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Metformin Therapy Attenuates Pro-inflammatory Microglia by Inhibiting NF-κB in Cuprizone Demyelinating Mouse Model of Multiple Sclerosis

Abdi M, Pasbakhsh P, Shabani M, Nekoonam S, Sadeghi A, Fathi F, et al.

Neurotox Res, 2021 Dec;39(6):1732-1746.
PMID: 34570348 DOI: 10.1007/s12640-021-00417-y

Multiple sclerosis (MS) is a chronic disorder characterized by reactive gliosis, inflammation, and demyelination. Microglia plays a crucial role in the pathogenesis of MS and has the dynamic plasticity to polarize between pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Metformin, a glucose-lowering drug, attenuates inflammatory responses by activating adenosine monophosphate protein kinase (AMPK) which suppresses nuclear factor kappa B (NF-κB). In this study, we indirectly investigated whether metformin therapy would regulate microglia activity in the cuprizone (CPZ)-induced demyelination mouse model of MS via measuring the markers associated with pro- and anti-inflammatory microglia. Evaluation of myelin by luxol fast blue staining revealed that metformin treatment (CPZ + Met) diminished demyelination, in comparison to CPZ mice. In addition, metformin therapy significantly alleviated reactive microgliosis and astrogliosis in the corpus callosum, as measured by Iba-1 and GFAP staining. Moreover, metformin treatment significantly downregulated the expression of pro-inflammatory associated genes (iNOS, H2-Aa, and TNF-α) in the corpus callosum, whereas expression of anti-inflammatory markers (Arg1, Mrc1, and IL10) was not promoted, compared to CPZ mice. Furthermore, protein levels of iNOS (pro-inflammatory marker) were significantly decreased in the metformin group, while those of Trem2 (anti-inflammatory marker) were increased. In addition, metformin significantly increased AMPK activation in CPZ mice. Finally, metformin administration significantly reduced the activation level of NF-κB in CPZ mice. In summary, our data revealed that metformin attenuated pro-inflammatory microglia markers through suppressing NF-κB activity. The positive effects of metformin on microglia and remyelination suggest that it could be used as a promising candidate to lessen the incidence of inflammatory neurodegenerative diseases such as MS.
Th17 and Treg cells function in SARS-CoV2 patients compared with healthy controls

Sadeghi A, Tahmasebi S, Mahmood A, Kuznetsova M, Valizadeh H, Taghizadieh A, et al.

J Cell Physiol, 2021 04;236(4):2829-2839.
PMID: 32926425 DOI: 10.1002/jcp.30047

In the course of the coronavirus disease 2019 (COVID-19), raising and reducing the function of Th17 and Treg cells, respectively, elicit hyperinflammation and disease progression. The current study aimed to evaluate the responses of Th17 and Treg cells in COVID-19 patients compared with the control group. Forty COVID-19 intensive care unit (ICU) patients were compared with 40 healthy controls. The frequency of cells, gene expression of related factors, as well as the secretion levels of cytokines, were measured by flow cytometry, real-time polymerase chain reaction, and enzyme-linked immunosorbent assay techniques, respectively. The findings revealed a significant increase in the number of Th17 cells, the expression levels of related factors (RAR-related orphan receptor gamma [RORγt], IL-17, and IL-23), and the secretion levels of IL-17 and IL-23 cytokines in COVID-19 patients compared with controls. In contrast, patients had a remarkable reduction in the frequency of Treg cells, the expression levels of correlated factors (Forkhead box protein P3 [FoxP3], transforming growth factor-β [TGF-β], and IL-10), and cytokine secretion levels (TGF-β and IL-10). The ratio of Th17/Treg cells, RORγt/FoxP3, and IL-17/IL-10 had a considerable enhancement in patients compared with the controls and also in dead patients compared with the improved cases. The findings showed that enhanced responses of Th17 cells and decreased responses of Treg cells in 2019-n-CoV patients compared with controls had a strong relationship with hyperinflammation, lung damage, and disease pathogenesis. Also, the high ratio of Th17/Treg cells and their associated factors in COVID-19-dead patients compared with improved cases indicates the critical role of inflammation in the mortality of patients.
Personal Protective Equipment for Endoscopy in Low-Resource Settings During the COVID-19 Pandemic: Guidance From the World Gastroenterology Organisation

Leddin D, Armstrong D, Raja Ali RA, Barkun A, Butt AS, Chen Y, et al.

