Zanthoxylum belongs to the Rutaceae family, and there are 81 Zanthoxylum species and 36 varieties in China. Most of the Zanthoxylum plants are used as culinary spice. In recent years, scholars in China and abroad have carried out in-depth research on Zanthoxylum plants, and found that the peculiar numbing sensation of Zanthoxylum plants originates from amides. It is also determined that amides are an important material basis for exerting pharmacological effects, especially in anti-inflammatory analgesia, anesthesia and other aspects. In this paper, 123 amides in 26 Zanthoxylum plants and their pharmacological activity that have been reported were summarized, which provided scientific reference for the clinical application of Zanthoxylum plants and the research and development of new drugs, and also facilitated the sustainable development and utilization of Zanthoxylum plant resources.
Zanthoxylum/chemistry* ; Amides/chemistry* ; Plant Extracts/pharmacology* ; China

BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.
Amides/*pharmacology ; Angiotensin II/pharmacology ; Animals ; Disease Models, Animal ; Fibrosis ; Fumarates/*pharmacology ; Kidney/*drug effects/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis, Interstitial/genetics/metabolism/pathology/*prevention & control ; RNA, Messenger/genetics/metabolism ; Renin/*antagonists & inhibitors/metabolism ; Renin-Angiotensin System/*drug effects ; Toll-Like Receptor 2/deficiency/drug effects/genetics/*metabolism ; Ureteral Obstruction/*drug therapy/genetics/metabolism/pathology

To discover novel antitumor rhodanine unsaturated ketones, a series of fluoroquinolone (rhodanine α, β-unsaturated ketone) amine derivatives (5a-5r) were designed and synthesized with fluoroquinolone amide scaffold as a carrier. The structures of eighteen title compounds were characterized by elemental analysis, 1H NMR and MS. The in vitro anti-proliferative activity against Hep-3B, Capan-1 and HL60 cells was evaluated by MTT assay. The results showed that the title compounds not only had more significant anti-proliferative activity against three tested cancer cell lines than that of the parent ciprofloxacin 1, but also exhibited the highest activity against Capan-1 cells. The SAR revealed that some compounds carrying aromatic heterocyclic rings or phenyl attached to an electron-withdrawing carboxyl or sulfonamide substituent were comparable to or better than comparison doxorubicin against Capan-1 cells. As such, it suggests that fluoroquinolone (rhodanine α, β-unsaturated ketone) amines are promising leads for the development of novel antitumor fluoroquinolones or rhodanine analogues.
Amides ; chemical synthesis ; pharmacology ; Antineoplastic Agents ; chemical synthesis ; pharmacology ; Cell Line, Tumor ; Fluoroquinolones ; chemical synthesis ; pharmacology ; HL-60 Cells ; Humans ; Ketones ; chemical synthesis ; pharmacology ; Rhodanine ; chemical synthesis ; pharmacology

Induced pluripotent stem cells (iPSCs) can be propagated indefinitely, while maintaining the capacity to differentiate into all cell types in the body except for the extra-embryonic tissues. This iPSC technology not only represents a new way to use individual-specific stem cells for regenerative medicine but also constitutes a novel method to obtain large numbers of disease-specific cells for biomedical research. However, the low efficiency of reprogramming and genomic integration of oncogenes and viral vectors limit the potential application of iPSCs. Chemical-induced reprogramming offers a novel approach to generating iPSCs. In this study, a new combination of small-molecule compounds (SMs) (sodium butyrate, A-83-01, CHIR99021, Y-27632) under conditions of transient folate deprivation was used to generate iPSC. It was found that transient folate deprivation combined with SMs was sufficient to permit reprogramming from mouse embryonic fibroblasts (MEFs) in the presence of transcription factors, Oct4 and Klf4, within 25 days, replacing Sox2 and c-Myc, and accelerated the generation of mouse iPSCs. The resulting cell lines resembled mouse embryonic stem (ES) cells with respect to proliferation rate, morphology, pluripotency-associated markers and gene expressions. Deprivation of folic acid, combined with treating MEFs with SMs, can improve the inducing efficiency of iPSCs and reduce their carcinogenicity and the use of exogenous reprogramming factors.
Amides ; pharmacology ; Animals ; Butyric Acid ; pharmacology ; Cell Differentiation ; drug effects ; Cell Line ; Cell Proliferation ; drug effects ; Extraembryonic Membranes ; cytology ; drug effects ; Folic Acid ; pharmacology ; Induced Pluripotent Stem Cells ; cytology ; drug effects ; Kruppel-Like Transcription Factors ; metabolism ; Mice ; Octamer Transcription Factor-3 ; metabolism ; Proto-Oncogene Proteins c-myc ; metabolism ; Pyrazoles ; pharmacology ; Pyridines ; pharmacology ; Pyrimidines ; pharmacology ; SOXB1 Transcription Factors ; metabolism ; Thiocarbamates ; pharmacology ; Thiosemicarbazones

