Interindividual variability in diabetic patients' response to opium poppy: an overview of impressive factors.

Diabetic patients always seek alternative treatments to lower their blood glucose level efficiently, because antidiabetic drugs produce adverse effects and many patients experience reduced response after a treatment period. Opium poppy (Papaver somniferum) is frequently consumed by diabetic patients for reduction of blood glucose level. Scientific studies found controversial results in the investigation of the blood glucose-lowering effects of opium poppy. In this regard, we explored the antidiabetic effect of opium poppy more closely. The antidiabetic or antihyperglycemic effect of P. somniferum alkaloids were reviewed. Next, opioid receptors and their role in diabetes were explored. In the final part origins of interindividual variabilities in opioid receptors and metabolizing enzymes' functions including genetic and epigenetic factors were reviewed.

Effect of CYP3A5*1 expression on tacrolimus required dose after liver transplantation: A systematic review and meta-analysis.

We systematically collected eligible data to measure the effect of CYP3A5*1 expression on personalized tacrolimus therapy. Six databases were searched for studies on adult liver transplant recipients and donors of liver graft which reported tacrolimus dose requirement, trough blood concentration, and/or concentration/dose (C/D) ratio in expressers and nonexpressers of CYP3A5*1. Eligible data were pooled by meta-analysis. Sixteen observational studies (1309 recipients, 1044 donors of liver graft) were included in the analyses. Tacrolimus C/D ratio was lower, and the dose was higher in recipient expressers of CYP3A5*1 and/or carriers of expresser liver graft at 1-4 weeks and 2-4, 6, and 12 months post-transplantation. Tacrolimus blood concentration was lower at the first two weeks. Pair expressers were affected by about twofold, and the effect was different between ethnic groups. CYP3A5*1 expression in recipients increased tacrolimus required dose by 0.023 at first, 0.022 at third, and 0.012 mg/kg/day at sixth month. Its expression in graft tissue increased tacrolimus required dose by 0.024 at first, 0.035 at third, and 0.032 mg/kg/day at sixth month. Considering CYP3A5*1 polymorphism can be helpful in individualization of tacrolimus efficient dose prior to administration, and it can remove initial high-risk lag time (over/underdose period before reaching target blood level) at first few days post-transplantation.

Effect of CYP3A5*1 expression on tacrolimus required dose for transplant pediatrics: A systematic review and meta-analysis.

This systematic review was designed to find out optimal tacrolimus dose in pediatrics according to their CYP3A5*1 genotype by performing meta-analysis. PubMed, Scopus, ISI web of Science, ProQuest, Cochrane library, and clinicaltrail.gov were systematically searched to find studies in which tacrolimus dose and/or blood concentration and/or concentration-to-dose (C/D) ratio were determined in genotype groups of CYP3A5*1 in pediatric population. Data were extracted at 14 time points post-transplantation and meta-analysis of mean and SD was performed. In all, 11 studies including 596 pediatric transplant recipients were entered into systematic review and meta-analysis. Analysis of tacrolimus required dose, blood concentration, and C/D ratio in 14 time points post-transplantation resulted in significant differences between expressers and non-expressers of CYP3A5*1. It seems that 0.06 mg/kg/day higher tacrolimus dose in expressers can produce same blood level as non-expressers. Using results of TDM for tacrolimus dose adjustment, it takes about 1 month for patients to reach stable and optimum tacrolimus blood concentration. This is too long time period which increases the risk of immunosuppressive over/under-dose and drug toxicity or organ rejection. Considering our results, defining genetic profile helps to predict the individual required dose more rapidly, actually before beginning of treatment.

Probiotic supplementation for management of cardiovascular risk factors in adults with type II diabetes: A systematic review and meta-analysis.

