Endogenous opioid peptides and prescription opioid drugs modulate pain, anxiety and stress by activating opioid receptors, currently classified into four subtypes. Here we demonstrate that ...ACKR3/CXCR7, hitherto known as an atypical scavenger receptor for chemokines, is a broad-spectrum scavenger of opioid peptides. Phylogenetically, ACKR3 is intermediate between chemokine and opioid receptors and is present in various brain regions together with classical opioid receptors. Functionally, ACKR3 is a scavenger receptor for a wide variety of opioid peptides, especially enkephalins and dynorphins, reducing their availability for the classical opioid receptors. ACKR3 is not modulated by prescription opioids, but we show that an ACKR3-selective subnanomolar competitor peptide, LIH383, can restrain ACKR3's negative regulatory function on opioid peptides in rat brain and potentiate their activity towards classical receptors, which may open alternative therapeutic avenues for opioid-related disorders. Altogether, our results reveal that ACKR3 is an atypical opioid receptor with cross-family ligand selectivity.
The Mars mission will result in an inevitable exposure to cosmic radiation that has been shown to cause cognitive impairments in rodent models, and possibly in astronauts engaged in deep space ...travel. Of particular concern is the potential for cosmic radiation exposure to compromise critical decision making during normal operations or under emergency conditions in deep space. Rodents exposed to cosmic radiation exhibit persistent hippocampal and cortical based performance decrements using six independent behavioral tasks administered between separate cohorts 12 and 24 weeks after irradiation. Radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in executive function and reduced rates of fear extinction and elevated anxiety. Irradiation caused significant reductions in dendritic complexity, spine density and altered spine morphology along medial prefrontal cortical neurons known to mediate neurotransmission interrogated by our behavioral tasks. Cosmic radiation also disrupted synaptic integrity and increased neuroinflammation that persisted more than 6 months after exposure. Behavioral deficits for individual animals correlated significantly with reduced spine density and increased synaptic puncta, providing quantitative measures of risk for developing cognitive impairment. Our data provide additional evidence that deep space travel poses a real and unique threat to the integrity of neural circuits in the brain.
Background & Aims Rifaximin is used to treat patients with functional gastrointestinal disorders, but little is known about its therapeutic mechanism. We propose that rifaximin modulates the ileal ...bacterial community, reduces subclinical inflammation of the intestinal mucosa, and improves gut barrier function to reduce visceral hypersensitivity. Methods We induced visceral hyperalgesia in rats, via chronic water avoidance or repeat restraint stressors, and investigated whether rifaximin altered the gut microbiota, prevented intestinal inflammation, and improved gut barrier function. Quantitative polymerase chain reaction (PCR) and 454 pyrosequencing were used to analyze bacterial 16S ribosomal RNA in ileal contents from the rats. Reverse transcription, immunoblot, and histologic analyses were used to evaluate levels of cytokines, the tight junction protein occludin, and mucosal inflammation, respectively. Intestinal permeability and rectal sensitivity were measured. Results Water avoidance and repeat restraint stress each led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function. Oral rifaximin altered the composition of bacterial communities in the ileum ( Lactobacillus species became the most abundant) and prevented mucosal inflammation, impairment to intestinal barrier function, and visceral hyperalgesia in response to chronic stress. Neomycin also changed the composition of the ileal bacterial community ( Proteobacteria became the most abundant species). Neomycin did not prevent intestinal inflammation or induction of visceral hyperalgesia induced by water avoidance stress. Conclusions Rifaximin alters the bacterial population in the ileum of rats, leading to a relative abundance of Lactobacillus . These changes prevent intestinal abnormalities and visceral hyperalgesia in response to chronic psychological stress.
The mesenteric venous reservoir plays a vital role in mediating blood volume and pressure changes and is richly innervated by sympathetic nerves; however, the precise nature of venous sympathetic ...regulation and its role during hypertension remains unclear. We hypothesized that sympathetic drive to mesenteric veins in spontaneously hypertensive (SH) rats is raised, increasing mean circulatory filling pressure (MCFP), and impairing mesenteric capacitance.
Arterial pressure, central venous pressure, mesenteric arterial, and venous blood flow were measured simultaneously in conscious male Wistar and SH rats. MCFP was assessed using an intraatrial balloon. Hemodynamic responses to volume changes (±20%) were measured before and after ganglionic blockade and carotid body denervation. Sympathetic venoconstrictor activity was measured in situ.
