at 680 mg/kg given at 08:00 h increased the amount of non-rapid eye movement sleep by 1.4-fold in a 2-h period after dosing in IMS mice. However, it did not alter the sleep-wake behaviors in normal mice. Immunohistochemistry showed that IMS increased c-Fos expression in the neurons of the stria terminalis and tuberomammillary nucleus by 1.8 and 1.6-fold, respectively. In addition, ZRASC (680 mg/kg) reversed the IMS-induced c-Fos expression. CONCLUSIONS: Our results suggest that ZRASC is an effective therapeutic strategy for both anxiety disorder and sleep disturbances in an anxiety-like mouse model.

Dosage Regimen Formulation and Therapeutic Effect Evaluation of Cyadox Nanosuspension Against Dairy Cow Mastitis Caused by Staphylococcus aureus.

AIMS: In this study, the dosage regimen establishment of cyadox nanosuspension against dairy cow mastitis caused by Staphylococcus aureus (S. aureus) was used as example to provide a general reference for the other novel nanocrystal preparations. METHODS: The effect of cyadox against S. aureus isolates from dairy cows were firstly estimated and then the dosing regimen of nanosuspension after intramammary administration was optimized according to the model of ex vivo pharmacokinetic (PK) and pharmacodynamic (PD). The therapeutic efficacy of the predicted dosage regimen was evaluated. RESULTS: The results demonstrated that cyadox has a concentration-dependent effect on S. aureus. The smallest and highest values of minimum inhibitory concentration (MIC) against 80 isolates was 8 and 64 µg/mL, respectively. The corresponding MIC 50 and MIC 90 was 16 and 32 µg/mL, respectively. The MIC against the pathogenic S. aureus SAHZ156001 in broth and milk were 16 and 32 µg/mL, respectively. The AUC 0-last and C max of cyadox in milk were 4442.877 µg*h/mL and 753.052 µg/mL, respectively. According to the inhibitory sigmoid E max modeling and dosage equation, the daily doses were predicted 1.6, 6.6, and 12.2 mL/gland to achieve bacteriostatic, bactericidal, and elimination effects. The dosage internal was daily administration for continuous three days. CONCLUSION: The clinical experiment showed that the efficient rates were 100, 100, and 90.9%, and the curative rates were 100, 81.8, and 63.6% in 12.2, 6.6 and 1.6 ml/gland groups, respectively. These results showed that cyadox nanosuspension had a good prospect as intramammary infusion to cure dairy cow mastitis infected by S. aureus. This study will be helpful for providing reference for nanocrystal preparation dosage regimen formulation.

Recent research progress of Uncaria spp. based on alkaloids: phytochemistry, pharmacology and structural chemistry.

Medicinal plants are well-known in affording clinically useful agents, with rich medicinal values by combining with disease targets through various mechanisms. Plant secondary metabolites as lead compounds lay the foundation for the discovery and development of new drugs in disease treatment. Genus Uncaria from Rubiaceae family is a significant plant source of active alkaloids, with anti-hypertensive, sedative, anti-Alzheimer's disease, anti-drug addiction and anti-inflammatory effects. This review summarizes and discuss the research progress of Uncaria based on alkaloids in the past 15 years, mainly in the past 5 years, including biosynthesis, phytochemistry, pharmacology and structural chemistry. Among, focusing on representative compounds rhynchophylline and isorhynchophylline, the pharmacological activities surrounding the central nervous system and cardiovascular system are described in detail. On the basis of case studies, this article provides a brief overview of the synthesis and analogues of representative compounds types. In summary, this review provides an early basis for further searching for new targets and activities, discussing the mechanisms of pharmacological activity and studying the structure-activity relationships of active molecules.

[Research progress of Rehmanniae Radix in prevention and treatment of osteoporosis].

Osteoporosis fracture with high disability and mortality is a difficult problem that seriously affects the life quality of individuals. At present, there is still a lack of anti-osteoporosis drugs with clear target and significant efficacy in the clinical practice. Rehmanniae Radix and its prescriptions have significant clinical effects. In this regard, more and more studies have reported the effects and mechanisms of Rehmanniae Radix and its active components, and the certain research outputs have been achieved. In this article, the PubMed, Web of science, China National Knowledge Infrastructure, and Wanfang database were searched to collect and organize the latest research progress of Rehmanniae Radix treatment of osteoporosis in the recent 10 years. We summarized the research dynamics as well as the function indexes and mechanisms of the raw and processed Rehmanniae Radix, active ingredients such as catalpol, aucubin, acteoside and Rehmanniae Radix polysaccharide, and their formulating prescriptions, and then excavated the potential active ingredients, targets and signaling pathways, including the effect on bone marrow mesenchymal stem cells, promoting the osteoblast proliferation and promoting osteogenesis differentiation(increasing alkaline phosphatase, typeⅠ collagen, osteoprotegerin, and osteocalcin and promoting calcium deposits), increasing the bone density, inhibiting the osteoclast quantity and differentiation, promoting the osteoclast apoptosis, and reducing tartrate resistant acid phosphatase and bone resorption pit area to provide the reference and develop new ideas for developing Rehmanniae Radix prescriptions for treatment of osteoporosis and exploring its mechanism.

A network pharmacology-based study on Alzheimer disease prevention and treatment of Qiong Yu Gao.

