Neuron–astrocyte signaling network in spinal cord dorsal horn mediates painful neuropathy of type 2 diabetes

Activation of the neuronal–glial network in the spinal cord dorsal horn (SCDH) mediates various chronic painful conditions. We studied spinal neuronal–astrocyte signaling interactions involved in the maintenance of painful diabetic neuropathy (PDN) in type 2 diabetes. We used the db/db mouse, an animal model for PDN of type 2 diabetes, which develops mechanical allodynia from 6 to 12 wk of age. In this study, enhanced substance P expression was detected in the presynaptic sensory fibers innervating lamina I–III in the lumbar SCDH (LSCDH) of the db/db mouse at 10 wk of age. This phenomenon is associated with enhanced spinal ERK1/2 phosphorylation in projection sensory neurons and regional astrocyte activation. In addition, peak phosphorylation of the NR1 subunit of N ‐methyl‐ D ‐aspartate receptor (NMDAR), along with upregulation of neuronal and inducible nitric oxide synthase (nNOS and iNOS) expression were detected in diabetic mice. Expression of nNOS and iNOS was detected in both interneurons and astrocytes in lamina I–III of the LSCDH. Treatment with MK801, an NMDAR inhibitor, inhibited mechanical allodynia, ERK1/2 phosphorylation, and nNOS and iNOS upregulation in diabetic mice. MK801 also reduced astrocytosis and glial acidic fibrillary protein upregulation in db/db mice. In addition, N(G)‐nitro‐L‐arginine methyl ester (L‐NAME), a nonspecific NOS inhibitor, had similar effects on NMDAR signaling and NOS expression. These results suggest that nitric oxide from surrounding interneurons and astrocytes interacts with NMDAR‐dependent signaling in the projection neurons of the SCDH during the maintenance of PDN. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/92403/1/22349_ftp.pd

Role of 12/15-lipoxygenase in nitrosative stress and peripheral prediabetic and diabetic neuropathies

This study evaluated the role for 12/15-lipoxygenase, which converts arachidonic acid to 12(S)- and 15(S)-hydroxyeicosatetraenoic acids, in nitrosative stress in peripheral nervous system and peripheral prediabetic and diabetic neuropathies. The experiments were performed in C57Bl6/J mice made diabetic with streptozotocin or fed high-fat diet, and human Schwann cells cultured in 5.5 mM or 30 mM glucose. 12/15-lipoxygenase overexpression and activation were present in sciatic nerve and spinal cord of diabetic and high fat diet-fed mice, as well as in human Schwann cells cultured in high concentrations of D-, but not L-glucose. 12/15-lipoxygenase inhibition with cinnamyl-3,4-dihydroxy-α-cyanocinnamate (8 mgkg(-1)d(-1) s.c., for 4 weeks after 12 weeks without treatment) alleviated accumulation of nitrated proteins in sciatic nerve and spinal cord, and large and small nerve fiber dysfunction, but not intraepidermal nerve fiber loss. 12/15-lipoxygenase gene deficiency alleviated nitrosative stress and nerve conduction deficit, but not small sensory fiber neuropathy, in high-fat diet fed mice. In conclusion, 12/15-lipoxygenase is implicated in nitrosative stress and peripheral neuropathy in mouse models of Type 1 and early Type 2 diabetes. Its presence in human Schwann cells and upregulation by high glucose suggest a potential involvement in human disease

Hypoglycemic activity of Phaseolus vulgaris (L.) aqueous extract in type 1 diabetic rats

The aim of the present study was to evaluate the hypoglycemic activity of the aqueous extract from the fruit walls of Phaseolus vulgaris pods and to examine the potential mechanism underlying the improvement of the glycemic level. In the course of the study, diabetes mellitus was induced in rats with a single intraperitoneal injection of streptozotocin (45 mg·kg−1 b.w.). Diabetic and control rats were then orally administered with a single-dose or repeated-dose (28 day) of P. vulgaris extract (200 mg·kg−1). Results show that the extract was found to possess significant hypoglycemic activity, and the study of glucose utilization by isolated rat hemidiaphragm suggests that the aqueous extract may enhance the peripheral utilization of glucose. The subsequent experiments have revealed that the P. vulgaris extract could increase glucose transporter 4 (GLUT-4) content in skeletal muscle cells of control and diabetic rats. Our data also indicate that the P. vulgaris extract did not affect the content of the insulin receptor, but significantly reduced the total tyrosine kinase activity in skeletal muscle cells of both experimental groups of rats. The present results clearly indicated that P. vulgaris extract may be beneficial for reducing hyperglycemia through its potency in regulation of glucose utilization via GLUT-4, but the current mechanism remains to be unidentified

