RESUMO
AIMS: Dipeptidyl peptidase 4 (DPP-4) is a valid molecular drug target from which its inhibitors have been developed as medicines for treating diabetes. The present study evaluated a new synthetic DPP-4-specific inhibitor of small molecule DBPR108 for pharmacology and pharmacokinetic profiles. MAIN METHODS: DBPR108 of various doses was orally administered to rats, diabetic mice, and dogs and the systemic circulating DPP-4 activities in the animals were measured to demonstrate the pharmacological mechanisms of action via DPP-4 inhibition. Upon an oral administration of DBPR108, the serum active GLP-1 and insulin levels of the rats challenged with an oral glucose ingestion were measured. Oral glucose tolerance test in diet-induced obese mice was performed to examine if DBPR108 increases the glucose tolerability in animals. KEY FINDINGS: Orally administered DBPR108 inhibited the systemic plasma DPP-4 activities in rats, dogs and diabetic mice in a dose-dependent manner. DBPR108 caused elevated serum levels of active GLP-1 and insulin in the rats. DBPR108 dose-dependently increased the glucose tolerability in diet-induced obese (DIO) mice and, furthermore, DIO mice treated with DBPR108 (0.1 mg/kg) in combination with metformin (50 or 100 mg/kg) showed a prominently strong increase in the glucose tolerability. SIGNIFICANCE: DBPR108 is a novel DPP-4-selective inhibitor of small molecule that demonstrated potent in vivo pharmacological effects and good safety profiles in animals. DBPR108 is now a drug candidate being further developed in the clinical studies as therapeutics for treating diabetes.
Assuntos
Butanos/farmacologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nitrilas/farmacologia , Pirrolidinas/farmacologia , Administração Oral , Animais , Área Sob a Curva , Peso Corporal , Butanos/farmacocinética , Diabetes Mellitus Experimental/tratamento farmacológico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Teste de Tolerância a Glucose , Hipoglicemiantes/farmacocinética , Insulina/metabolismo , Veias Jugulares/patologia , Masculino , Metformina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Nitrilas/farmacocinética , Pirrolidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
Whole body vibration (WBV) has been suggested to improve athletes' neuromuscular strength and power. This study investigated the effect of single WBV stimulation on volleyball-specific performance. The participants were 20 elite male volleyball players who performed a 1-min warm-up exercise on a vibration platform at a frequency of 30 Hz and peak-to-peak displacement of 2 mm. After the warm-up exercise, the participants performed a blocking agility test (BAT), 10-m sprinting test, agility T-test, and counter movement jump test. We compared the participants' performance at four time points (Pretest, Post 0, Post 1, and Post 2). The results revealed that the participants' BAT performance and maximum rate of force development improved significantly 1 min after the vibration stimulation (p < 0.01). The WBV (frequency of 30-Hz, peak-to-peak displacement of 2 mm) intervention significantly improved the volleyball-specific defensive performance and speed strength of the participants. Accordingly, by undergoing WBV as a form of warm-up exercise, the technique and physical fitness of volleyball players can be improved.
Assuntos
Desempenho Atlético , Força Muscular , Aptidão Física , Vibração , Voleibol , Exercício de Aquecimento , Adulto , Humanos , MasculinoRESUMO
Zinc(II)-dipicolylamine (Zn-DPA) has been shown to specifically identify and bind to phosphatidylserine (PS), which exists in bulk in the tumor microenvironment. BPRDP056, a Zn-DPA-SN38 conjugate was designed to provide PS-targeted drug delivery of a cytotoxic SN38 to the tumor microenvironment, thereby allowing a lower dosage of SN38 that induces apoptosis in cancer cells. Micro-Western assay showed that BPRDP056 exhibited apoptotic signal levels similar to those of CPT-11 in the treated tumors growing in mice. Pharmacokinetic study showed that BPRDP056 has excellent systemic stability in circulation in mice and rats. BPRDP056 is accumulated in tumors and thus increases the cytotoxic effects of SN38. The in vivo antitumor activities of BPRDP056 have been shown to be significant in subcutaneous pancreas, prostate, colon, liver, breast, and glioblastoma tumors, included an orthotopic pancreatic tumor, in mice. BPRDP056 shrunk tumors at a lower (~20% only) dosing intensity of SN38 compared to that of SN38 conjugated in CPT-11 in all tumor models tested. A wide spectrum of antitumor activities is expected to treat all cancer types of PS-rich tumor microenvironments. BPRDP056 is a first-in-class small molecule drug conjugate for cancer therapy.
