Comparison of the effect of 40 and 80 mg/day doses of atorvastatin on changes in lipid profiles among acute coronary syndrome patients: A randomized clinical trial study.

Background: Statins play a vital role in the management of high-risk patients with atherosclerotic cardiovascular disease. The aim of this study was to evaluate the effect of two doses of 40 and 80 mg of atorvastatin on lipid profiles and inflammatory markers among patients with acute coronary syndrome (ACS). Materials and Methods: This single-blind, randomized clinical trial was conducted on 60 patients with ACS referred to Heshmatiyeh Hospital, Sabzevar, Iran. Eligible subjects were randomly assigned to either 80 mg/day (atorvastatin, 80 mg/day) or 40 mg/day intervention (atorvastatin, 40 mg/day) groups. Serum lipid profiles (low-density lipoprotein [LDL], high-density lipoprotein [HDL], triglyceride [TG], and total cholesterol), an inflammatory marker (creatine phosphokinase [CPK]), and liver function biomarkers (alanine aminotransferase, aspartate aminotransferase) were assessed before starting treatment and 3 months later. Results: According to the paired t-test, there was a significant difference before and after intervention in each group regarding mean LDL and HDL values (P < 0.05). The result of the ANCOVA test revealed that the LDL and CPK was substantially lower in the 80 mg/day group as compared to the 40 mg/day group after 3-month intervention (62.45 ± 16.78 mg for 80 mg/day vs. 73.63 ± 20.00 for 40 mg/day P = 0.040 and 84.85 ± 6.53 IU/L for 80 mg/day vs. 120.70 ± 6.41 IU/L for 40 mg/day P = 0.001, respectively). Although the mean of HDL, TG, and cholesterol in the 80 mg/day group was lower than that of the 40 mg/day group after implementing the intervention, these differences were not statistically significant (P > 0.05). Conclusion: Findings suggest that increasing the dose of atorvastatin decreases the mean serum levels of LDL and CPK but has no effect on the mean serum HDL levels and liver function biomarkers.

The Role of 5-HT1A Receptors and Neuronal Nitric Oxide Synthase in a Seizur Induced Kindling Model in Rats.

BACKGROUND AND OBJECTIVE: Dentate gyrus (DG) has a high density of 5-HT1A receptors. It has neural nitric oxide synthase (nNOS), which is involved in neural excitability. The purpose of this study was to investigate the role of 5-HT1A receptors and nNOS of DG in perforant path kindling model of epilepsy. MATERIAL AND METHODS: To achieve this purpose, a receptor antagonist (WAY100635, 0.1 mg/kg, intracerebroventricular, i.c.v) and neuronal nitric oxide synthase inhibitor (7-NI, 15 mg/kg, intraperitoneal, i.p.) were injected during kindling aquisition. Adult male Wistar rats (280 ± 20 g) were used in this study Animals were kindled through the daily administration of brief electrical stimulations (10 stimulations per day) to the perforant pathway. Field potential recordings were performed for 20 min in DG beforehand. Additionally, glial fibrillary acidic protein (GFAP) expression rate in the DG was determined using immunohistochemistry as a highly specific marker for glia. RESULTS: WAY100635 (0.1 mg/kg) significantly attenuated the kindling threshold compared to the kindled + vehicle group (P < 0.001). The co-administration of WAY100635 with 7-NI, exerted a significant anticonvulsive effect. Furthermore, the slope of field Excitatory Post Synaptic Potentials (fEPSP) at the end of 10 days in the kindled + 7-NI + WAY100635 group was significantly lower than in the kindled + vehicle group (P < 0.001). Furthermore, immunohistochemistry showed that the density of GAFP+ cells in the kindled + 7-NI + WAY100635 group was significantly higher than in the kindled + vehicle group (P < 0.001). CONCLUSION: Our data demonstrate that antagonists of 5-HT1A receptors have proconvulsive effects and that astrocyte cells are involved in this process, while nNOS has an inhibitory effect on neuronal excitability.

