9days Of Treatment Research Articles

Coumarin derivative 7-isopentenyloxycoumarin induces in vivo antitumor activity by inhibit angiogenesis via CCL2 chemokine decrease.

Cancer is one of the most urgent problems in medicine. In recent years, cancer is the second leading cause of death globally. In search for more effective and less toxic treatment against cancer, natural products are used as prototypes in the synthesis of new anticancer drugs. The aim of this study was to investigate the in vivo toxicity and the mechanism of antitumor action of 7-isopentenyloxycoumarin (UMB-07), a coumarin derivative with antitumor activity. The toxicity was evaluated in vitro (hemolysis assay), and in vivo (micronucleus and acute toxicity assays). Ehrlich ascites carcinoma model was used to evaluate in vivo antitumor activity of UMB-07 (12.5, 25, or 50mg/kg, intraperitoneally, i.p.), after 9days of treatment, as well as toxicity. UMB-07 (2000μg/mL) induced only 0.8% of hemolysis in peripheral blood erythrocytes of mice. On acute toxicity assay, LD50 (50% lethal dose) was estimated at around 1000mg/kg (i.p.), and no micronucleated erythrocytes were recorded after UMB-07 (300mg/kg, i.p.) treatment. UMB-07 (25 and 50mg/kg) reduced tumor volume and total viable cancer cells. In the mechanism action investigation, no changes were observed on the cell cycle analysis; however, UMB-07 reduced peritumoral microvessels density and CCL2 chemokine levels. In addition, UMB-07 showed weak toxicity on biochemical, hematological, and histological parameters after 9days of antitumor treatment. The current findings suggest that UMB-07 has low toxicity and exerts antitumor effect by inhibit angiogenesis via CCL2 chemokine decrease.

Chronology and Determinants of Respiratory Function Changes Following Administration of Systemic Postnatal Corticosteroids in Extremely Preterm Infants

To describe the effect of systemic corticosteroids administered to treat evolving bronchopulmonary dysplasia on oxygen diffusion and ventilation efficiency. This was a retrospective cohort study of ventilated infants who received a 9-day course of dexamethasone in a tertiary neonatal unit. We calculated the transcutaneous oxygen saturation-to-fraction of inspired oxygen (FiO2) ratio (SFR), the ventilation perfusion ratio (VA/Q), and the ventilation efficiency index (VEI) before, during, and after the course of corticosteroids. The response to corticosteroids was calculated as the difference between the FiO2 percentage before starting steroids and the lowest FiO2 value during the course of steroid treatment. Seventy infants (38 males) with a median gestational age (GA) of 25.0weeks (IQR, 24.3-26.0weeks) and a median birth weight of 0.70kg (IQR, 0.63-0.82kg) were studied at a median postnatal age of 39days (IQR, 29-48days). The median SFR before treatment was 1.42 (IQR, 1.19-1.72), and the highest SFR was 2.35 (IQR, 1.87-2.83) after 9days of treatment. The median VA/Q before treatment was 0.14 (IQR, 0.11-0.18) and was significantly higher at 72hours after the start of treatment (0.22; IQR, 0.15-0.29; P<.001). The median VEI was 0.06 (IQR, 0.04-0.08) before treatment and was highest, 0.10 (IQR, 0.07-0.13) at 48hours after starting treatment. The median rate of response to corticosteroids was 28% (IQR, 20%-37%). GA was significantly related to the response to corticosteroids (ρ=0.283; P=.019). Oxygen diffusion continues to improve throughout the entire duration of a 9-day course of systemically administered corticosteroids in ventilated extremely preterm infants. More immature infants are less responsive to corticosteroids.

Effect of endoplasmic reticulum stress inhibition on hyperoxaluria-induced oxidative stress: influence on cellular ROS sources.

Hyperoxaluria-induced calcium oxalate crystallisation is associated with the generation of reactive oxygen species (ROS) via mitochondria and NADPH oxidase. Endoplasmic reticulum (ER) has emerged as an organelle which could influence mitochondrial functioning and ROS generation. Plugging an upstream pathway of mitochondrial and NADPH oxidase-induced ROS generation may have better prophylaxis. Therefore, we propose to investigate the linkage of hyperoxaluria-induced ROS generation with ER stress by inhibiting the later with 4-Phenylbutyric acid (4-PBA). Male wistar rats were divided into three groups: a normal control group, an ethylene glycol with ammonium chloride-induced hyperoxaluric group (EA) and a third group which has hyperoxaluric animals given 4-PBA at a dose of 300mg/kg. After 9days of treatment, animals were sacrificed and renal tissues were analysed for histopathological examination, ROS, mitochondrial dysfunction, ER stress markers, inflammatory markers and NADPH oxidase subunits expression. Hyperoxaluric rats exhibited a significant increase in the levels of ROS, subsequently up-regulated levels of ER stress markers, inflammatory indicators, NADPH oxidase subunits and compromised mitochondrial functioning. However, ER stress amelioration appreciably curtailed the alterations caused by hyperoxaluric abuse. Therefore, suggesting the major role of ER in hyperoxaluric manifestations thereby providing an opportunity to target ER stress for future therapeutic interventions.

