Paeoniflorin-6'-o-benzene sulfonate ameliorates the progression of adjuvant-induced arthritis by inhibiting the interaction between Ahr and GRK2 of fibroblast-like synoviocytes.

Aryl hydrocarbon receptor (Ahr) is thought to be a crucial factor that regulates immune responses, which may be involved in the pathogenesis of autoimmune inflammation including rheumatoid arthritis (RA). The results of our group in recent years have shown that Paeoniflorin-6'-O-benzene sulfonate (code: CP-25), a novel ester derivative of paeoniflorin, has a good effect on improving RA animal models. However, whether the anti-arthritis effect of CP-25 is related to Ahr remains unclear. Here, we showed that CP-25 treatment ameliorated adjuvant-induced arthritis (AA), a rat model of RA, by inhibiting Ahr-related activities in fibroblasts like synoviocytes (FLS). AA rats were treated with CP-25 or paroxetine from days 17 to 33 after immunization. We showed that CP-25 alleviated arthritis symptoms and the pathological changes. Treatment with CP-25 decreased the expression of Ahr in the synovium of AA rats. CP-25 inhibited the expression of Ahr and the G protein-coupled receptor kinase 2 (GRK2) as well as the co-expression of GRK2 with Ahr in FLS of AA rats. Furthermore, CP-25 down-regulated the production of Kyn in FLS of AA rats. These results suggested that CP-25 may inhibit the expression and activation of Ahr. Besides, treatment with CP-25 reduced the proliferation and migration of MH7A caused by Ahr activation. In addition, we also demonstrated that CP-25 down-regulated the total and nuclear expression of Ahr and the expression of GRK2 in Kyn-treated MH7A. Moreover, the co-expression and co-localization of Ahr and GRK2in Kyn-treated MH7A were also repressed by CP-25. The data presented here demonstrated that CP-25 suppressed FLS dysfunction in rats with AA, which were associated with reduced Ahr activation and the interaction between Ahr and GRK2.

The Sirtuin-1 relied antioxidant and antiaging activity of 5,5'-diferulic acid glucoside esters derived from corn bran by enzymatic method.

Maize is the food crop with the highest total output in the world. However, corn bran is only a by-product with low price. The 5,5'-diferulic acid glucoside esters (DFG) were obtained from corn bran using the enzymatic method. DFG showed obvious antioxidant capacity in cell, Caenorhabditis elegans (C. elegans) and in mouse. DFG decreased ROS and MDA content in 500 µM H2 O2 stimulated ARPE-19 cells to 48.6% and 32.2%, respectively. DFG decreased ROS content in C. elegans to 49.1% and MDA content in acute ethanol (50%, 12 ml/kg) stimulated mouse to 30.4%. DFG also increased SOD protein content significantly in cell, C. elegans and mouse to 175.5%, 120.1%, and 126.2%, respectively. DFG significantly extended the lifespan of C. elegans both under heat stress and natural situation. The median survival time was prolonged to 133.3% and 116.7%, respectively. This capacity relied on the SIR-2.1 activity. SIR-2.1 is an ortholog of human Sirtuin-1 (SIRT-1). DFG also upregulated SIRT-1 and PCG-1α expression level obviously in H2 O2 -stimulated ARPE-19 cells (to 134.4% and 127.1%, respectively) and in acute ethanol stimulated mouse eyes (to 135.1% and 111.5%, respectively) and liver (to 123.3% and 113.6%, respectively). These results indicate that DFG has multiple bioactivities. Our research provides a new application prospect of corn bran. And to our best knowledge, this is the first time, the sirtuins-relied lifespan extension activity of the 5,5'-diferulic acid extracted from corn bran was reported. PRACTICAL APPLICATIONS: The traditional method for extracting diferulic acid from corn bran is to use the strong alkali. Obviously, this is not welcomed by the food industry. We employed the biological enzyme method in a relatively mild pH range during the extraction process. It is more environmentally friendly and more economical. DFG can be added as a raw material for functional foods like yogurt, fruit juice, and cereals. As well, the solid precipitate obtained after extraction can also be used as high-quality dietary fiber to produce functional food. Meanwhile, concerning for the 5,5'-diferulic acid derived from corn bran, the relevant research is still not abundant. And to our best knowledge, we have reported for the first time about the effect of this kinds of diferulic acid on prolonging life span and its SIRT-1-dependent activity. It also provides a new perspective for the study of diferulic acid.