BACKGROUNDPreoperative incisional local anaesthesia with ropivacaine is a common method of providing post-laparoscopy pain relief. The pulmonary recruitment manoeuvre also provides pain relief, but the combined effect of these two methods on pain following laparoscopic procedures has not been reported. We investigated the efficacy of combining local anaesthetic infiltration of ropivacaine with pulmonary recruitment manoeuvre on postoperative pain following diagnostic hysteroscopy and laparoscopy.

METHODSThis prospective, randomized, controlled study involved 60 patients divided into two groups (n = 30, each). Group 1 received 20 ml of 0.5% ropivacaine injected peri-incisionally preoperatively, with intra-abdominal carbon dioxide removed by passive deflation. Group 2 received 20 ml of 0.5% ropivacaine injected peri-incisionally with five manual inflations of the lungs with a positive-pressure ventilation of 40 cmH2O at the end of surgery. The last inflation was held for 5 seconds. The intensity of postoperative incisional and shoulder pain was evaluated using a numerical rating scale at 0, 2, 4, 8, 12, 24 and 48 hours postoperatively by an independent blinded anaesthesiologist. Tramadol was given postoperatively for analgesia.

RESULTSCompared with group 1, incisional ropivacaine infiltration combined with pulmonary recruitment manoeuvre significantly reduced dynamic pain at 0 hour, 4 hours, and 24 hours postoperatively (4.1 ± 2.2 vs. 2.1 ± 1.9, P = 0.002; 2.7 ± 2.7 vs. 1.2 ± 1.3, P = 0.035; and 3.5 ± 2.1 vs. 2.1 ± 1.8, P = 0.03, respectively). Static incisional pain was significantly relieved at 0 hour, 2 hours, and 24 hours postoperatively (3.1 ± 1.7 vs. 1.6 ± 1.3, P = 0.001; 1.4 ± 1.3 vs. 0.5 ± 0.8, P = 0.012; and 2.3 ± 1.9 vs. 1.0 ± 1.5, P = 0.038, respectively). Group 2 had more patients without shoulder pain (P < 0.05) and fewer requiring tramadol (P < 0.05).

CONCLUSIONRopivacaine with pulmonary recruitment manoeuvre provided simple and effective pain relief after diagnostic hysteroscopy and laparoscopy.

Adolescent ; Adult ; Amides ; therapeutic use ; Anesthetics, Local ; pharmacology ; Female ; Humans ; Hysteroscopy ; methods ; Laparoscopy ; methods ; Middle Aged ; Pain, Postoperative ; drug therapy ; Positive-Pressure Respiration ; Shoulder Pain ; drug therapy ; Young Adult