RESUMO
A major obstacle to nanodrugs-mediated cancer therapy is their rapid uptake by the reticuloendothelial system that decreases the systemic exposure of the nanodrugs to tumors and also increases toxicities. Intralipid has been shown to reduce nano-oxaliplatin-mediated toxicity while improving bioavailability. Here, we have found that Intralipid reduces the cytotoxicity of paclitaxel for human monocytic cells, but not for breast, lung, or pancreatic cancer cells. Intralipid also promotes the polarization of macrophages to the anti-cancer M1-like phenotype. Using a xenograft breast cancer mouse model, we have found that Intralipid pre-treatment significantly increases the amount of paclitaxel reaching the tumor and promotes tumor apoptosis. The combination of Intralipid with half the standard clinical dose of Abraxane reduces the tumor growth rate as effectively as the standard clinical dose. Our findings suggest that pre-treatment of Intralipid has the potential to be a powerful agent to enhance the tumor cytotoxic effects of Abraxane and to reduce its off-target toxicities.
Assuntos
Paclitaxel Ligado a Albumina/farmacologia , Neoplasias da Mama/tratamento farmacológico , Imunidade Inata/efeitos dos fármacos , Fosfolipídeos/farmacologia , Óleo de Soja/farmacologia , Animais , Antineoplásicos , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Emulsões/farmacologia , Feminino , Xenoenxertos , Humanos , Camundongos , Nanopartículas/química , Oxaliplatina/farmacologia , Paclitaxel/química , Paclitaxel/farmacologia , Fosfolipídeos/imunologia , Óleo de Soja/imunologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Previous cross-sectional studies have reported that higher drop heights do not always result in improved performance, and may increase injury risk during drop jumps (DJ). The purpose of this study was to analyze the kinematics and kinetics during the DJ in order to determine the relative drop height that maximize performance without exposing the lower extremity joints to unnecessary loads. Twenty male Division I college volleyball players volunteered. Data were collected using 11 infrared cameras and two force platforms. Participants performed three maximal effort countermovement jumps (CMJ). Subsequently, 50, 75, 100, 125, and 150% CMJ height (CMJH) was used to scale their relative drop height for three DJ trials per height. There was a significant increase in the landing phase impulse when the drop height exceeded 100%CMJH (p<0.05). At 125% and 150%CMJH, the negative work of knee and ankle significantly increased. The incoming velocity, kinetic energy, landing depth, maximum ground reaction force, landing impulse and power absorption of knee and ankle all increased with drop height (p<0.05). DJ height and reactive strength index following the drop landing were not statistically different between any of the drop heights (p>0.05). 50% to 100%CMJH may be the appropriate individual relative drop height for the DJ.
Assuntos
Extremidade Inferior/fisiologia , Exercício Pliométrico , Voleibol/fisiologia , Articulação do Tornozelo/fisiologia , Fenômenos Biomecânicos , Estudos Transversais , Articulação do Quadril/fisiologia , Humanos , Cinética , Articulação do Joelho/fisiologia , Masculino , Estudos de Tempo e Movimento , Adulto JovemRESUMO
Sodium-dependent glucose co-transporter 2 (SGLT2) inhibition has been demonstrated to efficiently control hyperglycemia via an insulin secretion-independent pathway. The unique mode of action eliminates the risk of hypoglycemia and makes SGLT2 inhibitors an attractive option for the treatment of type 2 diabetes. In a continuation of our previous studies on SGLT2 inhibitors bearing different sugar moieties, sixteen new N-glucosyl indole derivatives were designed, synthesized, and evaluated for their inhibitory activity against hSGLT2. Of these sixteen, acethydrazide-containing N-glucosyl indole 9d was found to be the most potent SGLT2 inhibitor, and caused a significant elevation in urine glucose excretion in rats at 50â¯mg/kg, relative to the vehicle control.