The effect of acidic beverage versus mineral water on the change in serum phenobarbital concentrations: a randomized clinical trial on children with seizure.

OBJECTIVE: To assess the effect of an acidic beverage (Orange juice) on the change in serum Phenobarbital concentrations in children with seizure who take Phenobarbital as the main treatment. METHODS: We did a parallel design and placebo controlled randomized clinical trial. Patients attending Heshmatiyeh Hospital (Iran) were recruited from October 2016 to December 2017. Forty patients randomly assigned to either experimental group or control group. Firstly, 5 mL blood sample was taken from both groups to measure serum Phenobarbital concentration before experiment. Then, one oral dose of Phenobarbital (2.5 mg/kg) with 100 mL of corporate Orange juice (pH = 3.5) (experiment group) or 100 mL of mineral water (neutral pH) (control group) was given to each group, respectively. After 2 h of administration, another blood sample was taken. The high-performance liquid chromatographic system was used for measurement of serum Phenobarbital concentration. RESULTS: There was significant increase in serum Phenobarbital concentrations after taking Phenobarbital in experiment group in comparison to control group. Statistical analysis revealed a significant increase in change of serum Phenobarbital concentrations in experiment group versus control group. CONCLUSION: The results of the current trial indicate that the level of serum Phenobarbital in the experiment group was higher than that of control group.

Caffeine attenuates spermatogenic disorders in mice with induced chronic scrotal hyperthermia.

OBJECTIVE: Chronic scrotal hyperthermia (SHT) can lead to serious disorders of the male reproductive system, with oxidative stress playing a key role in the onset of these dysfunctions. Thus, we evaluated the impact of caffeine, a potent antioxidant, on cellular and tissue disorders in mice with chronic SHT. METHODS: In this experimental study, 56 adult male NMRI mice were allocated into seven equal groups. Apart from the non-treated control group, all were exposed to heat stress. Two groups, termed "preventive" and "curative," were orally administered caffeine. The preventive mice began receiving caffeine immediately prior to heat exposure, while for the curative group, a caffeine regimen was initiated 15 consecutive days following cessation of heat exposure. Each treated group was subdivided based on pairing with a positive control (Pre/curative [Cur]+PC) or a vehicle (Pre/Cur+vehicle). Upon conclusion of the study, we assessed sperm characteristics, testosterone levels, stereological parameters, apoptosis, antioxidant and oxidant levels, and molecular markers. RESULTS: Sperm parameters, testosterone levels, stereological parameters, biochemical factors (excluding malondialdehyde [MDA]), and c-kit gene expression were significantly elevated in the preventive and curative groups, especially the former, relative to the other groups. Conversely, expression levels of the heat shock protein 72 (HSP72) and nuclear factor kappa beta (NF-κß) genes, MDA levels, and apoptotic cell density were markedly lower in both caffeine-treated groups relative to the other groups, with more pronounced differences observed in the preventive group. CONCLUSION: Overall, caffeine attenuated cellular and molecular abnormalities induced by heat stress in the testis, particularly in the mice treated under the preventive condition.

Promotion of cutaneous diabetic wound healing by subcutaneous administration of Wharton's jelly mesenchymal stem cells derived from umbilical cord.

Wound healing is a major problem in diabetic patients, and current treatments have been confronted with limited success. The present study examined the benefit of Wharton's jelly mesenchymal stem cells (WJ-MSCs) derived from the human umbilical cord (UC) in wound healing in diabetic rats. Thirty days after inducing diabetes, a circular excision was created in the skin of rats, and the treatments were performed for 21 days. Two groups were studied, which included the Control group and WJ-MSCs group. The studied groups were sampled on the 7th, 14th, and 21st days after wounding. Histological ultrasound imaging of dermis and epidermis in the wound area for thickness and density measurement and skin elasticity were evaluated. Our results on post-wounding days 7, 14, and 21 showed that the wound closure, thickness, and density of new epidermis and dermis, as well as skin elasticity in the healed wound, were significantly higher in the WJ-MSCs group compared to the Control group. Subcutaneous administration of WJ-MSCs in diabetic wounds can effectively accelerate healing. Based on this, these cells can be used along with other treatment methods in the healing of different types of chronic wounds.

