PMID: 

Environ Toxicol Pharmacol. 2019 Jul 31 ;72:103238. Epub 2019 Jul 31. PMID: 31394428

Abstract Title: 

A comparative study of the role of crocin and sitagliptin in attenuation of STZ-induced diabetes mellitus and the associated inflammatory and apoptotic changes in pancreaticβ-islets.

Abstract: 

Type 1 diabetes mellitus (T1DM) describes a complex group of metabolic disorders associated with elevated blood glucose levels and increased risks of complications development. Exploring new drug therapies would reduce the increased diabetes-associated morbidity and mortality and will reduce the excessive health care costs. Crocin is the major active ingredient of saffron. In the current study, DM was induced by single intraperitoneal injection of streptozocin (50 mg/kg).DM progression was associated with a significant increase in blood glucose level with reduced insulin and increased glucagon secretion. Pancreatic malondialdehyde (MDA) content significantly escalated, while superoxide dismutase (SOD) activity, reduced glutathione (GSH) concentration, catalase activity, thioredoxin level and serum total antioxidant capacity significantly declined. This was associated with a significant increase in pancreatic caspase-3 contents and pancreatic infiltration with inflammatory cells in β-islets. Both sitagliptin and crocin significantly reduced blood glucose levels, enhanced pancreatic insulin expression and secretion and suppressed glucagon secretion with enhancement of anti-oxidant defenses and reduction of oxidative burden, with evident anti-inflammatory impacts. Interestingly, the effect of crocin on DM indices, inflammatory and apoptotic changes was comparable to that of sitagliptin; the standard oral hypoglycemic agent. Nevertheless, crocin had a superior effect compared to sitagliptin on blood sugar level, β-islets diameter and insulin immune-reactivity. In conclusion, crocin reduced blood glucose level mainly via reduction of oxidative burden, modulation of apoptotic pathway and attenuation of pancreatic inflammation.

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PMID: 

Diabetologia. 2019 06 ;62(6):1024-1035. Epub 2019 Mar 23. PMID: 30904939

Abstract Title: 

Metformin-induced changes of the gut microbiota in healthy young men: results of a non-blinded, one-armed intervention study.

Abstract: 

AIMS/HYPOTHESIS: Individuals with type 2 diabetes have an altered bacterial composition of their gut microbiota compared with non-diabetic individuals. However, these alterations may be confounded by medication, notably the blood-glucose-lowering biguanide, metformin. We undertook a clinical trial in healthy and previously drug-free men with the primary aim of investigating metformin-induced compositional changes in the non-diabetic state. A secondary aim was to examine whether the pre-treatment gut microbiota was related to gastrointestinal adverse effects during metformin treatment.METHODS: Twenty-seven healthy young Danish men were included in an 18-week one-armed crossover trial consisting of a pre-intervention period, an intervention period and a post-intervention period, each period lasting 6 weeks. Inclusion criteria were men of age 18-35 years, BMI between 18.5 kg/mand 27.5 kg/m, HbA 

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PMID: 

Pain. 2019 Jul 2. Epub 2019 Jul 2. PMID: 31219947

Abstract Title: 

Altered microbiome composition in individuals with fibromyalgia.

Abstract: 

Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue, and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole-genome sequencing. When comparing FM patients with unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate-metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine-learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (receiver operating characteristic area under the curve 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in nonvisceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.

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PMID: 

J Virol. 2019 Jul 3. Epub 2019 Jul 3. PMID: 31270225

Abstract Title: 

Antiretroviral therapy administration in healthy rhesus macaques is associated with transient shifts in intestinal bacterial diversity and modest immunological perturbations.

Abstract: 

Gastrointestinal immune system competency is dependent upon interactions with commensal microbiota, which can be influenced by wide-ranging pharmacologic interventions. In SIV-infected Asian macaque models of HIV infection, we previously noted that initiation of antiretroviral therapy (ART) is associated with a specific imbalance (dysbiosis) of the composition of the intestinal bacteriome. To determine if ART itself might contribute to dysbiosis or immune dysfunction, we treated healthy rhesus macaques with protease-, integrase- or reverse transcriptase inhibitors for 1-2 or 5-6 weeks and evaluated intestinal immune function and the composition of the fecal bacterial microbiome. We observed that individual antiretrovirals (ARVs) modestly altered intestinal T-cell pro-inflammatory responses without disturbing total or activated T-cell frequencies. Moreover, we observed transient disruptions in bacterial diversity coupled with perturbations in the relative frequencies of bacterial communities. Shifts in specific bacterial frequencies were not persistent post-treatment, however, with individual taxa showing only isolated associations with T-cell pro-inflammatory responses. Our findings suggest that intestinal bacterial instability and modest immunological alterations can result from ART itself. These data could lead to therapeutic interventions which stabilize the microbiome in individuals prescribed ART.Dysbiosis of the fecal microbiome is a common feature observed in ARV-treated people living with HIV. The degree to which HIV infection itself causes this dysbiosis remains unclear. Here we demonstrate that medications used to treat HIV infection can influence the composition of the GI tract immune responses and its microbiome in the non-human primate SIV model.

