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The lack of rationality evaluation method for drug combination has long restricted its clinical application. In view of this, this study took Shuanghuanglian Injection as model drug and established aquot;physical-chemical-biologicalquot; sequential analysis method, which is expected to provide clues for improving the safety and effectiveness of clinical drug combination. With the methods of insoluble particle testing, isothermal titration calorimetry(ITC), and real time cellular analysis(RTCA), the rationality of Shuanghuanglian Injection combined with Ampicillin Sodium for Injection was assessed. The results showed that the number of insoluble particlesgt;10 μm in the solution of the combination met the standard of Chinese Pharmacopoeia, while the number of insoluble particlesgt;25 μm did not meet the standard. ITC detection demonstrated that the change of Gibbs free energy(ΔG) was less than 0 during the fusion process, indicating that the process was spontaneous and enthalpy-driven reaction. Therefore, the interaction between the two was mainly chemical reaction, and the internal substances may change. RTCA found that Shuanghuanglian Injection alone and Ampicillin Sodium for Injection alone basically had no inhibitory effect on the growth of HEK293 T cells, while the combination of the two suppressed the growth of HEK293 T cells, suggesting that the combination was toxic to HEK293 T cells. This study showed that Shuanghuanglian Injection and Ampicillin Sodium for Injection reacted, yielding toxicity. This suggested that the two should not be combined for application. With thequot;physical-chemical-biologicalquot; sequential analysis, the molecular interaction of drugs was clarified. The method can be further applied for evaluating the rationality of other Chinese and western medicine injections.

Ethnopharmacological relevance Diabetes belongs to the category of “Xiao Ke Zheng” in the field of traditional Chinese medicine (TCM) and has been listed as one of the predominant diseases of TCM. Jinqi Jiangtang Tablet (JQJTT), a Chinese medicine formula composed of three herbs (Coptis chinensis, Astragalus membranaceus and Lonicera japonica), is an effective prescription for diabetes proved by randomized, double-blind, placebo-controlled trials. Aim of the review To analyze systematic and up-to-date classification information on the study of JQJTT, explain the problems existing in the current research of classics formulas, and further propose the solution, providing a reference for future study. Materials and methods Literatures on JQJTT were collected from a variety of databases, including PubMed, Google Scholar, Science Direct, Wiley, Web of Science, China National Knowledge Infrastructure, and WanFang Data. Information was also collected from books and reports, such as Chinese Pharmacopoeia, Chinese herbal classic books and reports of re-evaluation on post-marketing drugs conducted by companies. Results There are some problems for JQJTT: the quality control system is not perfect, the pharmacological functional mechanism is not fully explained, and clinical applications need to be reevaluated. A few of research directions for future research are proposed: (i) the chemical quality evaluation combined with bioassay to evaluate quality; (ii) interaction based on gut microbiota in vivo; (iii) the effects of interaction between components of the polypharmacy on pharmacokinetic studies; (iv) interaction mechanism between drugs and endogenous small molecules and biomacromolecules; (v) evidence-based medicine reconfirmation for clinical evaluation. Conclusions The recent research status of JQJTT was summarized and analyzed from the aspects of chemical constituents, quality control, pharmacokinetics studies, pharmacological properties and clinical applications. This review takes JQJTT as an example, points out some typical problems and opinions about the TCM formulas, highlights the importance of the secondary development of classical formula, and lays a foundation for the further research.

Drug combination is a common clinical phenomenon. However, the scientific implementation of drug combination is li-mited by the weak rational evaluation that reflects its clinical characteristics. In order to break through the limitations of existing evaluation tools, examining drug-to-drug and drug-to-target action characteristics is proposed from the physical, chemical and biological perspectives, combining clinical multicenter case resources, domestic and international drug interaction public facilities with the aim of discovering the common rules of drug combination. Machine learning technology is employed to build a system for evaluating and predicting the rationality of clinical drug combinations based onquot;drug characteristics-repository information-artificial intelligencequot; strategy, which will be debugged and validated in multi-center clinical practice, with a view to providing new ideas and technical references for the safety and efficacy of clinical drug use.