An In Vivo Study of Lactobacillus rhamnosus (PTCC 1637) as a New Therapeutic Candidate in Esophageal Cancer.

Objective: This study is aimed at investigating the effect of probiotic Lactobacillus rhamnosus on esophageal cancer in vivo and in vitro. Methods and Results: In this study, the cytotoxicity effects of L. rhamnosus supernatant and whole-cell culture on a cancer cell line (Kyse30) compared to 5fu were evaluated by the MTT assay. The real-time PCR method was used to analyse the L. rhamnosus supernatant effect on the expression of Wnt signaling pathway genes. An in vivo investigation in nude mice was done to assess the anti-tumor activity of L. rhamnosus supernatant and whole-cell culture. Both supernatant and whole-cell culture of L. rhamnosus reduced cell survival (Kyse30) P < 0.001. The supernatant of this bacterium significantly reduced the expression of Wnt signaling pathway genes. Administration of supernatant and whole-cell culture of L. rhamnosus expressively reduced tumor growth compared to the control group. The effects of this bacterium on tumor necrosis were quite evident, pathologically P < 0.01. Conclusion: This study is the first report that assessed the potential impact of L. rhamnosus, especially its supernatant on esophageal cancer and Wnt signaling pathway genes. Therefore, this bacterium can be a harmless candidate for esophageal cancer therapy.

ABCG2, SCN1A and CYP3A5 genes polymorphism and drug-resistant epilepsy in children: A case-control study.

PURPOSE: Drug Resistant -Epilepsy is still a major challenge in pharmacotherapy of epilepsy. Pharmacogenetic pathways are one of the most important elements that can help clinicians determine medication response and provide more efficient drug therapy, especially in cases of drug resistance. Genetic alterations in drug target and transporter proteins, in part, could explain the development of drug-resistant epilepsy. We sought to assess the association of CYP3A5 (rs776746), SCN1A (rs2298771) and ABCG2 (rs2231137) candidate polymorphisms with drug-resistant epilepsy among Iranian children with epilepsy. METHODS: In a hospital-based case-control study, 93 participants, including 45 men and 48 women aged 1.5 to 14 years old were recruited. Genotyping of CYP3A5 (rs776746), SCN1A (rs2298771) and ABCG2 (rs2231137) polymorphisms using the high-resolution melting (HRM) method were measured in 46 children with drug-resistant epilepsy and 47 healthy control subjects. The binary logistic regression model was used to estimate the odds ratio (OR) for each polymorphism per effect allele increase. RESULTS: The mean (standard deviation [SD]) age of the drug-resistant patients was 10.7 (9.0) years versus 7.3 (3.6) in the control group. In the case group, most of the patients with epilepsy were diagnosed with generalized seizure (about 87%) and negative epileptic history status (63%). Furthermore, idiopathic epilepsy was dominant in the case group (69%). There was a clinically meaningful increase in the chance of drug-resistant epilepsy in participants with candidate polymorphism in ABCG2 gene (per allele T increase, adjusted odds ratio [OR] 2.41, confidence interval [CI] 0.99 to 5.87, P=0.05). No significant association was found between CYP3A5 (per allele C increase, OR 0.92, CI 0.33 to 2.60, P= 0.88) and SCN1A (per allele *1 increase, OR 0.65, 95% CI 0.34 to 1.23, P= 0.19) with drug-resistant epilepsy. CONCLUSION: We found evidence for the relationship between the ABCG2 gene polymorphism and a higher chance of drug-resistant epilepsy in children. This finding may have important implications for understanding the role of ABCG2 gene polymorphism in children with drug-resistant epilepsy.