OBJECTIVE: To investigate the effect of pretreatment with neurotrophin-3 (NT-3) on intrathecal ropivacaine in rats. METHODS: A total of 144 male Sprague Dawley rats weighing 280-320 g were successfully implanted with microspinal cather following the improved methods of Yaksh. The rats were randomly divided into 4 groups and given saline (Group NS, n=36), 0.5% ropivacaine (Group M, n=36), 1% ropivacaine (Group R, n=36), and ropivacaine+NT-3 (Group T, n=36). The rats received 0.12 mL/ kg body weight of ropivacaine at 0.5% or 1%, or normal saline only, via an implanted intrathecal catheter at 90-min interval for 12 h in Group NS, M, R and T. In the meantime the rats also received NT-3 0.1 mg/kg in group T. On days 1, 3, 5, 7, 14 and 28, we assessed the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), behavioural change and histopathological damage score changed for possible neuronal injury within the spinal cord. RESULTS: Compared with Group NS and Group M, the PWMT and PWTL were significantly higher on 1, 3, 5 d and the histopathological damage score was significantly higher on 1, 3, 5, 7, 14 d in Group R (P<0.05). Compared with Group T, the PWMT and PWTL in Group R were significantly higher on 1, 3, 5 d and histopathological damage score was significantly higher on 5, 7, 14 d (P<0.05). CONCLUSION NT-3 pretreatment in mice has obvious protective effect against repeated intrathecal injection of 1% ropivacaine in the spinal nerve.
Amides ; adverse effects ; Animals ; Injections, Spinal ; Male ; Neurotrophin 3 ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Ropivacaine ; Spinal Cord ; drug effects

BACKGROUNDAliskiren is an oral renin inhibitor, which inhibits the first rate limiting step in the renin angiotensin aldosterone system. In this study, sympathetic nerve sprouting and the inducibility of ventricular fibrillation after aliskiren treatment in myocardial infarction were investigated.

METHODSMale Sprague Dawley rats after coronary artery ligation were randomly allocated to four groups: angiotensin converting enzyme inhibitor enalapril, angiotensin receptor blocker valsartan, β adrenergic receptor blocker carvedilol and rennin inhibitor aliskiren treatment for six weeks. Electrophysiological study, histological examination and Western blotting were performed.

RESULTSThe plasma norepinephrine level and sympathetic nerve innervation significantly increased in treated infarcted rats compared to untreated rats. Aliskiren treatment reduced the sympathetic nerve innervations after myocardial infarction. There is no significant difference in sympathetic nerve innervations after myocardial infarction among the enalapril, valsartan, carvediloand or aliskiren treated groups. Programmed electrical stimulation study showed that inducible ventricular arrhythmia was reduced, ventricular fibrillation threshold was increased and ventricular effective refractory period was prolonged in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats compared to untreated infarcted rats. Cardiomyocytic apoptosis in infarcted region was significantly decreased in enalapril, valsartan, carvedilol and aliskiren treated infarcted rats.

CONCLUSIONSAliskiren ameliorated cardiomyocytic apoptosis, attenuated the sympathetic nerve innervations and reduced the vulnerability of ventricular arrhythmias after myocardial infarction. Enalapril, valsartan and carvedilol have similar effects as aliskiren on cardiomyocytic apoptosis, sympathetic nerve innervations and vulnerability of ventricular arrhythmias after myocardial infarction.

Amides ; pharmacology ; therapeutic use ; Animals ; Fumarates ; pharmacology ; therapeutic use ; Male ; Myocardial Infarction ; blood ; drug therapy ; Norepinephrine ; blood ; Rats ; Rats, Sprague-Dawley ; Renin ; antagonists & inhibitors ; Sympathetic Nervous System ; drug effects ; Tachycardia, Ventricular ; prevention & control

OBJECTIVETo investigate the effects of ropivacaine on Gamma-aminobutyric acid(GABA)-activated currents in dorsal root ganglion (DRG) neurons in rats and discuss the analgesia mechanism of ropivacaine.

METHODSBy means of using whole-cell patch-clamp technique, to investigate the modulatory effects of ropivacaine on GABA-activated currents (I(GABA)) in acutely isolated dorsal root ganglion neurons.

RESULTS(1) In 48 out of 73DRG cells (65.7%, 48/73), to perfusion ropivacaine bromide (0.1 - 1 000 micromol/L) were sensitive. Which produce in 0 to 380 pA current. (2) The majority of the neurons examined (74.5%, 73/98) were sensitive to GABA. Concentration of 1 - 1 000 micromol/L GABA could activate a concentration-dependent inward current, which manifested obvious desensitization, and the inward currents could be blocked byGABA-receptor selective antagonist of bicuculline (100 micromol/L). (3) After the neurons were treated with ropivacaine (0.1 - 1000 micromol/L) prior to the application of GABA (100 micromol/L) 30 s, GABA currents were obviously increased. Ropivacaine could make dose-response curve of the GABA up, EC50 is 23.46 micromol/L. Ropivacaine shifted the GABA dose-response curve upward and increased the maximum response to the contrast about 153%.