[Effect of injecting mouse nerve growth factor in different ways on motor development, cerebral hemodynamics and biochemical metabolism in children with cerebral palsy].

OBJECTIVE: To compare the effect of acupoint injection and intramuscular injection with mouse nerve growth factor (mNGF) on gross motor function development of children with cerebral palsy (CP), and explore the treatment mechanism. METHODS: A total of 63 children with CP were randomly divided into an observation group (32 cases, 4 cases dropped off ) and a control group (31 cases, 3 cases dropped off). Based on the routine rehabilitation therapy, the control group received intramuscular injection of mNGF(18 µg/2 mL), and the observation group received acupoint injection of mNGF at Xinshu (BL 15), Ganshu (BL 18), Pishu (BL 20), Shenshu (BL 23), Sanjiaoshu (BL 22), Shenting (GV 24), Baihui (GV 20), Fengfu (GV 16), Dazhui (GV 14), etc. Of them, 5-6 acupoints alternately were selected each time, and each acupoint was given 0.3-0.5 mL, totally 18 µg/2 mL. Both treatment were carried out once every other day for six months. Before and after treatment, the children's development of brain function was assessed using gross motor function classification system (GMFCS). Before treatment (T0), after 2 (T2), 4 (T4) and 6 (T6) months of treatment, the motor function was evaluated by gross motor function measure (GMFM-88). The systolic peak velocity (Vs), mean velocity (Vm) and vascular resistance index (RI) of anterior cerebral artery (ACA) and middle cerebral artery (MCA) were measured, and the level of N-acetyl aspartate acid (NAA), choline (Cho), lactate (Lac) and creatine (Cr) from the basal ganglia, thalamus and periventricular white mater were detected by magnetic resonance spectroscopy (MRS) technology with MAGNETOM Skyra3.0T magnetic resonance imaging system before and after treatment. RESULTS: Compared with before treatment, the GMFCS classification of the observation group after treatment was significantly improved (P<0.05); after treatment, the difference of GMFCS classification between the two groups was not significant (P>0.05), however, the observation group had a 3.142 times of feasibility for good gross motor function development by more than level 1 compared to the control group (P<0.05). After 2, 4, and 6 months of treatment, the GMFM-88 scores of the two groups showed an upward trend (P<0.01), and the increase of the observation group was greater than that of the control group (P<0.05). Compared with before treatment, in the ACA and MCA, the Vs and Vm increased, RI decreased in both groups after treatment (P<0.01), and in the brain, NAA/Cr increased, Cho/Cr and Lac/Cr decreased (P<0.01), and after treatment, the Vs, Vm of ACA and MCA and NAA/Cr of brain in the observation group were higher than those in the control group (P<0.05), and the RI of ACA and MCA and Cho/Cr and Lac/Cr of brain in the observation group were lower than those in the control group (P<0.05). CONCLUSION: The mNGF acupoint injection has a better effect on the gross motor function in the children with cerebral palsy compared with the intramuscular injection, and the mechanism may be associated with exhibiting the double effects of acupoint effect and the targeting therapy of drug, which can effectively improve the cerebral hemodynamics and the metabolism of cerebral nervous substances.

Artificial Erythrina Alkaloids from Three Erythrina Plants, E. variegata, E. crista-galli and E. arborescens.

Fourteen unprecedented artificial Erythrina alkaloids were isolated from the Erythrina variegata, E. crista-galli and E. arborescens (Fabaceae). The structures of these alkaloids were determined by spectroscopic analyses. Their possible formations were proposed. All isolated compounds showed no cytotoxicity and hypoglycemic activity at cell screening bioassay.

Synthesis and biological evaluation of novel oleanolic acid analogues as potential α-glucosidase inhibitors.

Considerable interest has been attracted in oleanolic acid and its analogues because of their hypoglycemic activity. In this study, a series of novel oleanolic acid analogues against α-glucosidase were synthesized and their biological activities were evaluated in vitro and in vivo. In vitro α-glucosidase inhibition activity results indicated that most of the designed analogues exhibited prominent inhibition activities, especially compounds 10, 15, 16 and 26 which with the IC50 values of 0.33 ±â€¯0.01, 0.98 ±â€¯0.06, 0.69 ±â€¯0.01 and 0.72 ±â€¯0.21 µM, respectively. Enzyme kinetic studies on the most potent compounds reveled that derivatives 10, 15, 16 and 26 were noncompetitive inhibitors. Moreover, the docking studies were carried out to prove that the four compounds could interact with the hydrophobic region of the active pocket and form hydrogen bonds to enhance the binding affinity of them with the α-glucosidase. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the active compounds (10, 15, 16 and 26) against normal 3T3 cell line. Furthermore, the in vivo actual pharmacological potential studies on derivatives 10, 15, 16 and 26 showed that the hypoglycemic effects of them were comparable to that of positive control, acarbose.