Topical spray of Wharton's jelly mesenchymal stem cells derived from umbilical cord accelerates diabetic wound healing.

BACKGROUND AND AIM: Cell-based therapy utilizing mesenchymal stem cells (MSCs) is currently being investigated as a therapeutic agent for chronic wounds. There is no evidence regarding effectiveness of the spray and local transfer of this cellular product in diabetic wound healing. Accordingly, the present study, using clinical, pathological and biometric parameters, investigated the effectiveness of the spray of these cells in the healing of diabetic wounds in rats. METHODS: Three days after the induction of diabetes (50 mg/kg single dose of streptozotocin) a circular excision was created on the back of rats. Diabetic rats were divided into two groups (n = 21): Control and WJ-MSCs group. Sampling of the studied groups was performed on Days 7, 14, and 21 after wounding. Histological, ultrasound imaging of dermis and epidermis in the wound area for thickness and density measurement and skin elasticity were evaluated. RESULTS: Our results on Days 7, 14, and 21 after wounding showed that the wound closure, thickness, and density of new epidermis and dermis, as well as skin elasticity in healed wound were significantly higher in WJ-MSCs group compared with the Control group. CONCLUSION: Application of WJ-MSCs suspension spray on the wound area can accelerate healing in diabetic wounds. Our findings may potentially provide a helpful therapeutic strategy for patients with a diabetic wound.

The cytotoxicity and apoptotic effects of verbascoside on breast cancer 4T1 cell line.

BACKGROUND: Despite significant advancements in breast cancer therapy, novel drugs with lower side effects are still being demanded. In this regard, we investigated the anti-cancer features of verbascoside in 4 T1 mouse mammary tumor cell. METHODS: First, MTT assay was performed with various concentrations (ranging between 5 to 200 µM) of verbascoside and IC50 was calculated. Then the expression of Bax, Bcl-2, and caspase-3 was evaluated in treated 4 T1 cells. In addition, we investigated the expression of TLR4, MyD88, and NF-κB to ascertain the underlying mechanism of the anti-proliferative feature of verbascoside. Also, flow cytometry followed by double PI and Annexin V was conducted to confirm the apoptosis-inducing effect of verbascoside. RESULTS: Our results from MTT assay showed verbascoside inhibits proliferation of 4 T1 cancer cells (IC50 117 µM) while is safe for normal HEK293T cells. By qRT-PCR, we observed that verbascoside treatment (100, 117 and, 130 µM) increases the expression of caspase-3 and Bax while reduces the expression of Bcl-2. Also, verbascoside (100, 117 and, 130 µM) increased the expression of TLR4 only at 130 µM dose and the expression of MyD88 whereas reduced the expression of NF-κB at mRNA level. Flow cytometry analysis also confirmed verbascoside induces apoptosis in 4 T1 cells at 117 µM. CONCLUSION: Taken together, our data showed verbascoside is a safe natural compound for normal cells while has apoptosis-inducing feature through TLR4 axis on 4 T1 cells.

Impact of OCT4 and Its Related Signaling Pathways on Gastrointestinal Cancers: Focusing on Targeted Therapy.

There are many pieces of evidence support the effect of cancer stem cells on the initiation and progression of cancer. However, related mechanisms involved in these phenomena are far more complicated to understand. The function of different stemness factorsin cancer stem cells (CSCs) and their complex associations at different levels of cancer have been reported. Therefore, it seems that focusing on one master factor would be more helpful to complete the puzzle of singling pathways in these cells. Octamer-binding transcription factor 4 (OCT4) also known as POU domain, class 5, transcription factor 1(POU5F1), one of these key pluripotency factors, has important roles in both embryogenesis and tumorigenesis. In this review, we gathered information about the association of different markers with OCT4 expression in three types of gastrointestinal cancers including esophageal, gastric and colorectal cancers. OCT4 through different signaling pathways has an impact on different processes of gastrointestinal cancers such as proliferation, invasion, and metastasis. Based on the literature, OCT4 has great effects on cancer progression at different stages, therefore we suggested it has potential implications in therapeutic options.