BACKGROUND AND OBJECTIVE: As the pathological mechanisms of AD are complex, increasing evidence have demonstrated Chinese Medicine with multi-ingredients and multi-targets may be more suitable for the treatment of diseases with complex pathogenesis. Therefore, the study was to preliminarily decipher the bioactive compounds and potential mechanisms of Qiong Yu Gao (QYG) for AD prevention and treatment by an integrated network pharmacology approach. METHODS: Putative ingredients of QYG and significant genes of AD were retrieved from public database after screening. Then QYG ingredients target proteins/genes were obtained by target fishing. Compound-target-disease network was constructed using Cytoscape to decipher the mechanism of QYG for AD. KEGG pathway and GO enrichment analysis were performed to investigate the molecular mechanisms and pathways related to QYG for AD treatments. RESULTS: Finally, 70 compounds and 511 relative drug targets were collected. In which, 17 representative direct targets were found. Gene ontology enrichment analysis revealed that the adenylate cyclase-inhibiting G-protein coupled acetylcholine receptor signaling pathway was the key biological processes and were regulated simultaneously by the 17 direct targets. The KEGG pathway enrichment analysis found that three signaling pathways were closely related to AD prevention and treatment by QYG, including PI3K-Akt signaling pathway, regulation of actin cytoskeleton pathway and insulin resistance pathway. CONCLUSION: This study demonstrated that QYG exerted the effect of preventing and treating AD by regulating multi-targets with multi-components. Furthermore, the study demonstrated that a network pharmacology-based approach was useful for elucidation of the interrelationship between complex diseases and interventions of Chinese herbal medicines.

Phenylethanoid glycosides of Callicarpa kwangtungensis Chun exert cardioprotective effect by weakening Na+-K+-ATPase/Src/ERK1/2 pathway and inhibiting apoptosis mediated by oxidative stress and inflammation.

ETHNOPHARMACOLOGICAL RELEVANCE: Callicarpa kwangtungensis Chun (C. kwangtungensis) is a very famous herbal medicine with the function of promoting blood circulation and removing blood stasis which is beneficial for cardiovascular disease (CVD). Phenylethanoid glycosides (PGs) are the major class of active ingredients in C. kwangtungensis and present significant anti-oxidative and anti-inflammatory property related to apoptosis. Therefore, this study aimed to investigate the effects of total phenylethanoid glycosides of C. kwangtungensis (CK-PGs) on isoproterenol (ISO) induced myocardial ischemic injury (MI) and the mechanisms related to the apoptosis mediated by oxidative damage and inflammation. METHODS: The myocardial ischemia animal model was established as subcutaneous injecting ISO. Echocardiography and biomarkers were employed to determine the degree of myocardial damage. Histopathological changes were observed by hematoxylin and eosin test. The TUNEL staining and activity of caspase-3 were measured to detect the level of apoptosis which is medicated by the oxidative damage detected by the level of MDA, GSH and ROS tested with the kit and the inflammation reflected by TNF-α. The activity of Na+-K+-ATPase (NKA) was detected by the commercial kits, whose expression was measured by immunohistochemistry analysis. At last, Western blot analysis was used to measure Na+-K+-ATPase/Src/ERK1/2 and Bax/Bcl-2 pathway. RESULTS: CK-PGs showed cardioprotective effect against ISO-induced myocardial ischemic injury evidenced by improving heart function and lowering myocardial injury markers. CK-PGs could inhibit the level of apoptosis as shown by the decrease of the TUNEL-positive cells, the activity of caspase-3 and increase of the expression of Bax. CK-PGs also reduced oxidative stress and inflammation to suppress apoptosis by decreasing the level of ROS, MDA, and increasing GSH activity and lowering the level of TNF-α. In addition, CK-PGs exerted the protection by increasing the activity and the expression of NKA. Meanwhile, Na+-K+-ATPase/Src/ERK1/2pathway was weakened for the inhibition of apoptosis. CONCLUSIONS: CK-PGs could protect cardiomyocytes from myocardial injury through suppressing Na+-K+-ATPase/Src/ERK1/2 pathway and inhibiting apoptosis mediated by oxidative stress and inflammation.

The Nd:YAG Laser or Combined with Er:YAG Laser Therapy for Oral Venous Lakes.

Objective: The aim of the present study was to investigate the clinical treatment effect on oral venous lakes (OVL) treated with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser or a combination of erbium-yttrium aluminum garnet (Er:YAG) laser. Patients and methods: Between June 2015 and March 2017, nine patients, suffering from OVL in the mandibular regions, were treated with Nd:YAG laser or combination of Nd:YAG laser and Er:YAG laser in our department. The Nd:YAG laser was mainly performed for the treatment of nine initial lesions. The preset parameters were as follows: average power of 5 W, frequency of 100 Hz, microshort pulse (MSP), tip size of 300 µm, spot size of 3 mm, irradiation distance of 3-4 mm, and speed of 1-2 mm/sec, sequential treatment. The power density at work was 57 W/cm2. If postoperative scars occurred after the Nd:YAG treatment, the Er:YAG laser was used. The parameters were set as follows: power of 3.75 W, energy of 150 mJ, frequency of 25 Hz, very long pulse (VLP), tip size of 0.6 mm, 40% water, and 60% gas. The patients were followed up for 4-8 weeks. The therapeutic results were graded on a 4-point scale system. Adverse effects after laser treatment were evaluated and managed accordingly. Results: With single Nd:YAG laser, the therapeutic outcome was excellent in seven patients (77.8%) and good in two patients (22.2%). Scar tissue was encountered in two patients 2 weeks after Nd:YAG laser therapy, and then Er:YAG laser was used for the scar removal. No mucosal necrosis was found in any of the patients. Conclusions: The Nd:YAG laser or combined with Er:YAG laser was an effective and safe treatment for patients with OVL in the mandibular region.