A new erythrinan N-oxide alkaloid from Erythrina stricta.

This phytochemical study of stems and leaves of Erythrina stricta led to the isolation of twenty-three alkaloids, one of them previously unreported, 11ß-hydroxyerythratidine N-oxide. Their structures were elucidated on the basis of extensive 1D and 2D NMR spectroscopic analyses including HSQC, HMBC, 1H-1H COSY, NOESY, as well as HRESIMS data in addition to comparison with reports in the literature.

Lamellar keratoplasty using femtosecond laser intrastromal lenticule for limbal dermoid: case report and literature review.

Small incision refractive lenticule extraction (SMILE) is a femtosecond laser technique to correct myopia and myopic astigmatism. Herein, we report a technique where intrastromal lenticule obtained from the SMILE procedure served as a graft for lamellar keratoplasty in the management of a limbal dermoid. An 18-year-old woman presented to the clinic with a corneal-limbal mass in the right eye. Slit-lamp examination revealed a vascularized circular mass of approximately 6 mm × 5 mm, which was attached at 7 o'clock in the inferotemporal region of the corneal limbus; this suggested limbal dermoid. Anterior segment optical coherence tomography revealed superficial involvement of the cornea. The patient was treated with excision and lamellar keratoplasty by using femtosecond intrastromal lenticule. The lenticule was sutured over the cornea with 10-0 interrupted nylon sutures. On postoperative follow-up, best-corrected visual acuity was 20/20; there was no corneal neovascularization and no sign of rejection. This case of limbal dermoid was managed by simple surgical excision and lamellar keratoplasty with a SMILE-extracted lenticule. This method may serve as an alternative surgical approach for management of limbal dermoid.

Epidermal Growth Factor Receptor Mutations and Their Prognostic Value with Carcinoembryonic Antigen in Pathological T1 Lung Adenocarcinoma.

AIMS: The prognostic value of epidermal growth factor receptor (EGFR) mutations in the context of serum carcinoembryonic antigen levels remains controversial in T1 lung adenocarcinoma. METHODS: Clinical and pathological characteristics, preoperational carcinoembryonic antigen levels, EGFR mutations, and disease-free and overall survival were analysed retrospectively in 573 pathological T1 patients in East China. RESULTS: EGFR mutations were detected in 220 of 573 patients (38.4%). Patients with serum carcinoembryonic antigen levels ≥ 2.12 ng/mL had worse disease-free (P < 0.001) and overall survival (P < 0.001) than had others, although survival was comparable between patients with and without EGFR mutations. However, patients with exon 21 mutations in EGFR had significantly better overall survival than had patients with exon 19 mutations (P = 0.016), although disease-free survival was comparable (P = 0.424). Among patients with serum carcinoembryonic antigen levels ≥ 2.12 ng/mL, disease-free (P = 0.019) and overall survival (P < 0.001) was also better than that in those with exon 21 mutations. Finally, the exon 19 deletion was found to be an independent predictor of unfavourable overall survival (P = 0.037). CONCLUSIONS: EGFR mutations were associated with preoperational serum carcinoembryonic antigen levels ≥ 2.12 ng/mL. In patients with levels above this threshold, those with the exon 19 deletion have less favourable prognosis than have those with the exon 21 mutation.

Bisindole alkaloids from Tabernaemontana corymbosa.

Continued study in bioactive monoterpenoid alkaloids led to the isolation of nine undescribed alkaloids, taberyunines A-I, together with 32 known ones from the aerial parts of Tabernaemontana corymbosa Roxb. ex Wall (Apocynaceae). Among the undescribed alkaloids, taberyunines A-G and H-I were assigned to Aspidosperma-Aspidosperma and Vobasinyl-Ibogan type bisindoles, respectively. Their structures were determined by NMR spectra, MS data and X-ray diffraction. Taberyunine B showed significant cytotoxicity against three cancer cell lines.

Bioactive norditerpenoids from Cephalotaxus fortunei var. alpina and C. lanceolata.