Assuntos
Glucosídeos/farmacologia , Indóis/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/metabolismo , Animais , Compostos Benzidrílicos/farmacologia , Células CHO , Cricetulus , Glucosídeos/síntese química , Glucosídeos/química , Glucosídeos/farmacocinética , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacocinética , Estrutura Molecular , Ratos Sprague-Dawley , Inibidores do Transportador 2 de Sódio-Glicose/síntese química , Inibidores do Transportador 2 de Sódio-Glicose/química , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Relação Estrutura-AtividadeRESUMO
Treatment of hyperglycemia with drugs that block renal glucose reabsorption via inhibition of sodium-dependent glucose cotransporter 2 (SGLT2) is a novel approach to diabetes management. In this study, twenty-seven aryl C-glycosides bearing a C=N/C-N linkage at the glucosyl C6 position were designed, synthesized and evaluated for their inhibitory activity against human SGLT2 (hSGLT2). Compounds with good hSGLT2 inhibition were further investigated to determine their selectivity over hSGLT1. Of these, five representative aryl C-glycosides were chosen for pharmacokinetic analysis. Oxime 2a was determined to have the most promising pharmacokinetic properties and was selected for in vivo glucosuria and plasma glucose level studies, which found it to exhibit comparable efficacy to dapagliflozin (1). Furthermore, 2a was not found to exhibit either significant cytotoxicity (CC50 > 50 µM) or human ether-a-go-go related gene (hERG) inhibition (2% inhibition at 10 µM). Taken together, these efforts culminated in the discovery of oxime 2a as a potential SGLT2 inhibitor.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Monossacarídeos/farmacologia , Oximas/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Administração Intravenosa , Administração Oral , Animais , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Relação Dose-Resposta a Droga , Glucose/análise , Glucosídeos/administração & dosagem , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Estrutura Molecular , Monossacarídeos/química , Oximas/administração & dosagem , Oximas/química , Ratos , Ratos Sprague-Dawley , Transportador 2 de Glucose-Sódio , Relação Estrutura-AtividadeRESUMO
The aims of the present study were (a) to determine whether the two types of complex training and vibration complex training would improve the individual phenomenon of post-activation potentiation (PAP) for every athlete in a team setting; and (b) to compare the acute effect of resistance and plyometric exercise, whole body vibration, complex training and vibration complex training on vertical jump performance. The participants were ten male division I college volleyball and basketball players. They were asked to perform three vertical jumps as a pre-test and were then randomly assigned to one of five PAP protocols, resistance exercise using half squat exercise, plyometric exercise using drop jumps with individualized drop height, whole body vibration using squats on a vibration plate, complex training combining resistance exercise with plyometric exercise, vibration complex training combining whole body vibration with plyometric exercise. Three vertical jumps were performed four minutes after the PAP protocol as a post-test. A two-way repeated-measures analysis of variance was used to examine the differences among the five PAP protocols and between the two testing times. Our results showed that the post-test results were significantly improved compared to the pre-test for the vertical jump height (p = .015) in all PAP protocols. There was, however, an individual phenomenon of PAP in the response to all PAP protocols. In conclusion, this study found that resistance and plyometric exercise, whole body vibration, complex training and vibration complex training induce similar group PAP benefits. However, some athletes decreased their performances in some of the exercises in the study. Therefore, it is not recommended for coaches to arrange the exercises in a team setting.
RESUMO
Suppression of glucose reabsorption through the inhibition of sodium-dependent glucose co-transporter 2 (SGLT2) is a promising therapeutic approach for the treatment of type 2 diabetes. To investigate the effect of C6-substitution on inhibition of SGLT2 by N-indolylglucosides, a small library of 6-triazole, 6-amide, 6-urea, and 6-thiourea N-indolylglycosides were synthesized and tested. A detailed structure-activity relationship (SAR) study culminated in the identification of 6-amide derivatives 6a and 6o as potent SGLT2 inhibitors, which were further tested for inhibitory activity against SGLT1. The data obtained indicated that 6a and 6o are mildly to moderately selective for SGLT2 over SGLT1. Both compounds were also evaluated in a urinary glucose excretion test and pharmacokinetic study; 6a was found capable of inducing urinary glucose excretion in normal SD rats.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicosídeos/química , Glicosídeos/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Células CHO , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Glicosídeos/farmacocinética , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Transportador 2 de Glucose-Sódio/metabolismoRESUMO
Spontaneous reporting systems of adverse drug events have been widely established in many countries to collect as could as possible all adverse drug events to facilitate the detection of suspected ADR signals via some statistical or data mining methods. Unfortunately, due to privacy concern or other reasons, the reporters sometimes may omit consciously some attributes, causing many missing values existing in the reporting database. Most of research work on ADR detection or methods applied in practice simply adopted listwise deletion to eliminate all data with missing values. Very little work has noticed the possibility and examined the effect of including the missing data in the process of ADR detection. This paper represents our endeavor towards the exploration of this question. We aim at inspecting the feasibility of applying rough set theory to the ADR detection problem. Based on the concept of utilizing characteristic set based approximation to measure the strength of ADR signals, we propose twelve different rough set based measuring methods and show only six of them are feasible for the purpose. Experimental results conducted on the FARES database show that our rough-set-based approach exhibits similar capability in timeline warning of suspicious ADR signals as traditional method with missing deletion, and sometimes can yield noteworthy measures earlier than the traditional method.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Sistemas de Notificação de Reações Adversas a Medicamentos , Estudos de ViabilidadeRESUMO
We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4(+) cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.
