L-carnitine prevents lenvatinib-induced muscle toxicity without impairment of the anti-angiogenic efficacy.

Lenvatinib is an oral tyrosine kinase inhibitor that acts on multiple receptors involved in angiogenesis. Lenvatinib is a standard agent for the treatment of several types of advanced cancers; however, it frequently causes muscle-related adverse reactions. Our previous study revealed that lenvatinib treatment reduced carnitine content and the expression of carnitine-related and oxidative phosphorylation (OXPHOS) proteins in the skeletal muscle of rats. Therefore, this study aimed to evaluate the effects of L-carnitine on myotoxic and anti-angiogenic actions of lenvatinib. Co-administration of L-carnitine in rats treated with lenvatinib for 2 weeks completely prevented the decrease in carnitine content and expression levels of carnitine-related and OXPHOS proteins, including carnitine/organic cation transporter 2, in the skeletal muscle. Moreover, L-carnitine counteracted lenvatinib-induced protein synthesis inhibition, mitochondrial dysfunction, and cell toxicity in C2C12 myocytes. In contrast, L-carnitine had no influence on either lenvatinib-induced inhibition of vascular endothelial growth factor receptor 2 phosphorylation in human umbilical vein endothelial cells or angiogenesis in endothelial tube formation and mouse aortic ring assays. These results suggest that L-carnitine supplementation could prevent lenvatinib-induced muscle toxicity without diminishing its antineoplastic activity, although further clinical studies are needed to validate these findings.

Clinical observation of acupuncture combined with modern rehabilitation in the treatment of limb motor dysfunction after ischemic stroke: A randomized controlled trial.

BACKGROUND: Motor dysfunction is a common sequela of ischemic stroke. This study aimed to explore the effective treatment of ischemic stroke by combining acupuncture and modern rehabilitation training. METHODS: This study was a single-center, randomized controlled clinical trial conducted at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine, 90 cases were finally included, divided into 45 cases each in the body acupuncture group and the head acupuncture group. INTERVENTIONS: Both groups received basic drug treatment, modern rehabilitation training, and basic life care guidance; the body acupuncture group was treated with reference to acupuncture points from the classic textbook of acupuncture and moxibustion, and the head acupuncture group was given Zhu's scalp acupuncture treatment based on the body acupuncture group. Primary outcome index: unassisted muscle strength grading scale; secondary outcome index: assessment of activities of daily living; simplified Fugl-Meyer motor function rating scale. RESULTS: The Barthel scale score, Manual Muscle Testing scale score (upper and lower limbs), and simplified Fugl-Meyer scale score (upper and lower limbs) in the 2 groups were improved (P ≤ .05), and the efficacy of the head-acupuncture group was better than that of the body-acupuncture group (P ≤ .05); there was no significant improvement in the simplified Fugl-Meyer scale (hand) score in both groups (P ≥ .05). There was no significant improvement in these scores (P ≥ .05). The difference in efficiency between the 2 groups was not statistically significant (P ≤ .05), and the apparent efficiency in the cephalic needle group was higher than that in the body needle group (P ≤ .05). CONCLUSIONS: Simultaneous treatment with Zhu's scalp acupuncture and body acupuncture combined with modern rehabilitation training can significantly improve limb motor function in patients with ischemic stroke, and its efficacy is better than that of body acupuncture alone combined with modern rehabilitation training.

Lenvatinib causes reduced expression of carnitine/organic cation transporter 2 and carnitine deficiency in the skeletal muscle of rats.

Lenvatinib, an oral tyrosine kinase inhibitor, is widely used to treat several types of advanced cancers but often causes muscular adverse reactions. Although carnitine supplementation may prevent these effects, the mechanism underlying lenvatinib-induced skeletal muscle impairment remains poorly understood. To this end, we aimed to investigate the impact of lenvatinib on carnitine disposition in rats. Once-daily administration of lenvatinib repeated for two weeks did not affect urinary excretion or serum concentration of carnitines throughout the treatment period but ultimately decreased the L-carnitine content in the skeletal muscle. The treatment decreased the expression of carnitine/organic cation transporter (OCTN) 2, a key transporter of carnitine, in skeletal muscle at the protein level but not at the mRNA level. In cultured C2C12 myocytes, lenvatinib inhibited OCTN2 expression in a dose-dependent manner at the protein level. Furthermore, lenvatinib dose-dependently decreased the protein levels of carnitine-related genes, adenosine triphosphate content, mitochondrial membrane potential, and markers of mitochondrial function in vitro. These results reveal the deleterious effects of lenvatinib on OCTN2 expression, carnitine content, and mitochondrial function in skeletal muscle that may be associated with muscle toxicity.

Effect of a dentifrice containing different particle sizes of hydroxyapatite on dentin tubule occlusion and aqueous Cr (VI) sorption.

