A Role for Galanin-Like Peptide in the Integration of Feeding, Body Weight Regulation, and Reproduction in the Mouse

Galanin-like peptide (GALP) shares sequence homology with galanin and binds to galanin receptors in vitro. GALP neurons in the arcuate nucleus coexpress leptin receptors, and GALP mRNA expression is up-regulated by leptin. Based on these observations, we postulated that GALP plays a role in mediating leptin’s inhibitory effects on food intake (FI) and body weight (BW), as well as its stimulatory effect on the reproductive axis. To test these hypotheses, we performed several studies in which mice received intracerebroventricular injections of either GALP or vehicle. Acute GALP treatment elicited a dose-dependent suppression of FI and BW. Long-term treatment with GALP caused only transient reductions in FI and BW, demonstrating that the mice became refractory to continued exposure to GALP. GALP inhibited FI as early as 1 h post injection. Central injection of GALP suppressed locomotor activity and elicited the formation of a conditioned taste aversion. In male mice, serum levels of LH and testosterone were increased by GALP administration. Although we cannot rule out possible nonspecific effects of GALP on FI, the present observations are consistent with the argument that GALP is a downstream effector of leptin’s actions within the central nervous system.

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Metformin extends the lifespan of iMSUD mice by rescuing physiologic dysfunction and modulating mechanisms of mTORC1 activation

10.21203/rs.3.rs-39327/v1 ◽

2020 ◽

Author(s):

Yuehmei Hsu ◽

Sonnet Davis ◽

Chen-Yu Liao ◽

Samuel Larson ◽

Vanessa Nava ◽

...

Keyword(s):

Tca Cycle ◽

Serum Levels ◽

Term Treatment ◽

Type I ◽

Keto Acid ◽

Maple Syrup ◽

Ampk Signaling ◽

Long Term Treatment ◽

Branched Chain

Abstract Background- Dysregulation of branched chain amino acid (BCAA) catabolism caused by mutations in the metabolizing enzyme-branched chain alpha-keto acid dehydrogenase (BCKDH) leads to the fatal newborn disorder Maple Syrup Urine Disease (MSUD) and is linked to chronic diseases such as type 2 diabetes. Results- Here we show that a MSUD mouse model with severely reduced BCKDH activity exhibits glucose intolerance, altered mTOR signaling, decreased levels of TCA cycle intermediates, reduced distribution of Type I skeletal muscle fibers and activated AMP-activated protein kinase (AMPK) signaling, all of which can be ameliorated by long term treatment with metformin, which enhances the survival of these mice. Treatment with metformin was correlated with increased serum-levels of growth/differentiation factor GDF15 (GFD15) and adiponectin. We also found that branched chain keto acid regulates leucine-mediated activation of mTORC1 by preventing the dissociation of sestrin2-gator complex in vitro. Conclusions- In summary, our study suggests metformin could be an effective therapeutic candidate for MSUD patients and maps the crosstalk between key pathways that maintain metabolic homeostasis in MSUD.

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Erythropoietin affects GABAergic transmission in hippocampal neurons in vitro

Cellular & Molecular Biology Letters ◽

10.2478/s11658-008-0029-2 ◽

2008 ◽

Vol 13 (4) ◽

Cited By ~ 4

Author(s):

Tomasz Wójtowicz ◽

Jerzy Mozrzymas

Keyword(s):

