Effect of probiotics supplementation on glucose and oxidative stress in type 2 diabetes mellitus: a meta-analysis of randomized trials.

PURPOSE: The role of oxidative stress in pathogenesis of diabetes is well established. In addition, an association between gut microbiota and type 2 diabetes mellitus (T2DM) is widely observed in previously published reports. This meta-analysis critically examines the association between gut microbiota, and oxidative stress in T2DM. METHODS: A systematic search for clinical trials was performed in PubMed, Web of Science and Scopus web databases up to 1 Jan 2019. Primary search terms include "microbiota", "diabetes", and "oxidative stress". Study was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline. All clinical trials that compared the effects of probiotic supplementations with a control group using end points serum levels of fasting blood sugar (FBS), hemoglobin A1C (HbA1C) and oxidative stress biomarkers were included. Two independent researchers screened the data extracted from the relevant studies. The pooled standardized mean difference (SMD) was estimated using the random or fixed effects model. Heterogeneity among the studies was assessed using Q-test. RESULTS: Overall, 13 randomized clinical trials (RCTs) involving 840 subjects with T2DM were included in the meta-analysis. The analysis showed that probiotics intake resulted in significant improvement in serum levels of FBS [SMD: -0.35, 95% CI: (-0.59, -0.12)], total antioxidant status (TAS) [SMD: 0.33, 95% CI: (0.11, 0.55)], total glutathione (GSH) [SMD: 0.41, 95% CI: (0.26, 0.56)] and malondialdehyde (MDA) [SMD: -0.54, 95% CI: (-0.83, -0.26)]. No significant improvement was found in HbA1C [SMD: -0.06, 95% CI:(-0.82, 0.69)], and nitric oxide (NO) [SMD:-0.24, 95% CI:(-1.10, 0.62)] levels. CONCLUSION: It seems that gut microbiota can exert beneficial effects in diabetic patients via altering oxidative stress' biomarkers. The beneficial effect of gut microbiota however was modest on FBS and non-significant on HbA1C. These results need to be confirmed by conducting more reliable RCTs. PROSPERO REGISTRATION NUMBER: CRD42019134905. Graphical abstract Flow diagram of the study selection process.

Kynurenine Modulates MMP-1 and Type-I Collagen Expression Via Aryl Hydrocarbon Receptor Activation in Dermal Fibroblasts.

Dermal fibrosis is characterized by a high deposition of extracellular matrix (ECM) and tissue cellularity. Unfortunately all means of treating this condition are unsatisfactory. We have previously reported the anti-fibrotic effects of Kynurenine (Kyn), a tryptophan metabolite, in fibrotic rabbit ear model. Here, we report the mechanism by which Kyn modulates the expression of key ECM components in dermal fibroblasts. The results showed that Kyn activates aryl hydrocarbon receptor (AHR) nuclear translocation and up-regulates cytochrome-P450 (CYP1A-1) expression, the AHR target gene. A specific AHR antagonist, 6,2',4'-trimethoxyflavone, inhibited the Kyn-dependent modulation of CYP1A-1, MMP-1, and type-I collagen expression. Establishing the anti-fibrogenic effect of Kyn and its mechanism of action, we then developed nano-fibrous Kyn slow-releasing dressings and examined their anti-fibrotic efficacy in vitro and in a rat model. Our results showed the feasibility of incorporating Kyn into PVA/PLGA nanofibers, prolonging the Kyn release up to 4 days tested. Application of medicated-dressings significantly improved the dermal fibrosis indicated by MMP-1 induction, alpha-smooth muscle actin and type-I collagen suppression, and reduced tissue cellularity, T-cells and myofibroblasts. This study clarifies the mechanism by which Kyn modulates ECM expression and reports the development of a new slow-releasing anti-fibrogenic dressing. J. Cell. Physiol. 231: 2749-2760, 2016. © 2016 Wiley Periodicals, Inc.

Effects of kynurenine on CD3+ and macrophages in wound healing.

As prolongation of the inflammation phase in a healing process frequently leads to wound impairment, here we queried whether kynurenine (Kyn) could modulate this phase of wound healing. To address this, a protein microarray, quantitative polymerase chain reaction (qPCR), flow cytometry for immune cells and immune cell proliferation in the presence and absence of Kyn were conducted and compared. The result of a protein microarray revealed that the expression of 12 pro-inflammatory cytokines and chemokines was modulated in Kyn-treated mouse splenocytes as compared with those of control. These findings were then evaluated by conducting a qPCR for the gene expression of these factors and showed a significant reduction in the gene expression of majority of these cytokines and chemokines (interleukin [IL]-2, IL-17, C-X-C motif chemokine ligand [CXCL] 10, CXCL1, C-C motif ligand [CCL] 12, CXCL9, CCL4, CXCL2, and CCL5) in response to Kyn treatment. To test the anti-inflammatory effect of Kyn in an animal model, dorsal surface wounds were generated in a mouse model and wounds received daily topical application of either nothing (control), dermal cream (second control), or Kyn cream using uninjured skin tissue as another control. The wounded tissues were harvested on days 3, 6, and 10 postwounding. As anticipated, the results of fluorescence-activated cell sorting analysis revealed that upon wounding, the number of total infiltrated CD3+ cells and macrophages (CD11b+) significantly increased on day 3, peaked on day 6, and reduced on day 10 post-wounding. Interestingly, as compared with those of uninjured and dermal cream alone-treated wounds, Kyn treatment significantly reduced the number of infiltrated CD3+ cells, but not CD11b+ cells, at different time intervals examined. These findings collectively suggest that Kyn, as a small molecule, can potentially be used to overcome the difficulties associated with persistency of inflammation in healing wounds.