BACKGROUND: Dentin hypersensitivity is a common negative oral condition that can be treated with dentifrice containing hydroxyapatite (HA). The study evaluated the effect of nano-HA dentifrice on plugging the dentinal tubules for an anti-sensitivity reaction compared to a dentifrice containing common-sized particles. Also, the adsorption capacity of different particle sizes of HA mixed in a dentifrice and which is the optimal particle size was considered. METHODS: Fourty premolar dentine discs and fourty molar dentine discs were randomly divided into 4 groups: distilled water group, ordinary dentifrice group and 80, 300 nm HA dentifrice group. Each dentin disc was brushed with a dentifrice twice daily at 7600 rpm under 100 g force for 2 mins for 7 consecutive days and divided into two parts, half of the dentin disc was detected by the scanning electron microscope (SEM) and energy dispersive spectrometer (EDS), the other half was brushed with distilled water and observed by SEM. One milliliter dentifrice solution (80 nm HA dentifrice, 300 nm HA dentifrice, ordinary dentifrice) was added to 50 ml potassium dichromate solution for 1, 14, and 28 d. The residual Chromium (Cr6+) concentration in the supernatant was measured by the diphenylcarbon phthalocyanine hydrazine method. The elemental constitution in the precipitate was detected by EDS. The Kruskal-Wallis test was used to analyze surface mineralization and different plugging rates of dentinal tubules. The absorption capacity of dentifrices were also evaluated by the Kruskal-Wallis test. RESULTS: The plugging rate in the HA dentifrice group was higher than that in the ordinary dentifrice group, and the 80 nm HA dentifrice group showed the best result. The atomic percentages of Ca and P of 80 nm dentifrice group on the surface of dentinal tubules were the highest. The 80 nm HA dentifrice group showed the best adsorption and stable effect of Cr6+, followed by the 300 nm HA dentifrice group. The 300 nm HA dentifrice and the ordinary dentifrice showed desorption phenomenon. CONCLUSIONS: The dentifrice containing HA, especially the 80 nm HA dentifrice, exerts good dentinal tubule occlusion and surface mineralization effect. This dentifrice was also a good adsorbent of Cr6+.

Purification, characterization, and biological activities of broccolini lectin.

Plant lectins have displayed a variety of biological activities. In this study, for the first time, a 27 kDa arabinose- and mannose-specific lectin from Broccolini (Brassica oleracea Italica × Alboglabra), named as BL (Broccolini lectin), was purified by an activity-driven protocol. Mass spectrometry analysis and database search indicated that no matches with any plant lectin were found, but BL contained some peptide fragments (QQQGQQGQQLQQVISR, QQGQQQGQQGQQLQQVISR and VCNIPQVSVCPF QK). BL exhibited hemagglutinating activity against chicken erythrocytes at 4 µg/mL. BL retained full hemagglutinating activity at pH 7-8 and temperature 30-40°C, and had an optimal activity in Ca(2+) solution. Bioactivity assay revealed that BL exhibited dose-dependent inhibition activity on 5 bacterial species with IC50 values of 143.95-486.33 µg/mL, and on 3 cancer cells with IC50 values of 178.82-350.93 µg/mL. Notably, 5-fold reduction in IC50 values was observed on normal L-O2 vs cancerous HepG-2 cells (924.35 vs. 178.82 µg/mL). This suggests that BL should be promising in food and medicine.

Anti-inflammatory diterpenoids from the root bark of Acanthopanax gracilistylus.

Five new ent-pimarane (1-3, 7, and 8) and three new ent-kaurane diterpenoids (4-6) and a new oleanane triterpene acid (9), together with 22 known compounds, were isolated from the root bark of the medicinal herb Acanthopanax gracilistylus. The structures of 1-9 were established based on the interpretation of high-resolution MS and 1D- and 2D-NMR data. The absolute configurations of 7 and 11 were determined by single-crystal X-ray diffraction and electronic circular dichroism analysis. Compounds 7 and 8 represent rare naturally occurring structures based on the devinyl ent-pimarane skeleton. Compounds 3, 10, 14, 16, and 17 exhibited potent inhibitory effects on the release of interleukin-1ß (IL-1ß), interleukin-8 (IL-8), and tumor necrosis factor (TNF-α) in lipopolysaccharide-stimulated peripheral blood mononuclear cells.

A rapid and convenient method for preparative separation of three indissolvable polyphenols from Euphorbia pekinensis by the flexible application of solvent extraction combined with counter-current chromatography.