Autophagy has been reported to involve in the pathogenesis of type 2 diabetes mellitus (T2DM), which protects the insulin target tissues and pancreatic β-cells. However, autophagy is inhibited when the cells are lipid overload. That, in turn, increases the accumulation of fat. Lipotoxicity caused by excessive lipid accumulation contributes to pathogenesis of T2DM. Therefore, it is undeniable to break the vicious circles between lipid excess and autophagy deficiency. Lipophagy, a selective form of autophagy, is characterized by selective breakdown of lipid droplets (LDs). The nutritional status of cells contributes to the way of autophagy (selective or non-selective), while selective autophagy helps to accurately remove excess substances. It seems that lipophagy could be an effective means to decrease abnormal lipid accumulation that leads to insulin resistance and β-cell impairment by removing ectopic LDs. Based on this process, many natural compounds have been reported to decrease lipid accumulation in tissues through autophagy-lysosomal pathway, which gradually highlights the significance of lipophagy. In this review, we focus on the mechanisms that lipophagy improves T2DM and natural products that are applied to induce lipophagy. It is also suggested that natural herbs with rich contents of natural products inducing lipophagy would be potential candidates for alleviating T2DM.

Given the high and increasing prevalence of obesity, the safe and effective treatment of obesity would be beneficial. Here, we examined whether oral hydroxysafflor yellow A (HSYA), an active compound from the dried florets of Carthamus tinctorius L., can reduce high-fat (HF) diet-induced obesity in C57BL/6 J mice. Our results showed that the average body weight of HF group treated by HSYA was significantly lower than that of the HF group (P 0.01). HSYA also reduced fat accumulation, ameliorated insulin resistance, restored glucose homeostasis, reduced inflammation, enhanced intestinal integrity, and increased short-chain fatty acids (SCFAs) production in HF diet-fed mice. Sequencing of 16S rRNA genes in fecal samples demonstrated that HSYA reversed HF diet induced gut microbiota dysbiosis. Particularly, HSYA increased the relative abundances of genera Akkermansia and Romboutsia, as well as SCFAs-producing bacteria, including genera Butyricimonas and Alloprevotella, whereas it decreased the phyla Firmicutes/Bacteroidetes ratio of HF diet-fed mice. Additionally, serum metabolomics analysis revealed that HSYA increased lysophosphatidylcholines (lysoPCs), L-carnitine and sphingomyelin, and decreased phosphatidylcholines in mice fed a HF diet, as compared to HF group. These changed metabolites were mainly linked with the pathways of glycerophospholipid metabolism and sphingolipid metabolism. Spearman's correlation analysis further revealed that Firmicutes was positively while Bacteroidetes and Akkermansia were negatively correlated with body weight, fasting serum glucose and insulin. Moreover, Akkermansia and Butyricimonas had positive correlations with lysoPCs, suggestive of the role of gut microbiota in serum metabolites. Our findings suggest HSYA may be a potential therapeutic drug for obesity and the gut microbiota may be potential territory for targeting of HSYA.

Metastasis of cancer makes up the vast majority of cancer-related deaths, and it usually initiates from tumor cells invasiveness and develops through tumor neovasculature. In this work, we have fabricated a CD44/neuropilin dual receptor-targeting nanoparticulate system (tLyP-1-HT NPs) with endogenous or FDA approved components for treating metastatic triple negative breast cancer (TNBC). The enhanced specific targeting of tLyP-1-HT NPs to both metastatic tumor cells and metastasis-supporting tumor neovasculature was contributed by means of CD44/neuropilin dual receptor-mediated interaction. The NPs not only effectively suppress the invasive capability of tumor cells themselves, but also significantly restrain the metastasis incidence via extravasation as well as the eventual colonization in lungs. In all the three types of TNBC-bearing mice models, orthotopic, post-metastasis and metastasis prevention models, the docetaxel-loaded tLyP-1-HT NPs exhibited markedly enhanced anti-tumor and anti-metastasis efficacy. The inhibitory rates of tLyP-1-HT NPs against orthotopic tumor growth and lung metastasis achieved 79.6% and 100%, respectively. The metastasis inhibition rate and life extension rate of the tLyP-1-HT NPs against post-pulmonary metastasis mice reached 85.1% and up to 62.5%, respectively. All the results demonstrated the designed dual receptor-targeting multifunctional NPs hold great potential in treating metastatic TNBC and lung metastasis.