7-Isopenthenyloxycoumarin, Arctigenin, and Hesperidin Modify Myeloid Cell Leukemia Type-1 (Mcl-1) Gene Expression by Hormesis in K562 Cell Line.

Hormesis is a new concept in dose-response relationship. Despite of traditional dose-response curves, there is a low-dose stimulation and a high-dose inhibition in this case. Hormesis effect in apoptosis induction/inhibition by natural compounds is reported previously. Here, we searched this effect for myeloid cell leukemia type-1 (Mcl-1) gene expression by phytochemicals 7-isopenthenyloxycoumarin (7-IP), arctigenin (Arg), and hesperidin (Hsp). For this purpose, first we tested the cytotoxicity of various doses of these compounds against K562 leukemia cell lines for different times by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. After that we explored the effect of various doses of these phytochemicals on Mcl-1 gene expression for different times by real-time polymerase chain reaction method. We found that these phytochemicals have cytotoxicity against K562 cell line. Hesperidin is the most cytotoxic agent. We also found that these natural compounds have hormetic effect on Mcl-1 gene expression. The hormetic model in Mcl-1 gene expression is overcompensation stimulation. This phenomenon is reported for the first time. We conclude that 7-IP, Arg, and Hsp are cytotoxic against K562 cancerous cells and induce/inhibit Mcl-1 gene expression by hormesis dose-response relationship.

Effect of a reminder system using an automated short message service on medication adherence following acute coronary syndrome.

BACKGROUND: Medication non-adherence leads to a vast range of negative outcomes in patients with coronary artery disease. An automated web-based system managing short message service (SMS) reminders is a telemedicine approach to optimise adherence among patients who frequently forget to take their medications or miss the timing. AIM: This paper sought to investigate the effect of automated SMS-based reminders on medication adherence in patients after hospital discharge following acute coronary syndrome (ACS). METHODS: An interventional study was conducted at a tertiary teaching hospital in Malaysia. A total of 62 patients with ACS were equally randomised to receive either automated SMS reminders before every intake of cardiac medications or only usual care within eight weeks after discharge. The primary outcome was adherence to cardiac medications. Secondary outcomes were the heart functional status, and ACS-related hospital readmission and death rates. RESULTS: There was a higher medication adherence level in the intervention group rather than the usual care group, (χ(2) (2)=18.614, p<0.001). The risk of being low adherent among the control group was 4.09 times greater than the intervention group (relative risk =4.09, 95% confidence interval (CI) 1.82-9.18). A meaningful difference was found in heart functional status between the two study groups with better results among patients who received SMS reminders, (χ(2) (1) = 16.957, p<0.001). CONCLUSION: An automated SMS-based reminder system can potentially enhance medication adherence in ACS patients during the early post-discharge period.

Mcl-1 is up regulated by prenylated coumarin, umbelliprenin in jurkat cells.

Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy in the western world and exists as subtypes with very different clinical courses. Myeloid cell leukemia 1 (Mcl-1) is one member of Bcl-2 family proteins that has been shown to be expressed in various tissues and malignant cells, including CLL, where its expression is significantly associated with a failure to achieve complete remission following cytotoxic therapy. Induction of apoptosis by prenylated coumarin, umbelliprenin, in Jurkat cells was previously shown. We examined whether umbelliprenin can down-regulate Mcl-1 gene and protein in Jurkat cells. In this regard cells were incubated by umbelliprenin, and then down- regulation of Mcl-1 gene was studied by Real Time PCR method. Moreover, down-regulation of Mcl-1 protein was studied by western blot analysis. We showed that, expression of Mcl-1 mRNA was increased from 1 hour to 3 hours incubation, but this increase has a scale down pattern. Moreover umbelliprenin could inhibit Mcl-1 protein. In conclusion umbelliprenin treatment modulates Mcl-1 expression at both the transcriptional and posttranslational levels.