A rapid and convenient method was established to preparatively isolate the three ellagic acid types of compounds, which were the main polyphenols in Euphorbia pekinensis, by flexibly applying solvent extraction combined with counter-current chromatography (CCC). The total extract (extracted using 95% ethanol) of E. pekinensis was pretreated by two simple steps before CCC isolation, following the procedure: the total extract was extracted by classical solvent extraction using petroleum ether and ethyl acetate, respectively, and then the ethyl acetate extract was suspended using 95% ethanol, after being allowed to stand overnight, the sediment was obtained. Partial sediment (100 mg) was then directly separated by CCC with a two-phase solvent system composed of chloroform-95% ethanol-water-85% formic acid (50:50:50:5, v/v/v/v). About 22 mg of 3,3'-dimethoxy ellagic acid (1), 12 mg of 3,3'-di-O-methyl-4-O-(ß-D-xylopyranosyl)ellagic acid (2), and 35 mg of ellagic acid (3) with purities of 96.0, 95.2, and 95.4% were obtained respectively in one step within 4 h. After being purified by washing with methanol, the purities of the three compounds obtained were all above 98%. The purities were determined by HPLC and their chemical structures were further identified by (1)H and (13)C NMR spectroscopy. The recoveries were calculated as 84.6, 85.7, and 89.5%, respectively. The result demonstrated that the present isolation method was rapid, economical and efficient for the preparative separation of polyphenols from E. pekinensis.

(-)-Gossypol-enriched cottonseed oil inhibits proliferation and adipogenesis of human breast pre-adipocytes.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women. Obesity is an important risk factor for developing breast cancer and is one of few risk factors that women can modify to prevent cancer. (-)-Gossypol-enriched cottonseed oil [(-)-GPCSO] contains 65% (-)-gossypol and 35% (+)-gossypol. Previous studies have demonstrated that both (-)-gossypol and (-)-GPCSO have potent anticancer activity against multiple types of cancer, including breast cancer. In addition, (-)-GPCSO reduced body weight gain and food intake in young female rats. However, the role of (-)-GPCSO on adipogenesis in human breast pre-adipocytes remains unclear. MATERIALS AND METHODS: Primary human breast pre-adipocytes were induced to differentiate in adipogenic medium in the presence of (-)-GPCSO. The proliferation of pre-adipocytes was determined with a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2-H-tetrazolium (MTS) assay. Lipid accumulation and glycerol 3-phosphate dehydrogenase (GPDH) activity were measured during adipocyte differentiation. mRNA expression of cyclin-D1, B-cell lymphoma-2 (BCL-2), Peroxisome Proliferator-Activated Receptor-γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα) and leptin was analyzed by real-time PCR. RESULTS: (-)-GPCSO inhibited proliferation of pre-adipocytes and down-regulated the expression of cyclin-D1 and BCL-2. (-)-GPCSO also significantly decreased adipogenesis, as determined by inhibition of GPDH activity, triglyceride content (TG), and down-regulation of the expression of PPARγ, C/EBPα and leptin. CONCLUSION: These findings suggest that (-)-GPCSO has the potential as a food supplement to inhibit adipogenesis, and therefore, reduce obesity.

Chemical constituents of Spatholobus suberectus.

AIM: To investigate chemical constituents of Spatholobus suberectus Dunn. METHODS: Isolation and purification were carried out by column chromatographic methods. Compounds were characterized based on their physical characteristics and spectra data. RESULTS: Seventeen compounds were isolated from ethanol extract of S. suberectus. The structures were elucidated as prestegane B (1), (2R, 3R)-buteaspermanol (2), (+)-medioresinol (3), (2R, 3R)-3,7-dihydroxyflavanone (4), benzeneethanol (5), 4, 7, 2'-trihydroxy-4'-methoxyisoflavanol (6), naringenin (7), blumenol A (8), protocatechuic acid ethyl ester (9), liquiritigenin (10), 7, 4'-dihydroxy-8-methoxy-isoflavone (11), 3, 5, 7, 3', 5'-pentahydroxyflavanone (12), protocatechuic acid (13), glycyroside (14), 8-methylretusin-7-O-ß-D-glucopyranoside (15), 3, 3', 4', 5, 6, 7, 8-heptahydroxyflavan (16), and dulcisflavan (17). CONCLUSION: All compounds are firstly isolated from the title plant and compounds 1, 3 were isolated from the Spatholobus genus for the first time.

Effects of dentifrice containing hydroxyapatite on dentinal tubule occlusion and aqueous hexavalent chromium cations sorption: a preliminary study.