Association between gut health and gut microbiota in a polluted environment

Animals host complex bacterial communities in their gastrointestinal tracts, with which they share a mutualistic interaction. The numerous effects these interactions grant to the host include regulation of the immune system, defense against pathogen invasion, digestion of otherwise undigestible foodstuffs, and impacts on host behaviour. Exposure to stressors, such as environmental pollution, parasites, and/or predators, can alter the composition of the gut microbiome, potentially affecting host-microbiome interactions that can be manifest in the host as, for example, metabolic dysfunction or inflammation. However, whether a change in gut microbiota in wild animals associates with a change in host condition is seldom examined. Thus, we quantified whether wild bank voles inhabiting a polluted environment, areas where there are environmental radionuclides, exhibited a change in gut microbiota (using 16S amplicon sequencing) and concomitant change in host health using a combined approach of transcriptomics, histological staining analyses of colon tissue, and quantification of short-chain fatty acids in faeces and blood. Concomitant with a change in gut microbiota in animals inhabiting contaminated areas, we found evidence of poor gut health in the host, such as hypotrophy of goblet cells and likely weakened mucus layer and related changes in Clca1 and Agr2 gene expression, but no visible inflammation in colon tissue. Through this case study we show that inhabiting a polluted environment can have wide reaching effects on the gut health of affected animals, and that gut health and other host health parameters should be examined together with gut microbiota in ecotoxicological studies.ISSN:0048-9697ISSN:1879-102

The effect of C60 fullerene on the mechanokinetics of muscle gastrocnemius contraction in chronically alcoholized rats

The C60 fullerene effect (oral administration at a dose of 1 mg kg−1) on the selected biomechanical parameters of muscle gastrocnemius contraction, biochemical indicators of blood and muscle tissue as well as histological changes in rat muscle tissue after chronic alcoholization for 3, 6 and 9 months was studied in detail. Water-soluble C60 fullerenes were shown to reduce the pathological processes development in the muscle apparatus by an average of (35–40)%. In particular, they reduced the time occurrence of fatigue processes in muscle during the long-term development of alcoholic myopathy and inhibited oxidative processes in muscle, thereby preventing its degradation. These findings open up the possibility of using C60 fullerenes as potent antioxidants for the correction of the pathological conditions of the muscle system arising from alcohol intoxication

The long-term consequences of antibiotic therapy: Role of colonic short-chain fatty acids (SCFA) system and intestinal barrier integrity.

Epidemiological studies revealed that antibiotics exposure increases a risk of inflammatory bowel diseases (IBD) development. It remained largely unknown how antibiotic-induced dysbiosis confers the risk for enhanced inflammatory response. The aim of the present study was to test the hypothesis that SCFAs, their receptors and transporters mediate the antibiotic long-term effects on the functional state of colonic mucosa and susceptibility to the experimental colitis. Male Wistar rats were treated daily for 14 days with antibiotic ceftriaxone (300 mg/kg, i.m.) or vehicle; euthanized by CO2 inhalation followed by cervical dislocation in 1, 14 or 56 days after antibiotic withdrawal. We found increased cecum weight and sustained changes in microbiota composition after ceftriaxone treatment with increased number of conditionally pathogenic enterobacteria, E. coli, Clostridium, Staphylococcus spp. and hemolytic bacteria even at 56 days after antibiotic withdrawal. The concentration of SCFAs was decreased after ceftriaxone withdrawal. We found decreased immunoreactivity of the FFA2, FFA3 receptors, SMCT1 and increased MCT1 & MCT4 transporters of SCFAs in colon mucosa. These changes evoked a significant shift in colonic mucosal homeostasis: the disturbance of oxidant-antioxidant balance; activation of redox-sensitive transcription factor HIF1α and ERK1/2 MAP kinase; increased colonic epithelial permeability and bacterial translocation to blood; morphological remodeling of the colonic tissue. Ceftriaxone pretreatment significantly reinforced inflammation during experimental colitis 56 days after ceftriaxone withdrawal, which was confirmed by increased histopathology of colitis, Goblet cell dysfunction, colonic dilatation and wall thickening, and increased serum levels of inflammatory cytokines (TNF-α and IL-10). Since the recognition of the importance of microbiota metabolic activity rather than their composition in the development of inflammatory disorders, e.g. IBD, the present study is the first report on the role of the SCFA system in the long lasting side effects of antibiotic treatment and its implication in IBD development