β-N-Methylamino-L-Alanine Toxicity in PC12: Excitotoxicity vs. Misincorporation

The implication of β-N-methylamino-L-alanine (BMAA) in the development of neurodegenerative diseases worldwide has led to several investigations of the mechanism, or mechanisms, of toxicity of this cyanobacterially produced amino acid. The primary mechanism of toxicity that was identified is excitotoxicity, with a second possible mechanism, the misincorporation of BMAA into the primary protein structure and consequent cell damage, having been more recently reported. However, studies on excitotoxicity and misincorporation have been conducted independently and there are therefore no data available on the relative contribution of each of these mechanisms to the total toxicity of BMAA. The rat pheochromocytoma cell line PC12 is an ideal model for a study of this type, as glutamate receptor expression is modified by cell differentiation, which can be affected by exposure to nerve growth factor. In this study, the PC12 cell line was evaluated as a model to study BMAA toxicity via the two proposed mechanisms: excitotoxicity and protein misincorporation. BMAA and canavanine treatment of cultures of PC12 were evaluated for depolarization of the mitochondrial membrane. In canavanine-treated cultures, this was evident after 9days of treatment and was attributed to the primary mechanism of canavanine toxicity, protein misincorporation. However, no membrane depolarization was observed for BMAA-treated cultures even after 21days of continuous treatment at 500μM. Short-term exposure to both BMAA and canavanine resulted in a slight increase in necrosis in undifferentiated cells that was prevented in canavanine-treated cultures by co-incubation with arginine, but not in BMAA-treated cultures by co-incubation with serine. A slight increase in apoptosis was observed in undifferentiated cells treated with either BMAA or glutamate, and ROS production increased in glutamate-treated cells. However, the excitotoxicity was less pronounced than reported in previous studies with neuronal cells. In contrast, apoptosis was greatly increased in both BMAA- and glutamate-treated cells after differentiation and resulting mGluR1 increase, indicating that excitotoxicity is the main, if not only, mechanism of toxicity in PC12.

Congenital upper lid eversion and severe chemosis in a new born

The purpose of this study is to report a case of bilateral congenital eversion of the upper eyelid in an 8 h- old male baby. JD is an 8 h-old male baby born by normal vaginal delivery after prolonged labor, to a 24-year-old primigravida. Pregnancy was said to be term but was complicated by pregnancy-induced hypertension. A midwife delivered the baby and it was by spontaneous vertex delivery. He was said to have cried immediately after birth, but shortly afterward parents noticed a reddish fleshy swelling over the eyes and this made it difficult for them to see the eyeballs. The reddish swelling steadily increased in size necessitating their prompt referral to our center. On examination, a full term baby was seen with complete eversion of both upper eyelids and marked conjunctival chemosis. Ocular examination revealed normal globes with healthy cornea and briskly reactive pupils. The child was admitted and started on 3-hourly chloramphenicol ointment, ciloxan eye drop (ciprofloxacin hydrochloride United States Pharmacopeia equivalent to ciprofloxacin 0.3% w/v) - 8 times daily and 5% hypertonic saline patch over the chemosed conjunctiva. The pediatrician was also invited to co-manage the patient. After 9-days of treatment, the conjunctival chemosis fully resolved and lids reverted back to normal position. At 4-week follow-up, the lids continued to maintain their normal position and child could now open eyelids spontaneously. Congenital upper eyelid eversion is a rare clinical entity even though it is said to be commoner in blacks. Knowledge of its complete resolution with conservative management will help in future management of such cases thereby preventing complications that may arise from poorly treated cases.

Comparing the in vivo sonodynamic effects of dual- and single-frequency ultrasound in breast adenocarcinoma.