MCFP in vivo (10.8±1.6 versus 8.0±2.1 mm Hg;
=0.0005) and sympathetic venoconstrictor drive in situ (18±1 versus 10±2 µV;
<0.0001) were higher in SH rats; MCFP decreased in SH rats after hexamethonium and carotid body denervation (7.6±1.4;
<0.0001 and 8.5±1.0 mm Hg;
=0.0045). During volume changes, arterial pressure remained stable. With blood loss, net efflux of blood from the mesenteric bed was measured in both strains. However, during volume infusion, we observed net influx in Wistar (+2.3±2.6 mL/min) but efflux in SH rats (-1.0±1.0 mL/min;
=0.0032); this counterintuitive efflux was abolished by hexamethonium and carotid body denervation (+0.3±1.7 and 0.5±1.6 mL/min, respectively).
In SH rats, excessive sympathetic venoconstriction elevates MCFP and reduces capacitance, impairing volume buffering by mesenteric veins. We propose selective targeting of mesenteric veins through sympathetic drive reduction as a novel therapeutic opportunity for hypertension.
Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is ...increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule - lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule - lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function.
Polystyrene microplastics (PS-MPs) are the potential environmental pollutants that possess the ability to induce testicular damage. Astilbin (ASB) is a dihydroflavonol, abundantly reported in ...multiple plants that has various pharmacological properties. This research elucidated the mitigative potential of ASB against PS-MPs-instigated testicular toxicity. 48 adult male rats (200 ± 10 g) were distributed into 4 groups (n = 12): control, PS-MPs received (0.01 mg/kg), PS-MPs + ASB received (0.01 mg/kg + 20 mg/kg) and ASB supplemented group (20 mg/kg). After 56th day of the trial, animals were sacrificed and testes were harvested for the estimation of biochemical, hormonal, spermatogenic, steroidogenic, apoptotic and histological profiles. PS-MPs intoxication significantly (P < 0.05) lowered glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GSR) as well as catalase (CAT) activities, whereas elevated MDA as well as ROS levels. Besides, the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nuclear factor kappa-B (NF-κB) along with cyclooxygenase-2 (COX-2) activity were raised. PS-MPs treatment reduced luteinizing hormone (LH), plasma testosterone and follicle-stimulating hormone (FSH) level besides decreased epididymal sperm number, viability, motility as well as the count of HOS coil-tailed spermatozoa and increased sperm morphological irregularities. PS-MPs exposure lowered steroidogenic enzymes (17β-HSD, 3β-HSD and StAR protein along with Bcl-2 expression, besides increasing Caspase-3 and Bax expressions and histopathological alterations in testicular tissues. However, ASB treatment significantly reversed PS-MPs mediated damage. In conclusion, ASB administration is protective against PS-MPs-instigated testicular damage owing to its anti-inflammatory, anti-apoptotic, antioxidant and androgenic nature.
Display omitted
•PS-MPs exposure damaged biochemical, spermatogenic and histological profiles.•ASB increased antioxidant enzyme activities and decreased MDA and ROS levels.•ASB reversed the levels of inflammatory and apoptotic markers.•Moreover, ASB increased the expression of steroidogenic enzymes and hormone levels.•ASB also improved all the histopathological alterations in the testicular tissues.
Rat hepatocytes secrete free oligosaccharides Huang, Chengcheng; Seino, Junichi; Honda, Akinobu ...
Journal of biological chemistry/The Journal of biological chemistry,
03/2024, Letnik:
300, Številka:
3
Journal Article
Recenzirano
Odprti dostop
We recently established a method for the isolation of serum-free oligosaccharides, and characterized various features of their structures. However, the precise mechanism for how these glycans are ...formed still remains unclarified. To further investigate the mechanism responsible for these serum glycans, here, we utilized rat primary hepatocytes to examine whether they are able to secrete free glycans. Our findings indicated that a diverse array of free oligosaccharides such as sialyl/neutral free N-glycans (FNGs), as well as sialyl lactose/LacNAc-type glycans, were secreted into the culture medium by primary hepatocytes. The structural features of these free glycans in the medium were similar to those isolated from the sera of the same rat. Further evidence suggested that an oligosaccharyltransferase is involved in the release of the serum-free N-glycans. Our results indicate that the liver is indeed secreting various types of free glycans directly into the serum.