Assuntos
Injúria Renal Aguda/prevenção & controle , Quimiotaxia/efeitos dos fármacos , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Quinazolinas/química , Quinazolinas/farmacologia , Receptores CXCR4/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Triazóis/química , Triazóis/farmacologia , Animais , Citometria de Fluxo , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Transdução de SinaisRESUMO
The aim of this study was to investigate the acute effect of (a) a drop jump (DJ) protocol with 1 set per 5 repetitions and (b) a DJ protocol with 2 sets per 5 repetitions on countermovement jump (CMJ) height performance in volleyball players at recovery times of (a) 2 minutes, (b) 6 minutes, and (c) 12 minutes. The subjects were 10 male Division I college volleyball players. They were instructed to perform a pretest of 3 CMJs and then randomly assigned to perform (a) a DJ protocol with 1 set per 5 repetitions and (b) a DJ protocol with 2 sets per 5 repetitions. After the DJ, 3 CMJs were completed in 2, 6, and 12 minutes. A 2-way repeated-measures analysis of variance was used to examine the differences between training volumes and recovery times in CMJ height (H(CMJ)) and maximum ground reaction force. Both DJ training volumes significantly increased the H(CMJ). The H(CMJ) at post 2 minutes was greater than those at the pretest (p = 0.008), post 6 minutes (p = 0.004), and post 12 minutes (p = 0.002). In addition, the H(CMJ) at post 6 minutes was significantly greater than that at post 12 minutes (p = 0.018). Drop jumps in lower volume (e.g., within 10 repetitions) and short recovery time (e.g., within 2 minutes) can produce a positive acute effect on CMJ performance.
Assuntos
Desempenho Atlético/fisiologia , Movimento/fisiologia , Voleibol/fisiologia , Análise de Variância , Humanos , Perna (Membro)/fisiologia , Masculino , Exercício Pliométrico , Análise e Desempenho de Tarefas , Adulto JovemRESUMO
Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are the current focus on the indication for the management of hyperglycemia in diabetes. Here, a novel series of C-linked indolylxyloside-based inhibitors of SGLT2 has been discovered. Structure-activity relationship studies revealed that substituents at the 7-position of the indole moiety and a p-cyclopropylphenyl group in the distal position were necessary for optimum inhibitory activity. The pharmacokinetic study demonstrates that the most potent compound 1i is metabolically stable with a low clearance in rats. In further efficacy study, 1i is found to significantly lower blood glucose levels of streptozotocin (STZ)-induced diabetic rats.
Assuntos
Glicosídeos/síntese química , Glicosídeos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Células CHO , Técnicas de Química Sintética , Cricetinae , Cricetulus , Estabilidade de Medicamentos , Glicosídeos/química , Humanos , Hipoglicemiantes/química , Concentração Inibidora 50 , Masculino , Ratos , Ratos Sprague-Dawley , Transportador 1 de Glucose-Sódio/antagonistas & inibidoresRESUMO
BPR0C261 is a synthetic small molecule compound cytotoxic against human cancer cells and active prolonging the lifespan of leukemia mice. In the present study, we further investigated the mechanisms of its anticancer action and found that BPR0C261 inhibited microtubule polymerization through interacting with the colchicine binding sites on tubulins, disrupted microtubule arrangement and caused cell cycle arrest at G(2)/M phase in cancer cells. BPR0C261 also inhibited the clonogenic growths of cancer cells and showed cytotoxicity against human cervical cancer cells of multidrug-resistant phenotype. In addition, BPR0C261 concentration-dependently inhibited the proliferation and migration of HUVECs and disrupted the endothelial capillary-like tube formations in HUVEC and rat aorta ring cultures. Given orally, BPR0C261 inhibited angiogenesis in s.c. implanted Matrigel plugs in mice. Notably, its IC(50) values against the endothelial cell growths were approximately 10-fold lower than those against the cancer cells. It was found orally absorbable in mice and showed a good oral bioavailability (43%) in dogs. BPR0C261 permeated through the human intestinal Caco-2 cell monolayer, suggesting oral availability in humans. Orally absorbed BPR0C261 distributed readily into the s.c. xenografted tumors in nude mice in which the tumor tissue levels of BPR0C261 were found oral dose-dependent. BPR0C261 showed in vivo activities against human colorectal, gastric, and nasopharyngeal tumors in nude mice. Most interestingly, the combination of BPR0C261 plus cisplatin synergistically prolonged the lifespans of mice inoculated with murine leukemia cells. Thus, BPR0C261 is a novel orally active tubulin-binding antitumor agent with antimitotic, apoptosis-inducing, and vasculature disrupting activities.