BACKGROUND & AIMS: The effectiveness of probiotics in control of hypertension and dyslipidemia in diabetic patients remains unclear. Therefore, we systematically reviewed relevant data to elucidate the effects of probiotics on blood pressure and lipid profile of type 2 diabetic patients. METHODS: We searched PubMed, ISI Web of Knowledge, Scopus, The Cochrane Library, ClinicalTrials.gov, ProQuest Dissertations and Theses databases until May 2016. The primary outcomes were systolic blood pressure (SBP) and diastolic blood pressure (DBP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Other biochemical response and adverse effects were considered as secondary outcomes. Data was extracted from included studies and pooled in meta-analysis whenever possible (both standardized mean difference (SMD) analysis and weighted mean difference (WMD) analysis were performed). RESULTS: Eleven eligible randomized controlled trial (n = 641) were identified. Pooling data from these trials demonstrated probiotic consumption significantly decreased SBP (WMD, -3.28 mmHg; 95% confidence interval [CI], -5.38 to -1.18), DBP (WMD, -2.13 mmHg; 95% CI, -4.5 to 0.24), LDL-C (WMD, 8.32 mg/dl; 95% CI, -15.24 to -1.4), TC (WMD, -12.19 mg/dl; 955 CI -17.62 to -6.75) and TG (WMD, -24.48 mg/dl; 95% CI, -33.77 to -11.18) in type 2 diabetic patients compared with placebo. The methodological quality varied across trials included in this study. CONCLUSION: This systematic review suggests probiotics supplementation may be helpful for control of dyslipidemia and hypertension in type 2 diabetic patients. Conducting more trails with large sample size and long follow-up time still is necessary to develop clinical practice guidelines for management of cardiovascular risk factors in patient with type 2 diabetes.

Explant culture: An advantageous method for isolation of mesenchymal stem cells from human tissues.

Mesenchymal stem cell (MSC) research progressively moves towards clinical phases. Accordingly, a wide range of different procedures were presented in the literature for MSC isolation from human tissues; however, there is not yet any close focus on the details to offer precise information for best method selection. Choosing a proper isolation method is a critical step in obtaining cells with optimal quality and yield in companion with clinical and economical considerations. In this concern, current review widely discusses advantages of omitting proteolysis step in isolation process and presence of tissue pieces in primary culture of MSCs, including removal of lytic stress on cells, reduction of in vivo to in vitro transition stress for migrated/isolated cells, reduction of price, processing time and labour, removal of viral contamination risk, and addition of supporting functions of extracellular matrix and released growth factors from tissue explant. In next sections, it provides an overall report of technical highlights and molecular events of explant culture method for isolation of MSCs from human tissues including adipose tissue, bone marrow, dental pulp, hair follicle, cornea, umbilical cord and placenta. Focusing on informative collection of molecular and methodological data about explant methods can make it easy for researchers to choose an optimal method for their experiments/clinical studies and also stimulate them to investigate and optimize more efficient procedures according to clinical and economical benefits.

Effects of probiotic supplementation in patients with type 2 diabetes: systematic review and meta-analysis.

CONTEXT: The rising prevalence of type 2 diabetes requires increased efforts to find effective therapeutic agents for this complex condition. Following the recent observation that the gut microbiota is altered in diabetic patients, researchers investigated the effect of probiotics in patients with diabetes. OBJECTIVE: The aim of this systematic review was to assess the effects of probiotic consumption on glycemic control in diabetic patients. DATA SOURCES: PubMed, Scopus, Web of Science (formerly ISI Web of Knowledge), Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and ProQuest Dissertations and Theses databases were searched up to November 2015. STUDY SELECTION: Clinical trials in diabetic patients in whom probiotics were administered as an intervention were included. DATA EXTRACTION: Primary outcomes were fasting blood glucose, insulin concentration, insulin resistance, and hemoglobin A1c. Secondary outcomes were adverse events. DATA SYNTHESIS: Of the 2736 reports that were screened, 13 clinical trials met the inclusion criteria. Pooling data from eligible clinical trials revealed that probiotic supplementation significantly (P < 0.05) decreased fasting blood glucose and hemoglobin A1c in diabetic patients, although the participants' characteristics (eg, body mass index) and the number and type of probiotic microorganisms affected the clinical response. CONCLUSIONS: Administration of probiotics appears to have a beneficial role in the management of type 2 diabetes; however, more clinical studies with adequate sample sizes and sound methodology are required to inform the development of evidence-based treatment guidelines.

Dual Protective and Cytotoxic Benefits of Mesenchymal Stem Cell Therapy in Combination with Chemotherapy/Radiotherapy for Cancer Patients.