Berberine (BBR) is a non-prescription drug to treat various bacteria-associated diarrheas. However, BBR has also been reported to cause diarrhea in clinic, with underlying mechanisms poorly understood. Because altered gut microbial ecology is a potential basis for diarrhea, this study was conducted to investigate the impact of BBR on gut microbiota of treatment-emergent diarrhea. BBR treatment (200 mg/kg, i.g.) in normal rats exhibited no significant changes in serum biochemical parameters but mild diarrhea occurred, accompanied with the decreased gastrointestinal transit time and increased fecal moisture, suggestive of the local effects of BBR in the intestine. Colon histology revealed the decreased abundance of mucus-filled goblet cells in BBR group. Although BBR-treated rats had the enlarged cecum with watery caecal digesta, short-chain fatty acids concentration was significantly lower than control group. Additionally, BBR caused gut microbiota dysbiosis by evaluating the decreased observed species number and Shannon index. BBR increased the relative abundances of families Porphyromonadaceae and Prevotellaceae as well as genera Parabacteroides, Prevotellaceae_UCG-001 and Prevotellaceae_NK3B31_group. Spearman’s correlation analysis revealed family Prevotellaceae and genus Prevotellaceae_UCG-001 as the most prominent drivers of the BBR treatment-emergent diarrhea, correlating positively with fecal moisture but negatively with gastrointestinal transit time. This study therefore demonstrated that the treatment-emergent mild diarrhea of BBR was most likely due to the dysbiosis of the gut microbiota.

The phytochemical investigation on the fruits of Flueggea virosa resulted in the discovery of two new norsecurinine-derived alkaloid dimers, norsecurinamines A and B (1 and 2). Compound 1 is the first hetero-dimeric alkaloid possessing norsecurinine and donaxaridine units, and 2 represents the first example of NH-linked dimeric Securinega alkaloid. Their structures and absolute configuration were elucidated on the basis of extensive spectroscopic analysis as well as single-crystal X-ray diffraction method. A plausible biogenetic pathway of 1 was also proposed.

Berberine (BBR) is a potential novel agent to treat diabetes, but its oral bioavailability is restricted by the poor solubility, which greatly limits its clinical application. Here, a new drug delivery system of BBR-MgAl monolayer hydrotalcite (BBR/MLDH) was prepared to increase the solubility and bioavailability of BBR. The results showed that BBR/MLDH presented as a uniform hexagonal plate-like particle with a loading capacity of 28.61 %, a diameter of ∼70 nm and a thickness of ∼1.5 nm. The solubility and dissolution of BBR increased when loading onto MLDH. Compared with BBR, pharmacokinetics of BBR/MLDH in rats showed significant enhancement (P < 0.01) in area under the curve (AUC) and the peak plasma concentration (Cmax), suggesting the bioavailability of BBR was improved. Furthermore, BBR/MLDH showed more potent effects in reducing fasting blood glucose, ameliorating glucose tolerance and insulin resistance comparing to the equivalent dose of BBR. In a word, the solubility, oral bioavailability and hypoglycemic effect of BBR could be improved by loading onto MLDH.

Increased circulating branched-chain amino acids (BCAAs) have been involved in the pathogenesis of obesity and insulin resistance (IR). However, evidence relating berberine (BBR), gut microbiota, BCAAs, and IR is limited. Here, we showed that BBR could effectively rectify steatohepatitis and glucose intolerance in high-fat diet (HFD)-fed mice. BBR reorganized gut microbiota populations under both the normal chow diet (NCD) and HFD. Particularly, BBR noticeably decreased the relative abundance of BCAA-producing bacteria, including order Clostridiales; families Streptococcaceae, Clostridiaceae, and Prevotellaceae; and genera Streptococcus and Prevotella. Compared with the HFD group, predictive metagenomics indicated a reduction in the proportion of gut microbiota genes involved in BCAA biosynthesis but the enrichment genes for BCAA degradation and transport by BBR treatment. Accordingly, the elevated serum BCAAs of HFD group were significantly decreased by BBR. Furthermore, the Western blotting results implied that BBR could promote the BCAA catabolism in the liver and epididymal white adipose tissues of HFD-fed mice by activation of the multienzyme branched-chain α-ketoacid dehydrogenase complex (BCKDC), whereas by inhibition of the phosphorylation state of BCKDHA (E1α subunit) and branched-chain α-ketoacid dehydrogenase kinase (BCKDK). The ex vivo assay further confirmed that BBR could increase BCAA catabolism in both AML12 hepatocytes and 3T3-L1 adipocytes. Finally, data from healthy subjects and diabetics confirmed that BBR could improve glycemic control and modulate circulating BCAAs. Together, our findings clarified BBR improving IR associated not only with gut microbiota alteration in BCAA biosynthesis but also with BCAA catabolism in liver and adipose tissues.