Assuntos
Inibidores da Angiogênese/farmacologia , Antimitóticos/farmacologia , Antineoplásicos/farmacologia , Indóis/farmacologia , Tiazóis/farmacologia , Administração Oral , Animais , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cães , Humanos , Leucemia Experimental/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos , Microtúbulos/química , Microtúbulos/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
A novel series of N-linked ß-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(ß-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/síntese química , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/síntese química , Indóis/síntese química , Inibidores do Transportador 2 de Sódio-Glicose , Xilose/análogos & derivados , Animais , Células CHO , Cricetinae , Cricetulus , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/urina , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Glucose/metabolismo , Glucosídeos/farmacocinética , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xilose/síntese química , Xilose/farmacocinética , Xilose/farmacologiaRESUMO
A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
Assuntos
Inibidores da Dipeptidil Peptidase IV/síntese química , Nitrilas/síntese química , Pirrolidinas/síntese química , Administração Oral , Aminas , Animais , Disponibilidade Biológica , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Concentração Inibidora 50 , Nitrilas/farmacologia , Pirrolidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
PURPOSE: Gastric cancer is one of the leading cancerous diseases worldwide. It is diagnosed often at the advanced stage for which chemotherapy is the main treatment option. The prognosis remains poor for metastatic, especially the diffuse type, gastric cancers. We investigated the efficacy of intravenously administered paclitaxel treating metastases of locally disseminated gastric tumors of diffuse type. METHODS: Transfection of green fluorescent proteins (GFP)-expressing plasmid into human gastric cancer MKN45 cells of diffuse type was performed, and MKN45-GFP cells constitutively expressing GFP were isolated. The MKN45-GFP cells were orthotopically inoculated into the mouse peritoneal cavity, and tumor growth and organ metastases were monitored. Liver metastases were harvested, re-inoculated, monitored for liver metastases again, and harvested for further inoculation. This in vivo selection procedure was repeated to isolate a subline with high metastatic abilities demonstrated by in vitro invasion abilities using Transwell((R)) system. By visualizing the GFP-expressing tumors, the effects of intravenously administered paclitaxel against the growing peritoneally disseminated and metastasized tumors in nude mice without laparotomy were measured. RESULTS: An in vivo selected gastric cancer cell line MKN45-GFP-ip4 with high metastatic ability was established. Its invasion ability was inhibited by paclitaxel treatments in vitro. The growths of metastatic and intraperitoneally disseminated MKN45-GFP-ip4 tumors were significantly suppressed by intravenous paclitaxel treatments in nude mice. CONCLUSIONS: We found that intravenous paclitaxel is active against the metastases of human gastric cancer of peritoneal diffuse type, which warrants further investigations on optimizing the perioperative regimens with intravenous paclitaxel therapy for gastric cancer in patients.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Humanos , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Paclitaxel/administração & dosagem , Peritônio/patologia , Neoplasias Gástricas/patologia , TransfecçãoRESUMO
A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores da Dipeptidil Peptidase IV/síntese química , Ácido Glutâmico/química , Pirrolidinas/síntese química , Administração Oral , Animais , Dipeptidil Peptidase 4/sangue , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Desenho de Fármacos , Glucose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice.
Assuntos
Ciclopropanos/química , Ciclopropanos/farmacologia , Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Animais , Dipeptidil Peptidase 4/sangue , Teste de Tolerância a Glucose , Espectroscopia de Ressonância Magnética , Camundongos , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
Although Candida albicans cph1/cph1 efg1/efg1 mutant cells are not lethal to mice, they proliferated in infected mice instead of simply being cleared by the host immune system. Here, we have shown that the cph1/cph1 efg1/efg1 mutant partially protects mice from systemic infections by the lethal wild-type Candida albicans cells. Our results further indicate that a second dose of the cph1/cph1 efg1/efg1 mutant did not boost the degree of protection.