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PMID: 

EBioMedicine. 2019 Aug ;46:499-511. Epub 2019 Jul 18. PMID: 31327695

Abstract Title: 

Gut microbiome and serum metabolome analyses identify molecular biomarkers and altered glutamate metabolism in fibromyalgia.

Abstract: 

BACKGROUND: Fibromyalgia is a complex, relatively unknown disease characterised by chronic, widespread musculoskeletal pain. The gut-brain axis connects the gut microbiome with the brain through the enteric nervous system (ENS); its disruption has been associated with psychiatric and gastrointestinal disorders. To gain an insight into the pathogenesis of fibromyalgia and identify diagnostic biomarkers, we combined different omics techniques to analyse microbiome and serum composition.METHODS: We collected faeces and blood samples to study the microbiome, the serum metabolome and circulating cytokines and miRNAs from a cohort of 105 fibromyalgia patients and 54 age- and environment-matched healthy individuals. We sequenced the V3 and V4 regions of the 16S rDNA gene from faeces samples. UPLC-MS metabolomics and custom multiplex cytokine and miRNA analysis (FirePlex™ technology) were used to examine sera samples. Finally, we combined the different data types to search for potential biomarkers.RESULTS: We found that the diversity of bacteria is reduced in fibromyalgia patients. The abundance of the Bifidobacterium and Eubacterium genera (bacteria participating in the metabolism of neurotransmitters in the host) in these patients was significantly reduced. The serum metabolome analysis revealed altered levels of glutamate and serine, suggesting changes in neurotransmitter metabolism. The combined serum metabolomics and gut microbiome datasets showed a certain degree of correlation, reflecting the effect of the microbiome on metabolic activity. We also examined the microbiome and serum metabolites, cytokines and miRNAs as potential sources of molecular biomarkers of fibromyalgia.CONCLUSIONS: Our results show that the microbiome analysis provides more significant biomarkers than the other techniques employed in the work. Gut microbiome analysis combined with serum metabolomics can shed new light onto the pathogenesis of fibromyalgia. We provide a list of bacteria whose abundance changes in this disease and propose several molecules as potential biomarkers that can be used to evaluate the current diagnostic criteria.

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PMID: 

Front Psychiatry. 2019 ;10:473. Epub 2019 Jul 17. PMID: 31404299

Abstract Title: 

Association Between Gut Microbiota and Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

Abstract: 

Autism spectrum disorder (ASD) is characterized by stereotyped behavior and deficits in communication and social interactions. Gastrointestinal (GI) dysfunction is an ASD-associated comorbidity, implying a potential role of the gut microbiota in ASD GI pathophysiology. Several recent studies found that autistic individuals harbor an altered bacterial gut microbiota. In some cases, remodeling the gut microbiota by antibiotic administration and microbiota transfer therapy reportedly alleviated the symptoms of ASD. However, there is little consensus on specific bacterial species that are similarly altered across individual studies. The aim of this study is to summarize previously published data and analyze the alteration of the relative abundance of bacterial genera in the gut microbiota in controls and individuals with ASD using meta-analysis. We analyzed nine studies, including 254 patients with ASD, and found that children with ASD had lower percentages of,,, andand a higher percentage ofin the total detected microflora compared to controls. In contrast, children with ASD had lower abundance of,,, andand higher abundance of. This meta-analysis suggests an association between ASD and alteration of microbiota composition and warrants additional prospective cohort studies to evaluate the association of bacterial changes with ASD symptoms, which would provide further evidence for the precise microbiological treatment of ASD.

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PMID: 

Neurobiol Dis. 2019 Aug 21:104576. Epub 2019 Aug 21. PMID: 31445165

Abstract Title: 

Emerging roles for the intestinal microbiome in epilepsy.

Abstract: 

The gut microbiome is emerging as a key regulator of brain function and behavior and is associated with symptoms of several neurological disorders. There is emerging evidence that alterations in the gut microbiota are seen in epilepsy and in response to seizure interventions. In this review, we highlight recent studies reporting that individuals with refractory epilepsy exhibit altered composition of the gut microbiota. We further discuss antibiotic treatment and infection as microbiome-related factors that influence seizure susceptibility in humans and animal models. In addition, we evaluate how the microbiome may mediate effects of the ketogenic diet, probiotic treatment, and anti-epileptic drugs on reducing both seizure frequency and severity. Finally, we assess the open questions in interrogating roles for the microbiome in epilepsy and address the prospect that continued research may uncover fundamental insights for understanding risk factors for epilepsy, as well as novel approaches for treating refractory epilepsy.