Chlorogenic acid as a constituent of coffee is consumed regularly in the human diet. Chlorogenic acid intake has been associated with decreased risk of cardiovascular disease and type 2 diabetes. We ...hypothesized that chlorogenic acid would improve cardiovascular, liver, and metabolic responses in a rat model of metabolic syndrome induced by a high-carbohydrate, high-fat diet. Male Wistar rats (8-9 weeks old, 335 ± 2 g, n = 48) were divided into 4 groups and fed with corn starch diet (16 weeks); corn starch diet with chlorogenic acid in food for the last 8 weeks; high-carbohydrate, high-fat diet (16 weeks); or high-carbohydrate, high-fat diet with chlorogenic acid (~100 mg/kg/d) in food for the last 8 weeks. In high-carbohydrate, high-fat diet–fed rats, chlorogenic acid reduced energy intake and food efficiency to reduce visceral fat, especially retroperitoneal fat, and abdominal circumference; reversed the elevated systolic blood pressure; and attenuated left ventricular diastolic stiffness with reduced collagen deposition and infiltration of inflammatory cells in the left ventricle. Chlorogenic acid decreased inflammation and fat deposition in the liver along with reduced plasma liver enzyme activities of obese rats but did not change the plasma lipid profile. Chlorogenic acid increased diversity of gut microbiota, which may improve overall metabolism in the body. Thus, chronic dietary chlorogenic acid attenuated diet-induced inflammation as well as cardiovascular, liver, and metabolic changes, suggesting that chlorogenic acid has potential for further clinical evaluation.
Intravascular red cell hemolysis impairs nitric oxide (NO)-redox homeostasis, producing endothelial dysfunction, platelet activation, and vasculopathy. Red blood cell storage under standard ...conditions results in reduced integrity of the erythrocyte membrane, with formation of exocytic microvesicles or microparticles and hemolysis, which we hypothesized could impair vascular function and contribute to the putative storage lesion of banked blood.
We now find that storage of human red blood cells under standard blood banking conditions results in the accumulation of cell-free and microparticle-encapsulated hemoglobin, which, despite 39 days of storage, remains in the reduced ferrous oxyhemoglobin redox state and stoichiometrically reacts with and scavenges the vasodilator NO. Using stopped-flow spectroscopy and laser-triggered NO release from a caged NO compound, we found that both free hemoglobin and microparticles react with NO about 1000 times faster than with intact erythrocytes. In complementary in vivo studies, we show that hemoglobin, even at concentrations below 10 μmol/L (in heme), produces potent vasoconstriction when infused into the rat circulation, whereas controlled infusions of methemoglobin and cyanomethemoglobin, which do not consume NO, have substantially reduced vasoconstrictor effects. Infusion of the plasma from stored human red blood cell units into the rat circulation produces significant vasoconstriction related to the magnitude of storage-related hemolysis.
The results of these studies suggest new mechanisms for endothelial injury and impaired vascular function associated with the most fundamental of storage lesions, hemolysis.
The spatiotemporally controlled delivery of the pro-osteogenic factor rhBMP-2 would overcome most of the severe secondary effects linked to the products delivering this protein for bone regeneration. ...With this in mind, the aim of the present work was to develop a controlled rhBMP-2 release system using collagen–hydroxyapatite (CHA) scaffolds, which had been previously optimized for bone regeneration, as delivery platforms to produce a device with enhanced capacity for bone repair. Spray-drying and emulsion techniques were used to encapsulate bioactive rhBMP-2 in alginate and PLGA microparticles, with a high encapsulation efficiency. After incorporation of these microparticles into the scaffolds, rhBMP-2 was delivered in a sustained fashion for up to 28days. When tested in vitro with osteoblasts, these eluting materials showed an enhanced pro-osteogenic effect. From these results, an optimal rhBMP-2 eluting scaffold composition was selected and implanted in critical-sized calvarial defects in a rat model, where it demonstrated an excellent healing capacity in vivo. These platforms have an immense potential in the field of tissue regeneration; by tuning the specific therapeutic molecule to the tissue of interest and by utilizing different collagen-based scaffolds, similar systems can be developed for enhancing the healing of a diverse range of tissues and organs.
Display omitted
PDF