Cancer is a major health problem in the world, and scientists seek innovative treatment strategies with higher efficacy and lower toxicity than the existing therapeutic agents. In this way, stem cell researchers try to reveal new pathways that will eventually benefit patients. Stem cell research has proven that mesenchymal stem cells (MSCs) possess anticancer activities, and their protein-rich secretome showed similar effects. MSCs also secrete cytokines that play an active role in healing and regeneration processes. Because of their known plasticity, MSCs display a variety of characteristics and functions in different environments, depending on their interactions with various cell types and tissues. Therefore, we hypothesize that MSC therapy in combination with anticancer medicines can potentiate cytotoxic effects on cancer cells. In addition, because of their regenerative capacity, MSCs can protect normal tissues from adverse cytotoxic drug reactions. They may also help rescue injured tissues from these toxic damages or systemic pathological events that occur during cancer treatment. MSC therapy may double the beneficial effects on cancer and normal cells. As our knowledge of systems biology and biotechnological methodology is progressing, this idea can move forward as a treatment option.

Human Wharton's jelly mesenchymal stem cell secretome display antiproliferative effect on leukemia cell line and produce additive cytotoxic effect in combination with doxorubicin.

Mesenchymal stem cell (MSC) therapy moves toward clinic progressively. Recent evidences establish anticancer effect of mesenchymal stem cells. However multiple factors including type of cancer, MSC source, study design, and animal model play role in final outcome. Wharton's jelly - a newly approved source of MSCs - possesses superiorities to bone marrow as the conventional source; therefore investigation of its medical effects can produce beneficial results. In this survey we examined cytotoxic and proapoptotic effect of human Wharton's jelly MSC secretome on K562 human leukemia cells. MSCs were isolated from human Wharton's jelly of umbilical cord by explant culture method, then characterized according to ISCT criteria (morphology and plastic adherence, surface antigenicity and differentiation potential). MSC secretome was collected and its cytotoxic and proapoptotic effects on K562 cells in combination with doxorubicin were evaluated using BrdU cell proliferation assay and Annexin V-PI staining. Our results showed antiproliferative effect of mesenchymal stem cell secretome on K562 cancer cells, the effect was also added to cytotoxic effect of doxorubicin without induction of drug resistance. Human Wharton's jelly derived mesenchymal stem cells exerted cytotoxic effect on leukemia cells. Addition of that effect to anticancer effect of chemotherapeutic agents can leads to cytotoxic drug dose reduction and diminished side effects.

Human mesenchymal stromal cell therapy for prevention and recovery of chemo/radiotherapy adverse reactions.

Cancer treatment plans mainly include chemotherapy, radiotherapy and surgery, which exert serious adverse reactions immediately or during the long term after cancer therapy in many patients. In several cases, treatment-related adverse effects outweigh treatment benefits and worsen the patient's condition. This problem is not avoidable with current cancer therapy procedures; therefore, improved understanding and earlier prevention and reversion of treatment-related complications are particularly important before the lesions become progressive and irreversible. Mesenchymal stromal cell therapy is very promising in recent clinical research and investigations. Their potential properties such as regenerative and reparative functions and anti-inflammatory activity make them proper candidates for cell therapy to recover cancer patients from treatment-related adverse effects or may even prevent them. This article discuss benefits of applying human mesenchymal stromal cell therapy after current cancer treatment plans, with the purpose of prevention and healing of adverse reactions, faster patient recovery after radio/chemotherapy, reducing rates of treatment failure and cancer recurrence and increasing patient quality of life after treatment cessation.

Comparison of human mesenchymal stem cells isolated by explant culture method from entire umbilical cord and Wharton's jelly matrix.

Adult stem cells are of particular importance for applications in regenerative medicine. Umbilical cord was established recently as an alternative source of mesenchymal stem cell (MSC) instead of bone marrow (BM) and is superior to BM and other adult tissues according to several MSC properties. Additionally, for the purpose of cell therapy in clinical scale, steps of cell isolation, expansion and culture required to be precisely adjusted in order to obtain the most cost-effective, least time-consuming, and least labor-intensive method. Therefore, in this study, we are going to compare two simple and cost-effective explant culture methods for isolation of MSCs from human umbilical cord. One of the methods isolates cells from entire cord and the other from Wharton's jelly matrix. Isolated cells then cultured in simple medium without addition of any growth factor. MSCs obtained via both methods display proper and similar characteristics according to morphology, population doubling time, post-thaw survival, surface antigenicity and differentiation into adipocytes, osteocytes, and chondrocytes. MSCs can easily be obtained from the entire cord and Wharton's jelly, and it seems that both tissues are appropriate sources of stem cells for potential use in regenerative medicine. However, from technical large-scale preview, MSC isolation from entire cord piece is less labor-intensive and time-consuming than from Wharton's jelly part of the cord.

Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran.

Research has shown that there are significant ethnic variations in the frequency of highly functional mutations in genes coding for metabolic enzymes. However, few studies have examined the frequency distribution of major allelic variations within the population of Iran. The present study focused on the genotype profile of southern Iranians in order to compare the allelic frequencies of CYP2C9, CYP2C19, and VKORC1 -1639G>A (all of which have been shown to have significant roles in the metabolism of warfarin) with those of other populations. Therefore, genotyping was carried out on 150 subjects (50 healthy volunteers and 100 outpatient subjects) by polymerase chain reaction- restriction length polymorphism (PCR-RFLP). Findings indicated both similarities and differences in the distribution of polymorphic alleles of CYP2C9, CYP2C19 and VKORC1 between southern and northern Iranians. For example, the frequency of CYP2C9*3 among southern Iranians (9.8%) was found to be similar to the frequency found among Caucasians (in this case, Italians) (9.7%) but was higher than the frequency found among Africans (1%), Japanese (2.3%), and northern Iranians (0%). These findings confirmed significant inter-ethnic differences in CYP2C9 frequencies between southern and northern Iranians The reported frequency of CYP2C9*2 in our subjects (25.3%) was different from the frequencies seen in Caucasian (10-13%), African (2%) and Asian (0%) populations. The CYP2C19*2 and CYP2C19*3 allelic frequencies were similar to the Caucasian population. For VKORC1, the allelic frequency of -1639A (55.6%) was in accordance with Caucasian, but different from Chinese (96%) and African-American populations (13%). The findings confirmed some important interethnic differences in the metabolic capacity for drug clearance. Because the population of Iran consists of several ethnicities, this type of analysis can help explain the genetic diversity between the populations of northern and southern Iran. In addition, the results of this study will be useful for understanding clinical pharmacokinetics and drug dosage recommendations for Iranians.

The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: a cross-sectional study in Iran.

BACKGROUND: Warfarin is the most commonly prescribed oral anticoagulant drug for prophylaxis and treatment of venous and arterial thromboembolic disorders. Its anticoagulant effect is widely variable between patients because of pharmacodynamic, pharmacokinetic, and pharmacogenetic factors. OBJECTIVE: This study was conducted to identify the associations between demographic characteristics, warfarin maintenance dose, and genetic polymorphisms of cytochrome P450 (CYP) 2C19, CYP2C9, and vitamin K epoxide reductase complex subunit 1 (VKORC1). METHODS: This study was conducted from April 2005 to April 2008 at 3 warfarin clinics affiliated with Shiraz University of Medical Sciences. Blood samples were collected from patients with stable warfarin maintenance dose and a stable target international normalized ratio of 2 to 3. Patients who had a condition (including use of an interacting medication) affecting the metabolism of warfarin were excluded. CYP2C9, CYP2C19, and VKORC1 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. The associations between demographic characteristics (eg, age, sex, body surface area, weight, height), genetic factors, and maintenance warfarin dose were examined by multiple linear regression. The probability of F as a criterion for removal of a variable from the multiple linear regression was set at 0.1. RESULTS: One hundred patients were enrolled in the study; complete data were available for 55, who were included in the regression analysis. Among this smaller group, the mean (SD) age was 53 (11) years (range, 25-80 years) and mean weight was 72 (15) kg (range, 42-125 kg); the mean warfarin dose was 27.2 (13.4) mg/week. The allelic frequencies of CYP2C9*2 and CYP2C9*3 were 27% and 9%, respectively. The allelic frequencies of CYP2C19*2 and CYP2C19*3 were 11% and 1%, respectively. Fifteen percent of our patients carried a VKORC1 genotype GG, whereas the AA and GA genotypes were seen in 18% and 58% of patients, respectively. Multiple linear regression analysis found that sex (P = 0.045), height (P = 0.024), age (P = 0.081), and VKORC1 (P = 0.004) and CYP2C9 (P = 0.011) polymorphism had significant influence on the maintenance dose of warfarin. They were associated with 41.3% of the variability in warfarin maintenance dose requirement. VKORC1 polymorphism (partial R(2) = 20.3%) and height (partial R(2) = 20.3%) had the greatest effects on warfarin maintenance dose requirement. CONCLUSION: Among the demographic and genetic factors evaluated in these Iranian patients, sex, height, age, CYP2C9, and VKORC1 had significant effects on warfarin maintenance dose requirements.