In order to endow environmental protection features to dentifrice, hydroxyapatite (HA) was added to ordinary dentifrice. The effects on dentinal tubule occlusion and surface mineralization were compared after brushing dentine discs with dentifrice with or without HA. The two types of dentifrice were then added to 100 µg/ml of hexavalent chromium cation (Cr(6+)) solution in order to evaluate their capacities of adsorbing Cr(6+) from water. Our results showed that the dentifrice containing HA was significantly better than the ordinary dentifrice in occluding the dentinal tubules with a plugging rate greater than 90%. Moreover, the effect of the HA dentifrice was persistent and energy-dispersive spectrometer (EDS) revealed that the atomic percentages of calcium and phosphorus on the surface of dentine discs increased significantly. Adding HA to ordinary dentifrice significantly enhanced the ability of dentifrice to adsorb Cr(6+) from water with the removal rate up to 52.36%. In addition, the sorption was stable. Our study suggests that HA can be added to ordinary dentifrice to obtain dentifrice that has both relieving dentin hypersensitivity benefits and also helps to control environmental pollution.

Separation of four homoisoflavonoids from Caesalpinia sappan by high-speed counter-current chromatography.

INTRODUCTION: The main chemical constituents of Caesalpinia sappan are homoisoflavonoids. Conventional column chromatographic techniques used for isolation of this type of compounds are tedious, time-consuming and waste solvents. High-speed counter-current chromatography (HSCCC) could be a suitable alternative for the enrichment and purification of these target compounds from traditional Chinese medicine (TCM). OBJECTIVE: To establish a method to isolate four homoisoflavonoids in one-step separation from C. sappan by HSCCC. METHODOLOGY: The crude extract of C. sappan was fractionated by HSCCC using a two-phase solvent system consisting of chloroform-methanol-water (4:3:2, v/v/v). The separation conditions were: flow rate, 1.0 mL/min; revolution speed, 900 rpm; detection wavelength, 280 nm; separation temperature, 25 °C; sample size, 120 mg crude sample dissolved in a mixture of the upper and lower phases (10 mL each). The retention of the stationary phase was 83%. RESULTS: Five milligrams of 3'-deoxysappanol, 8 mg of 3-deoxysappanone B, 20 mg of 4-O-methylsappanol and 18 mg of brazilin were obtained in one-step separation from 120 mg of an ethyl acetate extracted fraction of C. sappan. Their purities were 99%, 97%, 90% and 85% by HPLC analysis. The mean recoveries of the four compounds were 83%, 86%, 93% and 85%, respectively. CONCLUSION: The study has shown that HSCCC is effective for the separation and enrichment of the target compounds at a large scale.

Liposomes containing (-)-gossypol-enriched cottonseed oil suppress Bcl-2 and Bcl-xL expression in breast cancer cells.

PURPOSE: We have demonstrated that (-)-gossypol-enriched cottonseed oil [(-)-GPCSO] can down-regulate Bcl-2 expression in MCF-7 and primary cultured human breast cancer epithelial cells (PCHBCECs). However, this agent has not been evaluated in vivo due to its limited solubility. We aimed to develop liposomes containing (-)-GPCSO to suppress Bcl-2/Bcl-xL expression. METHODS: (-)-GPCSO liposomes were prepared and evaluated for effects on breast cancer cell viability, MDA-MB-231 xenograft tumor growth, cellular Bcl-2 and Bcl-xL mRNA levels, and chemosensitivity to paclitaxel. RESULTS: (-)-GPCSO liposomes prepared had excellent stability. Cytotoxicity of (-)-GPCSO liposomes was significantly reduced compared to (-)-GPCSO in culture medium. Bcl-2 and Bcl-xL mRNA expression was down-regulated by (-)-GPCSO in culture medium or (-)-GPCSO liposomes in MDA-MB-231 cells. In PCHBCECs, Bcl-2 and Bcl-xL expression were down-regulated by (-)-GPCSO liposomes. (-)-GPCSO in culture medium induced only a mild reduction in Bcl-xL. In the MDA-MB-231 xenograft tumor model, (-)-GPCSO liposomes exhibited tumor-suppressive activity and significantly reduced intratumoral Bcl-2 and Bcl-xL expression. Cytotoxicity of paclitaxel was increased by pretreatment with (-)-GPCSO liposomes in MDA-MB-231 and PCHBCECs. CONCLUSIONS: Findings suggest that (-)-GPCSO liposomes warrant continued investigation as a chemosensitizer for breast cancers exhibiting Bcl-2-/Bcl-xL-mediated drug resistance.

Benzyl-beta-resorcylates from Cassia obtusifolia.

The seed of Cassia obtusifolia Linn have yielded three new compounds, 2-benzyl-4,6-dihydroxy benzoic acid (1), 2-benzyl-4,6-dihydroxy benzoic acid-6-O-beta-D-glucopyranoside (2) and 2-benzyl-4,6-dihydroxy benzoic acid-4-O-beta-D-glucopyranoside (3). Their structures were determined by spectroscopic methods, including (1)D- and (2)D NMR spectroscopy, HR-ESI-MS, as well as by comparison of their spectral data with those of related compounds.