Twenty-eight naturally occurring Cephalotaxus tropone analogues, including 19 previously undescribed ones, were identified from Cephalotaxus fortunei Hook. var. alpina H. L. Li and C. lanceolata K. M. Feng. The presence of the C20 cephinoids A-E revealed that these tropones were assigned to the norditerpenoids and were perhaps derived from labdane-type diterpenoids. These norditerpenoids showed excellent cytotoxicity against human cancer cells (IC50, 20-0.1 µM) in vitro. The SAR (structure-activity relationship) analysis disclosed that the tropone moiety and the lactone ring were crucial structural features for the observed activities. Further SAR analyses led to a new candidate, cephinoid H, which demonstrated an inhibition of 49.0% by administration to zebrafish at a dose of 60.0 ng/mL, compared to cisplatin (DDP, 22.4%) at 15.0 µg/mL. These compounds might affect the NF-κB signaling pathway rather than binding to microtubules. Additionally, the isolated norditerpenoids showed almost equal anti-inflammatory activities compared to the positive control, MG132.

Indole Alkaloids from Hunteria zeylanica.

Six new bisindole alkaloids, hunterizeylines A-F (1-6), three new monomers, hunterizeylines G-I (7-9), and 13 known alkaloids were isolated from an aqueous MeOH extract of the twigs and leaves of Hunteria zeylanica. Hunterizeyline H, geissoschizol, and dihydrocorynantheol displayed weak insecticidal activity against the aphid Rhodobium porosum, with IC50 values of 168.2, 360.5, and 290.6 µM, respectively.

Synthesis and biological evaluation of novel ursolic acid analogues as potential α-glucosidase inhibitors.

Ursolic acid (UA) is a major pentacyclic triterpenoid in plants, vegetables and fruits, which has been reported to have a potential anti-diabetic activity. Despite various semi-synthetic ursolic acid derivatives already described, new derivatives still need to be designed and synthesized to further improve the anti-diabetic activity. In the present study, two series of novel UA derivatives, were synthesized and their structures were confirmed. The enzyme inhibition activities of semi-synthesized analogues against α-glucosidase were screened in vitro. The results indicated that most of UA derivatives showed a significant inhibitory activity, especially analogues UA-O-i with the IC50 values of 0.71 ± 0.27 µM, which was more potential than other analogues and the positive control. Furthermore, molecular docking studies were also investigated to verify the in vitro study. Structure modification at the C-3 and C-2 positions of UA was an effective approach to obtain the desired ligand from UA, whose structure was in accordance with the active pocket. Besides, suitable hydrophobic group at the position of C-2 might play an important role for the docking selectivity and binding affinity between the ligand and the homology modelling protein. These results could be helpful for designing more potential α-glucosidase inhibitors from UA in the future.

Direct repression of the oncogene CDK4 by the tumor suppressor miR-486-5p in non-small cell lung cancer.

MicroRNAs are a class of non-coding single-stranded RNA, 20-23 nucleotide in length, which can be involved in the regulation of gene expression. Through binding with 3'-untranslated regions (3'-UTR), microRNAs can cause degradation of target mRNAs or inhibition of translation, and thus regulating the expression of genes at the post-transcriptional level. In this study, we found that miR-486-5p was significantly downregulated in non-small cell lung cancer (NSCLC) tissues and cell lines, suggesting that miR-486-5p might function as a tumor suppressor in lung cancer. Additionally, we showed that CDK4, an oncogene that plays an important role in cell cycle G1/S phase progression, was directly targeted by miR-486-5p. Furthermore, our data reveals that knockdown of CDK4 by siRNA can inhibit cell proliferation, promote apoptosis, and impede cell-cycle progression. In epigenetics, the upstream promoter of miR-486-5p was strongly regulated by methylation in NSCLC. Collectively, our results suggest that miR-486-5p could not only inhibit NSCLC by downregulating the expression of CDK4, but also be as a promising and potent therapy in the near future.

Five New Alkaloids from Cephalotaxus lanceolata and C. fortunei var. alpina.

Five new alkaloids (1-5) were isolated from the leaves and twigs of Cephalotaxus lanceolata and C. fortunei var. alpina along with 24 known alkaloids. The new structures were elucidated based on spectroscopic data including 1D and 2D NMR, FTIR, UV and MS. These new alkaloids showed no cytotoxicity to HeLa, SGC-7901 gastric cancer, and A-549 lung cancer cell lines.

Tanshinones suppress AURKA through up-regulation of miR-32 expression in non-small cell lung cancer.