Healing of excisional wound in alloxan induced diabetic sheep: A planimetric and histopathologic study.

Healing of skin wound is a multi-factorial and complex process. Proper treatment of diabetic wounds is still a major clinical challenge. Although diabetes mellitus can occur in ruminants, healing of wounds in diabetic ruminants has not yet been investigated. The aim of this study was to evaluate healing of ovine excisional diabetic wound model. Eight 4-month-old Iranian Makoui wethers were equally divided to diabetic and nondiabetic groups. Alloxan monohydrate (60 mg kg(-1), IV) was used for diabetes induction. In each wether, an excisional wound was created on the dorsum of the animal. Photographs were taken in distinct times for planimetric evaluation. Wound samples were taken on day 21 post-wounding for histopathologic evaluations of epidermal thickness, number of fibroblasts and number of new blood vessels. The planimetric study showed slightly delay in wound closure of diabetic animals, however, it was not significantly different from nondiabetic wounds (p ≥ 0.05). Furthermore, epidermal thickness, number of fibroblasts and number of blood vessels were significantly lower in diabetic group (p < 0.05). We concluded that healing of excisional diabetic wounds in sheep may be compromised, as seen in other species. However, contraction rate of these wounds may not be delayed due to metabolic features of ruminants and these animals might go under surgeries without any serious concern. However, healing quality of these wounds may be lower than normal wounds.

Establishing a cGMP pancreatic islet processing facility: the first experience in Iran.

It has been predicted that one of the greatest increase in prevalence of diabetes will happen in the Middle East bear in the next decades. The aim of standard therapeutic strategies for diabetes is better control of complications. In contrast, some new strategies like cell and gene therapy have aimed to cure the disease. In recent years, significant progress has occurred in beta-cell replacement therapies with a progressive improvement of short-term and long term outcomes. In year 2005, considering the impact of the disease in Iran and the promising results of the Edmonton protocol, the funding for establishing a current Good Manufacturing Practice (cGMP) islet processing facility by Endocrinology and Metabolism Research Center was approved by Tehran University of Medical Sciences. Several islet isolations were performed following establishment of cGMP facility and recruitment of all required equipments for process validation and experimental purpose. Finally the first successful clinical islet isolation and transplantation was performed in September 2010. In spite of a high cost of the procedure it is considered beneficial and may prevent long term complications and the costs associated with secondary cares. In this article we will briefly describe our experience in setting up a cGMP islet processing facility which can provide valuable information for regional countries interested to establish similar facilities.

The prevalence of polyp in colon of patients with acromegaly.

Several studies have shown that patients with acromegaly are at increased risk of developing colorectal polyps and cancer. The prevalence of polyp in colon of patients with acromegaly was variously reported between 23% and 53%. This study was conducted to determine the prevalence of polyp and cancer of colon in patients with acromegaly. Twenty-three patients with acromegaly were evaluated with colonoscopy for the presence of colonic polyps and cancer. Three patients were found to have colonic polyps. This translates to a prevalence rate of 13%. We recommend that screening colonoscopy be carried out once every three years in all acromegalic patients over the age of 40 years.

The status of biochemical parameters in varying degrees of vitamin D deficiency.

Vitamin D (Vit D) is an essential element for the regulation of serum calcium, phosphate, and alkaline phosphatase (Alk Ph). Because the Vit D serum level is not usually measured directly, Vit D deficiency is diagnosed indirectly by changes in serum calcium, phosphate, and Alk Ph leves. The current study assessed the status of these biochemical parameters in subjects with different degrees of Vit D deficiency. We selected 1,210 subjects, between 20 and 69 years old, randomly from the Tehran population. Subjects with diseases or medications that modified bone metabolism were excluded from the study. Serum 25(OH) D, calcium, phosphate, Alk Ph, and parathyroid hormone (PTH) levels were measured and the status of these biochemical parameters was compared in subjects with different degrees of Vit D deficiency. Vit D deficiency was diagnosed in 79.6% of the subjects. Different degrees of Vit D deficiency were classified as follows: group 1, severe; group 2, moderate; and group 3, mild. Serum PTH levels in the Vit D-deficient groups were significantly higher than that in group 4 (normal Vit D). Serum calcium and phosphate levels in groups 1 and 2 were significantly lower than those in groups 3 and 4. No significant difference was seen in serum Alk Ph in the groups with different degrees of Vit D deficiency. The sensivity for at least one biochemical variable (calcium, phosphorus, or Alk Ph) for the detection of severe, moderate, and mild Vit D deficiency was 24.2%, 13.8%, and 6%, respectively. When the serum 25(OH) D level was reduced to less than 25 nmol/l (groups 1 and 2), the effects of Vit D deficiency on calcium and phosphate levels were obvious. Therefore, the usual biochemical parameters (calcium, phosphate, Alk Ph) alone do not have sufficient sensitivity to detect mild deficiency of Vit D.

