Background Ventral tegmental area (VTA) brain-derived neurotrophic factor (BDNF) contributes to time-dependent increases in cue-induced cocaine seeking after withdrawal (incubation of cocaine craving). Here, we studied the role of glial cell line– derived neurotrophic factor (GDNF) in incubation of cocaine craving because, like BDNF, GDNF provides trophic support to midbrain dopamine neurons. Methods We first trained rats to self-administer intravenous cocaine for 10 days (6 hours/d, cocaine injections were paired with a tone-light cue). We then manipulated VTA GDNF function and assessed cue-induced cocaine seeking in extinction tests after withdrawal from cocaine. Results VTA injections of an adeno-associated virus (AAV) vector containing rat GDNF cDNA (5 ×108 viral genomes) on withdrawal Day 1 increased cue-induced cocaine seeking on withdrawal days 11 and 31; this effect was not observed after VTA injections of an AAV viral vector containing red fluorescent protein (RFP). Additionally, VTA, but not substantial nigra (SN), GDNF injections (1.25 μg or 12.5 μg/side) immediately after the last cocaine self-administration session increased cue-induced drug seeking on withdrawal days 3 and 10; this effect was reversed by VTA injections of U0126, which inhibits the activity of extracellular signal-regulated kinases (ERK). Finally, interfering with VTA GDNF function by chronic delivery of anti-GDNF monoclonal neutralizing antibodies via minipumps (600 ng/side/d) during withdrawal Days 1–14 prevented the time-dependent increases in cue-induced cocaine seeking on withdrawal days 11 and 31. Conclusions Our results indicate that during the first weeks of withdrawal from cocaine self-administration, GDNF-dependent neuroad-aptations in midbrain VTA neurons play an important role in the development of incubation of cocaine craving.
Decline in successful conception decreases more rapidly after 38 years of age owing to follicular depletion and decreased oocyte quality. However, limited information is available regarding the underlying mechanism and the useful treatment. This study aimed to evaluate the effects of growth hormone supplementation on oocyte maturation in vivo in aged and young mice and to determine its effect on mitochondrial function. The influence of three different doses of recombinant human growth hormone (rhGH) (0.4, 0.8 and 1.6 mg/kg/day) for 8 weeks before ovarian stimulation was analyzed. Superovulated oocytes were released from the oviduct of 12-week-old and 40-week-old female C57BL/6J mice 14–16 h after administration of human chorionic gonadotropin. Ovarian follicle and morphological analysis and oocyte maturation parameters were then evaluated. This study is the first, to our knowledge, to report that medium- and high-dose rhGH significantly increases antral follicles in aged mice but anti-Müllerian hormone (AMH) levels. Furthermore, derived oocytes, MII-stage oocyte rate, ATP levels, mitochondrial membrane potential and frequencies of homogeneous mitochondrial distribution increased. In contrast, in both aged and young mice, the mtDNA copy numbers per oocyte were similar before rhGH administration, and upon saline administration, they did not differ significantly. We conclude that medium-dose rhGH supplementation before standard ovarian stimulation regimens improves oocyte quality in aged mice, probably by enhancing mitochondrial functionality.
Visceral hypersensitivity induced by stress is quite common in irritable bowel syndrome (IBS) patients. Probiotics play an important role in reducing visceral hypersensitivity in IBS patients. However, the mechanism has not been clearly elucidated. In this study, we investigated the role of nod-like receptor pyrin domain-containing protein 6 (NLRP6) in Clostridium butyricum-regulated IBS induced by stress. Our results showed that NLRP6 was down-regulated in IBS group colon tissues. In addition, IL-18, IL-1β, myeloperoxidase (MPO), d-lactic acid (D-LA), and CD172a were up-regulated in the IBS group of colonic mucous. IL-18 and IL-1β were also increased after the NLRP6 gene was silenced. Pathological score suggested low inflammation of colonic mucous rather than terminal ileum. Water-avoidance stress (WAS) showed visceral hypersensitivity to colonic distension. However, treatment with Clostridium butyricum reversed these results, exerting a beneficial effect. In conclusion, Clostridium butyricum may exert a beneficial action on visceral hypersensitivity of IBS by inhibiting low grade inflammation of colonic mucous through its action on NLRP6.