Dual-frequency ultrasound has recently been shown to extensively enhance the acoustic cavitation yield in water. In this study, the in vivo antitumor effect of simultaneous, dual-frequency ultrasound at low-level intensity (I SATA=2W/cm(2) for 1MHz and I SATA=0.2W/cm(2) for 150kHz) in combination with an intravenous injection of 5mg/kg hematoporphyrin (Hp) was investigated in a model of breast adenocarcinoma in Balb/c mice. Seventy-one tumor-bearing mice were divided into nine treatment groups: control, sham, Hp injection, and single- and dual-frequency sonication in the presence and absence of Hp. The tumor growth delay was then calculated based on the tumor volume at various times after treatment using the following parameters: relative volume percent, [Formula: see text] and [Formula: see text] times (to reach five and two times the initial volume), percent of tumor growth inhibition ratio, and survival period. Our results showed no significant difference between the 150kHz and 1MHz single-frequency groups when compared with the sham group after 9days of treatment (p>0.05). However, treatment with dual-frequency ultrasound significantly delayed tumor growth when compared with the sham group (p<0.05) after 9days of treatment. Furthermore, in vivo experiments showed that combined dual-frequency sonication controlled tumor growth more effectively than single-frequency sonication. Evaluation of the therapeutic effects of single- and dual-frequency ultrasound in sonodynamic therapy revealed that treatment with the combination of dual-frequency ultrasound and Hp resulted in a significant reduction in the relative volume percent of tumors after 3days of treatment (p<0.05) compared with the controls. Additionally, the T 5 time and the survival period in the group treated with the combination therapy was significantly longer than those in all the other groups (p<0.05). These findings were further verified histopathologically. In conclusion, our results reveal that sonodynamic therapy using dual-frequency ultrasound is able to extend the survival time of animals compared with single-frequency sonication.

Time course in calpain activity and autolysis in slow and fast skeletal muscle during clenbuterol treatment

Calpains are Ca2+ cysteine proteases that have been proposed to be involved in the cytoskeletal remodeling and wasting of skeletal muscle. Cumulative evidence also suggests that β2-agonists can lead to skeletal muscle hypertrophy through a mechanism probably related to calcium-dependent proteolytic enzyme. The aim of our study was to monitor calpain activity as a function of clenbuterol treatment in both slow and fast phenotype rat muscles. For this purpose, for 21days we followed the time course of the calpain activity and of the ubiquitous calpain 1 and 2 autolysis, as well as muscle remodeling in the extensor digitorum longus (EDL) and soleus muscles of male Wistar rats treated daily with clenbuterol (4mg·kg-1). A slow to fast fiber shift was observed in both the EDL and soleus muscles after 9days of treatment, while hypertrophy was observed only in EDL after 9days of treatment. Soleus muscle but not EDL muscle underwent an early apoptonecrosis phase characterized by hematoxylin and eosin staining. Total calpain activity was increased in both the EDL and soleus muscles of rats treated with clenbuterol. Moreover, calpain 1 autolysis increased significantly after 14days in the EDL, but not in the soleus. Calpain 2 autolysis increased significantly in both muscles 6 hours after the first clenbuterol injection, indicating that clenbuterol-induced calpain 2 autolysis occurred earlier than calpain 1 autolysis. Together, these data suggest a preferential involvement of calpain 2 autolysis compared with calpain 1 autolysis in the mechanisms underlying the clenbuterol-induced skeletal muscle remodeling.

Impaired hippocampal neurogenesis is involved in cognitive dysfunction induced by thiamine deficiency at early pre-pathological lesion stage

It has not been reported whether thiamine deficiency (TD) affects hippocampal neurogenesis or not. Here, we explored the influence of TD at early pre-pathological lesion stage on hippocampal neurogenesis and the correlation between affected hippocampal neurogenesis and cognitive dysfunction. We prepared TD mouse model by feeding a thiamine-depleted diet. Learning and memory functions of TD mice were tested with Y-maze. Hippocampal neurogenesis was studied with BrdU, PCNA, Dcx, and NeuN immunohistochemical staining. The results showed significant decline in learning ability and hippocampal neurogenesis simultaneously since 9-days of treatment when the model mice did not exhibit regular pathological lesion, the loss of cholinergic neurons, decrease of NeuN-positive hippocampal cell, and abnormal long-term potentiation of hippocampal CA1 and CA3. Re-administering thiamine reversed the weakened learning ability as well as the impaired hippocampal neurogenesis induced by TD at early pre-pathological lesion stage. The present study demonstrated that hippocampal neurogenesis was vulnerable to TD and the impaired hippocampal neurogenesis is greatly involved in cognitive dysfunction induced by TD at early pre-pathological lesion stage.