Diabetes mellitus following pituitary adenomectomy in euglycemic patients with acromegaly.

Insulin resistance, impaired glucose tolerance and diabetes mellitus (DM) secondary to acromegaly generally improve following treatment of the underlying disease. In rare cases, in spite of normoglycaemia in the presence of active acromegaly, patients develop diabetes mellitus following pituitary adenomectomy to the extent of requiring insulin therapy. We report 7 patients who developed diabetes mellitus after pituitary adenomectomy. Regular measuring of blood glucose in post-pituitary surgery patients is recommended as a necessary step even in the previously normoglycaemics.

Diagnostic value of frozen section examination in thyroid nodule--surgery at the Shariati Hospital (1997-2000).

INTRODUCTION: There is controversy regarding the use and accuracy of frozen section (FS) in managing thyroid nodules. We compared the diagnostic value of FS with that of permanent histopathology examination and fine needle aspiration (FNA). MATERIALS AND METHODS: Permanent, FS, and FNA sample reports were compared in 214 patients between 1997 and 2000. FS, FNA, and permanent pathology (gold standard) results were compared using McNemar's test. RESULTS: 160 women and 54 men (mean age: 42.3 +/- 5.4 yr) took part in the study; 163 patients (76%) had benign and 51 (24%) malignant lesions; 76% of our thyroid cancer cases were papillary, 13.5% follicular, 6% medullary carcinoma, 4% Hürthle cell carcinoma, and 0.5% anaplastic carcinoma. FNA yielded definite results in 150 patients (sensitivity 72%, specificity 96%, and precision 90%). In 64 patients with equivocal FNA, FS was performed (sensitivity 36%, specificity 73%, and precision 85%). The observed difference between FNA and FS was not statistically significant. DISCUSSION: When FNA results are inconclusive, FS does not provide any further information. In suspected cases of papillary, undifferentiated, or medullary carcinomas, FS can confirm FNA findings and guide surgical therapy.

Clinico-pathological features of thyroid cancer as observed in five referral hospitals in Iran--a review of 1177 cases.

In this study some of the clinical and pathological aspects of thyroid carcinomas in Iran are defined. Until fairly recently, Iran was an area of endemic iodine deficiency. The medical records of 1177 confirmed cases of thyroid cancer treated over a 15-year period at 5 tertiary referral centers were reviewed. The female/male ratio was 1.8/1. Mean age was 42.8 +/- 0.9 years, male patients being significantly older. The most common clinical presentation (initial manifestation) was a central neck mass; 28.6% of the tumors had metastasized, usually to the cervical lymph nodes, by the time the patient presented with disease. The mean size of non-metastatic tumors was 5.0 cm at their longest diameter. The distribution of tumors in our study did not reflect the expectations for an iodine-deficient area, where follicular thyroid carcinoma is common, but rather what is seen in iodine-rich areas. Papillary and follicular types accounted for79.7% and 8.8% of cases, respectively.

Treatment of hyperfunctioning thyroid nodules by percutaneous ethanol injection.

BACKGROUND: Autonomous thyroid nodules can be treated by a variety of methods. We assessed the efficacy of percutaneous ethanol injection in treating autonomous thyroid nodules. METHODS: 35 patients diagnosed by technetium-99 scanning with hyperfunctioning nodules and suppressed sensitive TSH (sTSH) were given sterile ethanol injections under ultrasound guidance. 29 patients had clinical and biochemical hyperthyroidism. The other 6 had sub-clinical hyperthyroidism with suppressed sTSH levels (<0.24 &mgr;IU/ml) and normal thyroid hormone levels. Ethanol injections were performed once every 1-4 weeks. Ethanol injections were stopped when serum T3, T4 and sTSH levels had returned to normal, or else injections could no longer be performed because significant side effects. Patients were followed up at 3, 6 and, in 15 patients, 24 months after the last injection. RESULTS: Average pre-treatment nodule volume [18.2 PlusMinus; 12.7 ml] decreased to 5.7 PlusMinus; 4.6 ml at 6 months follow-up [P < 0.001]. All patients had normal thyroid hormone levels at 3 and 6 months follow-up [P < 0.001 relative to baseline]. sTSH levels increased from 0.09 PlusMinus; 0.02 &mgr;IU/ml to 0.65 PlusMinus; 0.8 &mgr;IU/ml at the end of therapy [P < 0.05]. Only 3 patients had persistent sTSH suppression at 6 months post-therapy. T4 and sTSH did not change significantly between 6 months and 2 years [P > 0.05]. Ethanol injections were well tolerated by the patients, with only 2 cases of transient dysphonia. CONCLUSION: Our findings indicate that ethanol injection is an alternative to surgery or radioactive iodine in the treatment of autonomous thyroid nodules.