Preeclampsia, new onset hypertension in pregnancy, affects ~ 5 -10% of the world’s population. Preeclampsia is the leading cause of morbidity and mortality for both the mother and fetus. As of today, there is no cure for this disease except for delivery of the fetal-placental unit. The exact causation and onset of the disease is unknown. However, recent studies have shown a strong correlation between mitochondrial dysfunction and preeclampsia. Circulating mitochondrial DNA, elevated reactive oxygen species, angiotensin II type-1 receptor agonistic autoantibodies (AT1-AA), activated natural killer cells, and upregulated inflammatory responses all contribute to mitochondrial dysfunction and the pathophysiology of preeclampsia. This review summarizes the current literature of both experimental and clinical observations that support the hypothesis that mitochondrial dysfunction contributes to the pathophysiology of preeclampsia and may be a precursor to the disease onset. This review will also address the use of therapies to improve mitochondrial dysfunction in preeclampsia.
In the liver, glucokinase (GCK) facilitates hepatic glucose uptake during hyperglycemia and is essential for the regulation of a network of glucose-responsive genes involved in glycolysis, glycogen synthesis, and lipogenesis. To better understand the consequences of changes in response to a liver-specific deficiency of GCK function, we examined the expression profiles of genes involved in glucose metabolism in the liver, pancreas, muscle and adipose tissue in heterozygous liver-specific Gck knockout (Gck(w/-)) mice. Our results showed that with the development of a liver GCK deficiency, significant decreases in the mRNA levels for insulin receptor and Glut2 were observed in the liver, and HkII in muscle, while glucagon mRNA increased markedly in the pancreas. The levels of circulating glucagon hormone levels increased with increased mRNA levels. Depite a decrease in muscle HkII levels, the hexokinase activity level did not change. Our findings suggest that in liver-specific Gck(w/-) mice, peripheral tissues use different strategies to tackle with hyperglycemia even at a young age. By identifying the specific changes that occur in different tissues at an early stage of glucokinase deficiency, potentially we can develop interventions to prevent further progression to diabetes.
Abstract. Sepsis is characterized by a severe inflammatory response to infection. With the spread of sepsis, various tissues, including the lungs, liver and kidney, may be damaged. This may finally develop into multiple organ dysfunction syndrome. Sphingomyelin and cholesterol are two main lipids involved in sepsis. The metabolism of sphingomyelin and cholesterol in the livers of mice with sepsis needs to be clarified. To achieve this, the present study intraperitoneally injected mice with PBS, lipopolysaccharide (LPS; 10 mg/kg) and LPS + pyrrolidine dithiocarbamate (PDTC; 30 mg/kg). Subsequently, sphingomyelin and cholesterol content were measured using kits, the sphingomyelin synthase (SMS) activity was measured using thin layer chromatography, and the expression levels of SMS1 and 2, hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), ATP binding cassette subfamily A member 1 (ABCA1), scavenger receptor class B member 1 (SR-B1) and apolipoprotein A1 (Apo A1) were determined by western blotting in the livers of mice. Results demonstrated that, in the LPS group, sphingomyelin and cholesterol content was significantly increased (P<0.001; n= 6), the SMS activity significantly enhanced (P<0.001; n=6), the expression levels of SMS2, HMGCR, ABCA1 and SR-B1 were augmented (P<0.05; n=6), and the expression of Apo A1 was decreased (P<0.05; n=6), whereas SMS1 level only slightly increased with no statistical significance (P>0.05; n=6), compared to the levels in the control group. However, PDTC was able to attenuate these alterations. These results indicated that sphingomyelin and cholesterol content may increase in the liver dysfunction of sepsis by increasing the expression of SMS2, HMGCR, SR-B1 and ABCA1, and downregulating Apo A1.
The parathyroid hormone receptor 2 (PTH2R) is a class B1 G protein–coupled receptor (GPCR) involved in the regulation of calcium transport, nociception mediation, and wound healing. Naturally occurring mutations in PTH2R were reported to cause hereditary diseases, including syndromic short stature. Here, we report the cryogenic electron microscopy structure of PTH2R bound to its endogenous ligand, tuberoinfundibular peptide (TIP39), and a heterotrimeric Gs protein at a global resolution of 2.8 Å. The structure reveals that TIP39 adopts a unique loop conformation at the N terminus and deeply inserts into the orthosteric ligand-binding pocket in the transmembrane domain. Molecular dynamics simulation and site-directed mutagenesis studies uncover the basis of ligand specificity relative to three PTH2R agonists, TIP39, PTH, and PTH-related peptide. We also compare the action of TIP39 with an antagonist lacking six residues from the peptide N terminus, TIP(7-39), which underscores the indispensable role of the N terminus of TIP39 in PTH2R activation. Additionally, we unveil that a disease-associated mutation G258D significantly diminished cAMP accumulation induced by TIP39. Together, these results not only provide structural insights into ligand specificity and receptor activation of class B1 GPCRs but also offer a foundation to systematically rationalize the available pharmacological data to develop therapies for various disorders associated with PTH2R.
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