J Clin Gastroenterol, 2020 9 11;54(10):833-840.
PMID: 32909973 DOI: 10.1097/MCG.0000000000001411

Performance of endoscopic procedures is associated with a risk of infection from COVID-19. This risk can be reduced by the use of personal protective equipment (PPE). However, shortage of PPE has emerged as an important issue in managing the pandemic in both traditionally high and low-resource areas. A group of clinicians and researchers from thirteen countries representing low, middle, and high-income areas has developed recommendations for optimal utilization of PPE before, during, and after gastrointestinal endoscopy with particular reference to low-resource situations. We determined that there is limited flexibility with regard to the utilization of PPE between ideal and low-resource settings. Some compromises are possible, especially with regard to PPE use, during endoscopic procedures. We have, therefore, also stressed the need to prevent transmission of COVID-19 by measures other than PPE and to conserve PPE by reduction of patient volume, limiting procedures to urgent or emergent, and reducing the number of staff and trainees involved in procedures. This guidance aims to optimize utilization of PPE and protection of health care providers.
The influence of fasting and energy-restricted diets on leptin and adiponectin levels in humans: A systematic review and meta-analysis

Varkaneh Kord H, M Tinsley G, O Santos H, Zand H, Nazary A, Fatahi S, et al.

Clin Nutr, 2021 04;40(4):1811-1821.
PMID: 33158587 DOI: 10.1016/j.clnu.2020.10.034

BACKGROUND & AIMS: Fasting and energy-restricted diets have been evaluated in several studies as a means of improving cardiometabolic biomarkers related to body fat loss. However, further investigation is required to understand potential alterations of leptin and adiponectin concentrations. Thus, we performed a systematic review and meta-analysis to derive a more precise estimate of the influence of fasting and energy-restricted diets on leptin and adiponectin levels in humans, as well as to detect potential sources of heterogeneity in the available literature.
METHODS: A comprehensive systematic search was performed in Web of Science, PubMed/MEDLINE, Cochrane, SCOPUS and Embase from inception until June 2019. All clinical trials investigating the effects of fasting and energy-restricted diets on leptin and adiponectin in adults were included.
RESULTS: Twelve studies containing 17 arms and a total of 495 individuals (intervention = 249, control = 246) reported changes in serum leptin concentrations, and 10 studies containing 12 arms with a total of 438 individuals (intervention = 222, control = 216) reported changes in serum adiponectin concentrations. The combined effect sizes suggested a significant effect of fasting and energy-restricted diets on leptin concentrations (WMD: -3.690 ng/ml, 95% CI: -5.190, -2.190, p ≤ 0.001; I2 = 84.9%). However, no significant effect of fasting and energy-restricted diets on adiponectin concentrations was found (WMD: -159.520 ng/ml, 95% CI: -689.491, 370.451, p = 0.555; I2 = 74.2%). Stratified analyses showed that energy-restricted regimens significantly increased adiponectin (WMD: 554.129 ng/ml, 95% CI: 150.295, 957.964; I2 = 0.0%). In addition, subsequent subgroup analyses revealed that energy restriction, to ≤50% normal required daily energy intake, resulted in significantly reduced concentrations of leptin (WMD: -4.199 ng/ml, 95% CI: -7.279, -1.118; I2 = 83.9%) and significantly increased concentrations of adiponectin (WMD: 524.04 ng/ml, 95% CI: 115.618, 932.469: I2 = 0.0%).
CONCLUSION: Fasting and energy-restricted diets elicit significant reductions in serum leptin concentrations. Increases in adiponectin may also be observed when energy intake is ≤50% of normal requirements, although limited data preclude definitive conclusions on this point.
Uniting the global gastroenterology community to meet the challenge of climate change and non-recyclable waste

Leddin D, Omary MB, Veitch A, Metz G, Amrani N, Aabakken L, et al.

Gut, 2021 11;70(11):2025-2029.
PMID: 34620696 DOI: 10.1136/gutjnl-2021-325789
Uniting the Global Gastroenterology Community to Meet the Challenge of Climate Change and Non-Recyclable Waste

Leddin D, Omary MB, Veitch A, Metz G, Amrani N, Aabakken L, et al.

Gastroenterology, 2021 11;161(5):1354-1360.
PMID: 34629165 DOI: 10.1053/j.gastro.2021.08.001
Uniting the Global Gastroenterology Community to Meet the Challenge of Climate Change and Nonrecyclable Waste

Leddin D, Omary MB, Veitch A, Metz G, Amrani N, Aabakken L, et al.

J Clin Gastroenterol, 2021 10 8;55(10):823-829.
PMID: 34617932 DOI: 10.1097/MCG.0000000000001619

Climate change has been described as the greatest public health threat of the 21st century. It has significant implications for digestive health. A multinational team with representation from all continents, excluding Antarctica and covering 18 countries, has formulated a commentary which outlines both the implications for digestive health and ways in which this challenge can be faced.