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PMID: 

Exp Ther Med. 2019 Sep ;18(3):2262-2270. Epub 2019 Jul 23. PMID: 31452713

Abstract Title: 

Supplementation of triple viable probiotics combined with dietary intervention is associated with gut microbial improvement in humans on a high-fat diet.

Abstract: 

Numerous animal studies have demonstrated that oral probiotics may have a beneficial role in preventing obesity, inflammatory bowel disease and even colorectal cancer, which are all associated with a high-fat diet (HFD). However, the underlying beneficial effects of combined probiotic and dietary intervention on the gut microbiota of 'non-patient' individuals previously on an HFD have yet to be fully elucidated. In the present study, fecal samples were obtained from 36 volunteers on a high-fat diet and after dietary intervention for 4 months, and 16S rDNA sequencing was applied to identify how probiotics and dietary intervention had altered the composition of the microbiota. The results demonstrated that probiotics treatment and dietary intervention in combination raised the diversity of lumen microbes compared with their individual applications. A markedly separated distribution (β-diversity) was observed, confirming the difference in gut microbiota composition among the treatment groups. Bacterial taxonomic analysis demonstrated that the relative abundance of 30 species was altered among the groups following dietary intervention and/or probiotic supplementation. The majority of the species that exhibited a population increase belonged to two butyrate-producing families,and, whereas the species with reduced populations mainly belonged to thefamily. Collectively, these results suggest that combined probiotic and dietary intervention is able to improve the gut microbiota composition of human subjects on an HFD.

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PMID: 

An Acad Bras Cienc. 2019 May 23 ;91(2):e20181235. Epub 2019 May 23. PMID: 31141017

Abstract Title: 

Assessment of Anti-inflammatory and Antioxidant Properties of Safranal on CCI4-Induced Oxidative Stress and Inflammation in Rats.

Abstract: 

The present study aimed to determine the antioxidative and anti-inflammatory effects of safranal on damage induced by CCl4. Experimental animals were divided into five groups. The first group was determined as the control group and no treatment was conducted. Second group rats were administered 1 mL/kg-day CCI4 during the experiment. Rats in Groups 3, 4 and 5 were administered 1 mL/kg-day CCI4 and 25 mg/kg, 50 mg/kg; 100 mg/kg safranal, respectively via gavage. Oxidative-antioxidant parameters, liver function enzymes and inflammatory cytokine levels were determined in liver samples obtained from the rats. Data analysis demonstrated that oxidative stress and inflammation markers were significantly higher in CCI4 administered groups (p

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PMID: 

Metab Brain Dis. 2019 Aug 17. Epub 2019 Aug 17. PMID: 31422512

Abstract Title: 

Safranal, an active ingredient of saffron, attenuates cognitive deficits in amyloidβ-induced rat model of Alzheimer's disease: underlying mechanisms.

Abstract: 

Alzheimer's disease (AD) is the most prevalent neurodegenerative amyloid disorder with progressive deterioration of cognitive and memory skills. Despite many efforts, no decisive therapy yet exists for AD. Safranal is the active constituent of saffron essential oil with antioxidant, anti-inflammatory, and anti-apoptotic properties. In this study, the possible beneficial effect of safranal on cognitive deficits was evaluated in a rat model of AD induced by intrahippocampal amyloid beta (Aβ). Safranal was daily given p.o. (0.025, 0.1, and 0.2 ml/kg) post-surgery for 1 week and finally learning and memory were evaluated in addition to assessment of the involvement of oxidative stress, inflammation, and apoptosis. Findings showed that safranal treatment of amyloid β-microinjected rats dose-dependently improved cognition in Y-maze, novel-object discrimination, passive avoidance, and 8-arm radial arm maze tasks. Besides, safranal attenuated hippocampal level of malondialdehyde (MDA), reactive oxygen species (ROS), protein carbonyl, interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor α (TNFα), nuclear factor-kappa B (NF-kB), apoptotic biomarkers including caspase 3 and DNA fragmentation, glial fibrillary acidic protein (GFAP), myeloperoxidase (MPO), and acetylcholinesterase (AChE) activity and improved superoxide dismutase (SOD) activity and mitochondrial membrane potential (MMP) with no significant effecton nitrite, catalase activity, and glutathione (GSH). Furthermore, safranal prevented CA1 neuronal loss due to amyloid β. In summary, safranal treatment of intrahippocampal amyloid beta-microinjected rats could prevent learning and memory decline via neuronal protection and at a molecular level through amelioration of apoptosis, oxidative stress, inflammation, cholinesterase activity, neutrophil infiltration, and also by preservation of mitochondrial integrity.

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