Poor site-specific delivery and incapable deep-penetration into tumor are the intrinsic limitations to successful chemotherapy. Here, the tumor-homing penetrating peptide tLyP-1-functionalized nanoparticles (tLPTS/HATS NPs), composed of two modularized amphiphilic conjugates of tLyP-1-PEG-TOS (tLPTS) and TOS-grafted hyaluronic acid (HATS), had been fabricated for tumor-targeted delivery of docetaxel (DTX). The prepared tLPTS/HATS NPs had about 110 nm in mean diameter, high drug encapsulation efficiency (93%), and sustained drug release behavior. In vitro studies demonstrated that the tLPTS/HATS NPs exhibited enhanced intracellular delivery and much better anti-invasion ability, cytotoxicity, and apoptosis against both invasive PC-3 and MDA-MB-231 cells as compared to the non-tLyP-1-functionalized HATS NPs. The remarkable penetrability and inhibitory effect on both PC-3 and MDA-MB-231 multicellular tumor spheroids were also identified for the tLPTS/HATS NPs. In vivo biodistribution imaging demonstrated the tLPTS/HATS NPs possessed much more lasting accumulation and extensive distribution throughout tumor regions than the HATS NPs. The higher in vivo therapeutic efficacy with lower systemic toxicity of the tLPTS/HATS NPs was also verified by the PC-3 xenograft model in athymic nude mice. These results suggested that the designed novel tLPTS/HATS NPs were endowed with tumor recognition, internalization, penetration, and anti-invasion, and thus might be a promising anticancer drug delivery vehicle for targeted cancer therapy.

Multidrug resistance (MDR) presents a clinical obstacle to cancer chemotherapy. The main purpose of this study was to evaluate the potential of a hyaluronic acid (HA) and α-tocopheryl succinate (α-TOS) based nanoparticle to enhance cancer cell recognition and overcome MDR, and to explore the underlying mechanisms. A multifunctional nanoparticle, HTTP-50 NP, consisted of HA-α-TOS (HT) conjugate and d-α-tocopheryl polyethylene glycol succinate (TPGS) with docetaxel loaded in its hydrophobic core. The promoted tumor cell recognition and accumulation, cytotoxicity, and mitochondria-specific apoptotic pathways for the HTTP-50 NP were confirmed in MCF-7/Adr cells (P-gp-overexpressing cancer model), indicating that the formulated DTX and the conjugated α-TOS in the HTTP-50 NP could synergistically circumvent the acquired and intrinsic MDR in MCF-7/Adr cells. In vivo investigation on the MCF-7/Adr xenografted nude mice models confirmed that HTTP-50 NP possessed much higher tumor tissue accumulation and exhibited pronouncedly enhanced antiresistance tumor efficacy with reduced systemic toxicity compared with HTTP-0 NP and Taxotere. The mechanisms of the multifunctional HTTP-50 NP to overcome MDR and enhance antiresistance efficacy may be contributed by CD44 receptor-targeted delivery and P-gp efflux inhibition, and meanwhile to maximize antitumor efficacy by synergism of DTX and mitocan of α-TOS killing tumor cells.

There are several obstacles in the process of successful treatment of malignant tumors, including toxicity to normal cells, inefficiency of drug permeation and accumulation into the deep tissue of solid tumor, and multidrug resistance (MDR). In this work, we prepared docetaxel (DTX)-loaded hybrid micelles with DSPE–PEG and TPGS (TPGS/DTX-M), where TPGS serves as an effective P-gp inhibitor for overcoming MDR, and active targeting hybrid micelles (FA@TPGS/DTX-M) with targeting ligand of folate on the hybrid micelles surface offering active targeting to folate receptor-overexpressed tumor cells. A systematic comparative evaluation of these micelles on cellular internalization, sub-cellular distribution, antiproliferation, mitochondrial membrane potential, cell apoptosis and cell cycle, permeation and inhibition on 3-dimensional multicellular tumor spheroids, as well as antitumor efficacy and safety assay in vivo were well performed between sensitive KB tumors and resistant KBv tumors, and among P-gp substrate or not. We found that the roles of folate and TPGS varied due to the sensitivity of tumors and the loaded molecules in the micelles. Folate and folate receptor-mediated endocytosis played a leading role in internalization, permeation and accumulation for sensitive tumors and non-substrates of P-gp. On the contrary, TPGS played the predominant role which dramatically decreased the efflux of drugs both when the tumor is resistant and for P-gp substrate. These findings are very meaningful for guiding the design of carrier delivery system to treat tumors. The antitumor efficacy in xenograft nude mice model and safety assay showed that the TPGS/DTX-M and FA@TPGS/DTX-M significantly exhibited higher antitumor activity against resistant KBv tumors than the marketed formulation and normal micelles owing to the small size (approximately 20 nm), hydrophilic PEGylation, TPGS inhibition of P-gp function, and folate receptor-modified endocytosis, permeation and accumulation in solid tumor, as well as synergistic effects of DTX-induced cell division inhibition, growth restraint and TPGS-triggered mitochondrial apoptosis in tumor cells. In conclusion, folate-modified TPGS hybrid micelles provide a synergistic strategy for effective delivery of DTX into KBv cells and overcoming MDR.

