Uptake and transport of a novel anticancer drug-delivery system: lactosyl-norcantharidin-associated N-trimethyl chitosan nanoparticles across intestinal Caco-2 cell monolayers

In this paper, novel liver-targeting nanoparticles (NPs), lactosyl-norcantharidin (Lac-NCTD)-associated N-trimethyl chitosan (TMC) NPs (Lac-NCTD-TMC-NPs), were prepared using ionic cross-linkage. The physical properties, particle size, and encapsulation efficiency of the nanoparticles were then investigated. The continuous line of heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2) cell monolayer model was used to study the transport mechanism of Lac-NCTD, and the effects of factors such as time, temperature, pH level, drug concentration, enhancers, and inhibitors. This model was also used to indicate the differences among Lac-NCTD, Lac-NCTD-associated chitosan NPs (Lac-NCTD-CS-NPs), and Lac-NCTD-TMC- NPs in the absorption and transportation of membranes. Drug concentration levels were measured using high-performance liquid chromatography. Active transport and paracellular transport were suggested to be both the primary and secondary mechanisms for Lac-NCTD absorption, respectively. Lac-NCTD uptake and absorption were not controlled by pH levels, but were positively correlated to uptake time, and negatively correlated to temperature. The basolateral to apical apparent permeability coefficients (Papps) were higher than those of the apical to basolateral values. The inhibitor of P-glycoprotein and the multidrug resistance-associated protein 2 significantly enhanced the uptake amount of Lac-NCTD. Compared with Lac-NCTD, Lac-NCTD-CS-NPs and Lac-NCTD-TMC-NPs significantly enhanced drug absorption. Additionally, the latter exhibited stronger action. Lac-NCTD-NPs could penetrate the plasma membrane of Caco-2 cells and translocate into the cytoplasm and even into the nucleus. Nanoparticles were uptaken into Caco-2 cells through the endocytosis pathway

Pharmacokinetics, tissue distribution, and metabolites of a polyvinylpyrrolidone-coated norcantharidin chitosan nanoparticle formulation in rats and mice, using LC-MS/MS

A novel formulation containing polyvinylpyrrolidone (PVP) K30-coated norcantharidin (NCTD) chitosan nanoparticles (PVP–NCTD–NPs) was prepared by ionic gelation between chitosan and sodium tripolyphosphate. The average particle size of the PVP–NCTD–NPs produced was 140.03 ± 6.23 nm; entrapment efficiency was 56.33% ± 1.41%; and drug-loading efficiency was 8.38% ± 0.56%. The surface morphology of NCTD nanoparticles (NPs) coated with PVP K30 was characterized using various analytical techniques, including X-ray diffraction and atomic force microscopy. NCTD and its metabolites were analyzed using a sensitive and specific liquid chromatography-tandem mass spectrometry method with samples from mice and rats. The results indicated the importance of the PVP coating in controlling the shape and improving the entrapment efficiency of the NPs. Pharmacokinetic profiles of the NCTD group and PVP–NCTD–NP group, after oral and intravenous administration in rats, revealed that relative bioavailabilities were 173.3% and 325.5%, respectively. The elimination half-life increased, and there was an obvious decrease in clearance. The tissue distribution of NCTD in mice after the intravenous administration of both formulations was investigated. The drug was not quantifiable at 6 hours in all tissues except for the liver and kidneys. The distribution of the drug in the liver and bile was notably improved in the PVP–NCTD–NP group. The metabolites and excretion properties of NCTD were investigated by analyzing rat feces and urine samples, collected after oral administration. A prototype drug and two metabolites were found in the feces, and seven metabolites in the urine. The primary elimination route of NCTD was via the urine. The quantity of the parent drug eliminated in the feces of the PVP–NCTD–NP group, was 32 times greater than that of the NCTD group, indicating that the NPs dramatically increased the reduction quantity from liver to bile. We conclude that PVP–NCTD–NPs are an adequate formulation for enhancing the absorption of NCTD, and significantly improving therapeutic effects targeting the hepatic system. Decarboxylation and hydroxylation were the dominant metabolic pathways for NCTD. Metabolites were mainly excreted into rat kidney and finally into urine