Tanshinone is the liposoluble constituent of Salia miltiorrhiza, a root used in traditional herbal medicine which is known to possess certain health benefits. Although it is known that tanshinones, including tanshinone I (T1), tanshinone IIA (T2A), and cryptotanshinone (CT), can inhibit the growth of lung cancer cells in vitro, the mechanism under which they act is still unclear. AURKA, an oncogene, encodes a serine-threonine kinase which regulates mitotic processes in mammalian cells. Here, we reported that tanshinones mediate AURKA suppression partly through up-regulating the expression of miR-32. We found that tanshinones could inhibit cell proliferation, promote apoptosis, and impede cell-cycle progression, thus performing an antineoplastic function in non-small cell lung cancer (NSCLC). Additionally, we demonstrated that tanshinones attained these effects in part by down-regulating AURKA, corroborating previous reports. Our results showed that in NSCLC, similar effects were obtained with knock-down of the AURKA gene by siRNA. We also verified that AURKA was the direct target of miR-32. Collectively, our results demonstrated that tanshinones could inhibit NSCLC by suppressing AURKA via up-regulating the expressions of miR-32 and other related miRNAs.

Cytotoxic indole alkaloids from Tabernaemontana officinalis.

Continued interest in cytotoxic alkaloids resulted in the isolation of 37 alkaloids including 29 known monoterpenoid indole alkaloids from the aerial parts of Tabernaemontana officinalis. Of the remaining 8 alkaloids, six were bisindole alkaloids named taberdivarines A-F (1-6) and the two were monomers named taberdivarines G and H (7-8). Alkaloids 1 and 2 are voaphylline-vobasinyl type bisindole alkaloids, a structural type previously unknown, while 3-6 exhibited cytotoxicity against three human cancer cell lines HeLa, MCF-7, and SW480 with IC50 values ranging from 1.42 to 11.35 µM.

Missed Diagnosis of an Intraorbital Foreign Body of Homemade Fireworks Origin: A Case Report.

PURPOSE: We report a rare case of traumatic injury to the eye caused by homemade fireworks in a Chinese juvenile patient with a metal ring left in the orbit after having been sutured at the Emergency Department. METHODS: An 11-year-old boy presented with a traumatic injury to the right eye from homemade fireworks. Following initial assessment involving maxillofacial computed tomography (CT) and suturing at the Emergency Department, he was transferred to our department for further evaluation because of his poor sight 1 day later. On examination, a skin laceration beneath the right eyebrow was noted, but the superior orbit was not fully visible on the maxillofacial CT performed 1 day previously. Therefore, an orbital CT scan was carried out on the second day, which showed a hyperdense ring embedded in the superior border of the orbital wall; the ring was surgically removed. On postoperative day 7, a fundus examination revealed resolving vitreous hemorrhage, blunt traumatic retinal detachment, and a large retinal tear superior to the macula. The patient refused to take surgery for retinal detachment into consideration. Therefore, we opted for oral steroids and careful observation. RESULTS: After 2 months' observation, the large retinal tear had healed and white fibrous scar tissue had developed, and the retinal detachment superior to the macula had reattached itself spontaneously. The patient's vision had further improved to 20/200. During 1 year of follow-up, he remained clinically stable. CONCLUSION: To avoid missing the diagnosis, a complete history of the mechanism of injury and accurate imaging still prove most useful. Complete removal of the foreign body by the emergency physician is necessary because of the ocular toxicity of an iron-containing foreign body. As evidenced by the current case, oral steroids and observation for a period of several months is a management of choice for traumatic retinal detachment and retinal tear superior to the macula associated with homemade fireworks in children.

Dimeric Erythrina alkaloids from the flower of Erythrina variegata.

Unprecedented dimeric Erythrina alkaloids, spirocyclic (6/5/6/6) erythrivarine A (1) and spiro-fused (6/5/7/6) rings erythrivarine B (2), were isolated from the cultivated plant, E. variegata. The structures were determined on the basis of 1D and 2D NMR, FTIR, UV, and mass spectroscopic data and X-ray crystal diffraction. The biogenetic relationship of 1 and 2 is proposed.

Indole alkaloids from leaves and twigs of Rauvolfia verticillata.

Seven new indole alkaloids, rauverines A-G (1-7), and 19 known indole alkaloids were isolated from the leaves and twigs of Rauvolfia verticillata. All compounds showed no cytotoxicity against five human cancer cell lines, human myeloid leukemia (HL-60), hepatocellular carcinoma (SMMC-7721), lung cancer (A-549), breast cancer (MCF-7), and colon cancer (SW480) cells.