Purpose: The purposes of this study were to analyze the technique movement as grand battement derrie in Chinese dance, to examine the tiny change in muscles during this skill, and to know what factor dominate this technique. Methods: Twenty-two female university in dance department students volunteered to participate in this study. Strength of bilateral paraspinatus muscles and gluteus muscles were calculated using load-cells, flexibility of trunk and hip were evaluated by goniometers, and the fine changes of muscular activity were measured by electromyography. All subjects performed eight times of grand battement in Chinese dance and scored by professional dancer to define the esthetics score of this technique. Results: The dominant side exhibited shorter reaction time than non-dominant side in paraspinatus muscles and gluteus muscles, high level group showed longer muscular activity and shorter resting time than lower level group, which were observed by electromyography. Higher level group were significant greater and better than lower level group in gluteus muscular strength and hip flexibility, but not in trunk. There was significant positive correlation between muscular strength of gluteus and score of technique, but not in trunk. There was significant positive correlation between hip flexibility and esthetics score of technique, yet not in trunk. Conclusion: There are faster reaction times in dominate side to provide the stability before motion occurred. The gluteus muscles and hip flexibilities are the key factor for the performance in grand battement derrie in Chinese dance.

Background: Warm-up before exercise could increase blood flow of whole body, increase muscles and skin temperature, prevent injury within exercise. Passive warm-up can increase temperature of muscles as active warm-up do, but it won’t cause the muscle fatigue. To use heat packs or to apply ultrasound is the way for passive warm-up. Purpose: To determine the effects of two different modalities of passive warmup and exercise without warm-up on exercise performance and recovery on muscle damage. Methods: Eight volunteers were participated in this study (age =23.88±5.06 y/o), and all of them were involved into three groups as control group (CON), heat packing group (HP) and ultrasound group (USD). CON never received any warm-up protocol before eccentric exercise, HP received 15 minutes of superficial heat with electrical heat pack before exercise, and USD received 7 minutes of deep heat with ultrasound diathermy before exercise. Each subject processed 30 repeated bouts of eccentric exercise with 80% MVC level. Serum CK, MVC, ROM and CIR were measured before, immediately after exercise and at 2nd, 4th, 7th, and 10th days post-exercise. Results: When measuring serum CK and CIR, there were no significant difference between CON, HP and USD (p>0. 05). When measuring ROM and MVC, there were significant difference between CON, HP and USD (p

Introduction The most common symptoms after ankle sprains were chronic ankle instability, proprioception defect and probable neuromuscular adaptation. The purpose of this study was to identify the normal landing pattern using detailed biomechanical analysis including analysis of the kinematics and ground reaction force, and to compare the landing pattern in the subjects with recurrent ankle sprain and normal subjects. METHODS Ten male adults were recruited in this study (5 subjects with recurrent lateral ankle sprains group, 5 subjects with normal control group). All subjects would be asked to perform maximal standing jumps and drop landing from 3 platforms with different heights (0.37 m, 0.67 m, & 0.97 m, respectively). Those movements were collected by VICON 512 (Oxford Metrics, UK) motion analysis system and the kinematics was analyzed using self making software with MATLAB. The ground reaction force of both lower limbs was recorded by two AMTI force platforms, and the kinetic data were calculated with inverse dynamics. RESULTS In the different landing height, the main differences of kinematics were the maximum flexion angles of hip and knee joints in normal landing patterns and the flexion angles increased with the landing height, as well as the flexion of pelvis, hip abduction, and knee external rotation in the subjects with recurrent ankle sprains. When compare those two groups, the landing pattern in the subjects with recurrent ankle sprain was significant smaller than normal subjects in knee flexion (65.71°±6.43° vs. 70.19°±13.76°) and hip flexion (34.15°±5.42° vs. 42.54°±10.07°). The time to maximum angles in ankle dorsiflexion and foot pronation were also quite different between these two groups. The maximum vertical ground reaction force in sprain group was significant smaller than normal group. CONCLUSION In this study, we have revealed the adaptation of performing drop landing in the individuals with recurrent ankle sprains. It could be considered as a recommendation of the rehabilitation..