Electroacupuncture for poststroke spasticity (EAPSS): protocol for a randomised controlled trial

Introduction Spasticity is a common complication of stroke. Current therapies for poststroke spasticity (PSS) have been reported to be associated with high costs, lack of long-term benefit and unwanted adverse events (AEs). Electroacupuncture (EA) has been used for PSS, however, its efficacy and safety is yet to be confirmed by high-quality clinical studies. This study is designed to evaluate the add-on effects and safety profile of EA when used in combination with usual care (UC). Methods and analysis This study is a parallel group randomised controlled trial. A total of 136 participants will be included and randomly assigned to either the treatment group (EA plus UC) or the control group (UC alone). Prior to the main trial, a pilot study involving 30 participants will be conducted to assess the feasibility of the trial protocol. EA will be administered by registered acupuncturists for 20min to 30 min, three times per week for 4 weeks. The primary outcome measure (Modified Ashworth Scale) and secondary outcome measures (Fugl-Meyer Assessment and Barthel Index) will be evaluated at baseline, the end of treatment (week 4) and the end of follow-up (week 8). AEs will be monitored, recorded and reported, and their causality will be explored. Ethics and dissemination Ethics approval was obtained from the ethics committees of Guangdong Provincial Hospital of Chinese Medicine and RMIT University in December 2016. The results will be disseminated in a peer-reviewed journal, and PhD theses and might be presented at international conferences

Soil-transmitted helminth infections and physical fitness in school-aged Bulang children in southwest China: results from a cross-sectional survey

BACKGROUND: Chronic soil-transmitted helminth (STH) infections have been associated with reduced physical fitness, but available evidence is limited. The aim of this cross-sectional survey was to assess the feasibility of measuring children's physical fitness and to relate it to STH infections. Our study was carried out among school-aged children of the Bulang ethnic group in rural southwest People's Republic of China (P.R. China). Standardized, quality-controlled methods were employed to determine STH infections (Kato-Katz technique), haemoglobin levels, anthropometry (body weight and height) and physical fitness (20-m shuttle run test). RESULTS: A compliance of 87% suggested good acceptance of the methods used. Among 69 children with complete data records, infection prevalence of Trichuris trichiura, Ascaris lumbricoides and hookworm were 81%, 44% and 6%, respectively. The maximum volume of oxygen that can be utilized within 1 min during exhaustive exercise (VO2 max estimate) of T. trichiura-infected children was 1.94 ml kg1 min1 lower than that of their non-infected counterparts (P = 0.005). Until exhaustion, T. trichiura-infected children had completed 6.14 20-m laps less (P = 0.004). Additionally, the mean VO2 max estimate of stunted children was lowered by 1.63 ml kg1 min1 (P = 0.002) and they completed 5.32 20-m laps less (P = 0.001) compared to children of normal stature. No significant association between stunting and infection with any STH species could be established. CONCLUSIONS: Implementation of physical fitness tests in rural, resource-constraint settings is feasible. The physical fitness of children who are stunted or infected with STHs, particularly T. trichiura, is significantly impaired. We have launched a larger study and will determine the dynamics of school-aged children's physical fitness over a 7-month period after administration of anthelminthic drugs

SPECIFIC NEUROPROTECTIVE EFFECTS OF MANUAL STIMULATION OF REAL ACUPOINTS VERSUS NON-ACUPOINTS IN RATS AFTER MIDDLE CEREBRAL ARTERY OCCLUSION