CONCLUSIONThe enhancement of ropivacaine to DRG neurons activation of GABA current, can lead to enhancement of pre-synaptic inhibition at the spinal cord level. This may be one of the reasons for the anesthetic effect and analgesia for ropivacaine in epidural anesthesia.

Amides ; pharmacology ; Animals ; Ganglia, Spinal ; cytology ; physiology ; Membrane Potentials ; drug effects ; Neurons ; cytology ; drug effects ; physiology ; Patch-Clamp Techniques ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-A ; physiology

OBJECTIVE: To observe the influence of ropivacaine on the proliferation and migration of rat bone marrow mesenchymal stem cells (BMSCs) and provide basis for the clinical application of BMSCs. METHODS: Rat BMSCs were isolated and cultured by adherence method. Surface markers of BMSCs were examined by flow cytometry. Multipotent differentiation of BMSCs was detected by induced adipogenesis, osteogenesis and muscular differentiation. Proliferation of BMSCs was examined by CCK-8 and Brdu incorporation after ropivacaine treatment at different concentrations. Migration of BMSCs was tested by cell scratch assay and Millicell experiment. RESULTS: Cultured cells had representative appearance and surface markers of BMSC, and they had potential multiple differentiation. Ropivacaine treatment at 50 and 100 μmol/L significantly reduced the proliferation rate of BMSCs and Brdu incorporation rate. There was significant difference compared with the control group (P<0.05). Cellular scratch assay and migration experiment indicated that ropivacaine significantly reduced the migration of BMSCs. There was significant difference compared with the control group (P<0.05). All these mentioned effects of ropivacaine on BMSCs were dose-dependent. There was significant difference between groups (P<0.05). CONCLUSION Ropivacaine can significantly reduce the proliferation and migration of rat BMSCs, suggesting that the influence of local anesthetics on BMSCs has to be taken into account when BMSCs are used in clinical practice.
Amides ; pharmacology ; Animals ; Bone Marrow Cells ; Cell Differentiation ; Cell Movement ; drug effects ; Cell Proliferation ; drug effects ; Cells, Cultured ; Flow Cytometry ; Mesenchymal Stem Cells ; cytology ; drug effects ; Rats ; Ropivacaine

Sphingosylphosphorylcholine (SPC) induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) into smooth muscle-like cells expressing alpha-smooth muscle actin (alpha-SMA) via transforming growth factor-beta1/Smad2- and RhoA/Rho kinase-dependent mechanisms. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have been known to have beneficial effects in the treatment of cardiovascular diseases. In the present study, we examined the effects of simvastatin on the SPC-induced alpha-SMA expression and Smad2 phosphorylation in hASCs. Simvastatin inhibited the SPC-induced alpha-SMA expression and sustained phosphorylation of Smad2 in hASCs. SPC treatment caused RhoA activation via a simvastatin-sensitive mechanism. The SPC-induced alpha-SMA expression and Smad2 phosphorylation were abrogated by pretreatment of the cells with the Rho kinase inhibitor Y27632 or overexpression of a dominant negative RhoA mutant. Furthermore, SPC induced secretion of TGF-beta1 and pretreatment with either Y27632 or simvastatin inhibited the SPC-induced TGF-beta1 secretion. These results suggest that simvastatin inhibits SPC-induced differentiation of hASCs into smooth muscle cells by attenuating the RhoA/Rho kinase-dependent activation of autocrine TGF-beta1/Smad2 signaling pathway.
Amides/pharmacology ; Blotting, Western ; Cell Differentiation/*drug effects ; Cells, Cultured ; Enzyme-Linked Immunosorbent Assay ; Humans ; Immunohistochemistry ; Mesenchymal Stem Cells/*cytology/*drug effects ; Myocytes, Smooth Muscle/*cytology/*drug effects ; Phosphorylcholine/*analogs & derivatives/pharmacology ; Pyridines/pharmacology ; Simvastatin/*pharmacology ; Sphingosine/*analogs & derivatives/pharmacology ; rhoA GTP-Binding Protein/antagonists & inhibitors/metabolism