Umbelliprenin from Ferula szowitsiana Activates both Intrinsic and Extrinsic Pathways of Apoptosis in Jurkat T-CLL cell line.

Umbelliprenin is a prenylated compound, which belongs to the class of sesquiterpene coumarins. It is extracted from dried roots of Ferula szwitsiana collected from the mountains of Golestan forest (Golestan Province, north of Iran). Induction of apoptosis in Jurkat T-CLL cells has been previously shown. In this study, effect of umbelliprenin on proapoptotic caspases (caspase-8 and -9) and antiapoptotic Bcl-2 family protein was studied. Jurkat cells were incubated with umbelliprenin. Cells were then lysed and activation of proteins was studied by Western blot analysis. In this study, we showed that umbelliprenin activates intrinsic and extrinsic pathways of apoptosis by the activation of caspase-8 and -9 respectively. Inhibition of Bcl-2 was also shown. In conclusion, umbelliprenin induced apoptosis in Jurkat cells through caspase-dependent apoptosis pathway.

Umbelliprenin Induces Apoptosis in CLL Cell Lines.

Chronic lymphocytic leukemia (CLL) remains an incurable disease that requires innovative new approaches to improve therapeutic outcome. Many Ferula species, including F. asa-foetida, synthesize terpenyloxy coumarins. One of these coumarins is umbelliprenin, which has been implicated with induction of apoptosis in some cancer cell lines. In this study induction of apoptosis by umbelliprenin on Jurkat T-CLL and Raji B-CLL cell lines was studied. In this regard, cells were incubated with various concentrations of umbelliprenin in-vitro for different times and assayed for apoptosis with annexin V-FITC/PI double staining flowcytometry method. Results showed that umbelliprenin induced apoptosis in leukemic cells in a dose- and time-dependent manner and that CLL cells were more susceptible to umbelliprenin induced cell death than normal peripheral blood mononuclear cell (PBMCs). Moreover, we study the induction of apoptosis in Jurkat cells by umbelliprenin in the presence of interleukin 4 (IL-4) as an agent that causes resistance to apoptosis in CLL cells, was also student. We showed that IL-4 can not reduce apoptotic effect of umbelliprenin. The preferential toxicity of umbelliprenin for CLL cells, supports the hypothesis that oral administration of umbelliprenin in the form of foods or folk medicines containing this coumarin, might enhance protection against the development of CLL in man with little side effects. In conclusion, umbelliprenin may be an effective therapeutic agent in the treatment of CLL, and thus clinical studies with umbelliprenin may be appropriate.

Opium addiction increases interleukin 1 receptor antagonist (IL-1Ra) in the coronary artery disease patients.

BACKGROUND: There is evidence that opium addiction has immunosuppressant effects. Coronary artery disease (CAD) is a condition resulted from atherosclerosis which is dependent on the immune response. PURPOSE: To evaluate plasma levels of interleukin-6 and interleukin-1Ra in 30 patients with three-vessel coronary artery disease, ejection fraction of more than 35% and to evaluate their changes after prognostic treadmill test in 15 opium addicted and 15 non-addicted patients. METHODS: The participants underwent prognostic treadmill test and plasma levels of interleukin-6 (IL-6) and interleukin-1Ra (IL-1Ra) were evaluated with ELISA method before, just after and 4 hours after the test. RESULTS: IL-1Ra (2183 pg/ml) tended to decrease over time in the opium addicted group (1372 pg/ml after prognostic treadmill test and 1034 pg/ml 4 hours after that), although such decrease did not reach the statistical significance. IL-1Ra levels were significantly higher in opium addicted than in non addicted patients. Opium addiction had no significant effect on IL-6 changes. CONCLUSION: Consumption of opium in CAD patients is associated with higher IL-1Ra levels.