The objective of this study was to investigate the effectiveness and specific effects of acupuncture on ischemic-induced damage in rats after permanent middle cerebral artery occlusion. Cerebral ischemia was induced by middle cerebral artery occlusion in male Wistar rats. The rats were divided into the following 4 groups: normal controls, ischemic, real acupuncture-treated (Shuigou, DU26), and non-acupoint-treated groups. On the third postoperative day, neurological deficit scores, cerebral blood flow, infarction volume, and neuronal cell death counts were measured. In the real acupuncture-treated group, the neurological deficit scores and cerebral blood flow were improved (p < 0.05) and the infarction volume and neuronal cell death counts were reduced (p < 0.01) compared to the ischemic and non-acupoint-treated groups. The present study demonstrated that real acupuncture was effective against focal ischemia-induced damage in rats after middle cerebral artery occlusion, and the effects were specifically related to the right needling location

Novel norcantharidin-loaded liver targeting chitosan nanoparticles to enhance intestinal absorption

In this paper, two novel liver-targeting nanoparticles, norcantharidin-loaded chitosan nanoparticles (NCTD-CS-NPs) and norcantharidin-associated galactosylated chitosan nanoparticles (NCTD-GC-NPs), were prepared using ionic cross-linkage. The physical properties, particle size, encapsulation efficiency, and drug release characteristics of the nanoparticles were investigated in vitro. To investigate the intestinal absorption mechanisms of the two preparations, a series of experiments was carried out, including in situ circulation method, in vitro everted gut sacs, and Ussing chamber perfusion technique. The absorption rate constants (Ka) of NCTD at different segments were found to be duodenum > jejunum > ileum > colon. The concentration had no distinctive effect on absorption kinetics, suggesting that drug absorption is not dose-dependent. The transport of NCTD was found to be inhibited by P-glycoprotein (P-gp) inhibitor, indicating that NCTD might be the substrate of P-gp. The order of the absorption enhancer effects were as follows: low molecular weight chitosan (CS-8kDa) > high molecular weight chitosan (CS-30kDa) > Poloxamer > sodium dodecyl sulfate (SDS) > sodium deoxycholate (SDCh). The results indicate that the chitosan nanoparticles can improve intestinal absorption of NCTD

Towards a global One Health index: a potential assessment tool for One Health performance

BACKGROUND: A One Health approach has been increasingly mainstreamed by the international community, as it provides for holistic thinking in recognizing the close links and inter-dependence of the health of humans, animals and the environment. However, the dearth of real-world evidence has hampered application of a One Health approach in shaping policies and practice. This study proposes the development of a potential evaluation tool for One Health performance, in order to contribute to the scientific measurement of One Health approach and the identification of gaps where One Health capacity building is most urgently needed. METHODS: We describe five steps towards a global One Health index (GOHI), including (i) framework formulation; (ii) indicator selection; (iii) database building; (iv) weight determination; and (v) GOHI scores calculation. A cell-like framework for GOHI is proposed, which comprises an external drivers index (EDI), an intrinsic drivers index (IDI) and a core drivers index (CDI). We construct the indicator scheme for GOHI based on this framework after multiple rounds of panel discussions with our expert advisory committee. A fuzzy analytical hierarchy process is adopted to determine the weights for each of the indicators. RESULTS: The weighted indicator scheme of GOHI comprises three first-level indicators, 13 second-level indicators, and 57 third-level indicators. According to the pilot analysis based on the data from more than 200 countries/territories the GOHI scores overall are far from ideal (the highest score of 65.0 out of a maximum score of 100), and we found considerable variations among different countries/territories (31.8–65.0). The results from the pilot analysis are consistent with the results from a literature review, which suggests that a GOHI as a potential tool for the assessment of One Health performance might be feasible. CONCLUSIONS: GOHI—subject to rigorous validation—would represent the world’s first evaluation tool that constructs the conceptual framework from a holistic perspective of One Health. Future application of GOHI might promote a common understanding of a strong One Health approach and provide reference for promoting effective measures to strengthen One Health capacity building. With further adaptations under various scenarios, GOHI, along with its technical protocols and databases, will be updated regularly to address current technical limitations, and capture new knowledge. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40249-022-00979-9