Hippocampal Neurons ◽

Term Treatment ◽

Current Frequency ◽

Gabaergic Transmission ◽

Endogenous Factors ◽

Long Term Treatment ◽

The Central Nervous System ◽

Neuronal Functions ◽

The Impact

AbstractErythropoietin is a potent regulator of erythropoiesis. It acts via the specific membrane receptor (EpoR). Erythropoietin is also known to be present in the central nervous system, and its concentration and the expression of EpoR change during development, which raises the possibility that this modulator might be involved in the regulation of neuronal functions in the developing brain. The GABAergic system undergoes profound changes during development and is particularly susceptible to modulation by endogenous factors. Therefore, we decided to investigate the impact of Epo on GABAergic transmission in hippocampal neurons developing in vitro. An analysis of miniature IPSCs (mIPSCs) revealed that a long-term treatment with Epo (48 or 72 h) resulted in a major acceleration of the decaying phase of these currents while the amplitude and current frequency remained unchanged. Interestingly, this effect was restricted to the youngest considered age group (6-8 DIV), indicating that Epomediated modulation of mIPSCs depends on the developmental stage of the neurons. We conclude that Epo may exert a modulatory action on GABAergic transmission in developing neural networks.

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Effect of [Asu,]eel calcitonin on prolactin release in normal subjects and patients with prolactinoma

Acta Endocrinologica ◽

10.1530/acta.0.1080297 ◽

1985 ◽

Vol 108 (3) ◽

pp. 297-304 ◽

Cited By ~ 6

Author(s):

Hidesuke Kaji ◽

Kazuo Chihara ◽

Naoto Minamitani ◽

Hitoshi Kodama ◽

Tetsuya Kita ◽

...

Keyword(s):

Body Weight ◽

Bolus Injection ◽

Normal Subjects ◽

Regular Insulin ◽

Prolactin Release ◽

Saline Administration ◽

The Central Nervous System ◽

Plasma Prl ◽

Male Subjects

Abstract. The effect of [Asu]eel calcitonin (ECT), an equipotent analogue of eel CT, on prolactin (Prl) secretion was examined in 12 healthy male subjects and in 6 patients with prolactinoma. In healthy subjects, ECT (0.5 μg/kg body weight · h) or saline was infused for 2 h and TRH was injected iv as a bolus of 500 μg at 1 h of ECT or saline administration. ECT did not affect basal Prl levels during 1 h of infusion. TRH caused a significant increase of plasma Prl with peak values of 75.2 ± 11.6 ng/ml in ECT-infused subjects, which did not differ from those infused with saline (68.5 ± 8.3 ng/ml). Next, an iv bolus injection of regular insulin (0.1 U/kg body weight) was followed by an infusion of ECT or saline alone. Plasma Prl peaks after hypoglycaemic stress were significantly lower in ECT-infused subjects than those in saline-injected controls (ECT, 16.5 ± 3.1 vs 33.5 ± 9.6 ng/ml, P < 0.05). In patients with prolactinoma, basal levels of plasma Prl ranging from 42.0–4130 ng/ml failed to change during iv infusion of ECT. Moreover, ECT (10−9–10−6m) did not affect Prl release from prolactinoma tissues perifused in vitro. These findings suggest that ECT may not act directly on the pituitary to modify Prl release. Rather, peripherally administered ECT appears to suppress Prl release via the central nervous system.

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Single-Oocyte Gene Expression Suggests That Curcumin Can Protect the Ovarian Reserve by Regulating the PTEN-AKT-FOXO3a Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms22126570 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6570

Author(s):

Yue Lv ◽

Rui-Can Cao ◽

Hong-Bin Liu ◽

Xian-Wei Su ◽

Gang Lu ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Reserve ◽

Primordial Follicle ◽

Term Treatment ◽

New Drugs ◽

Gene Profiling ◽

Primordial Follicles ◽

Long Term Treatment ◽

Follicle Activation

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

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Evaluation of Small Molecule Combinations against Respiratory Syncytial Virus In Vitro

Molecules ◽

10.3390/molecules26092607 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2607

Author(s):

Yuzhen Gao ◽

Jingjing Cao ◽

Pan Xing ◽

Ralf Altmeyer ◽

Youming Zhang

Keyword(s):

Respiratory Syncytial Virus ◽

Confidence Interval ◽

The Elderly ◽

Term Treatment ◽

Fusion Inhibitors ◽

Long Term Treatment ◽

Statistical Program ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is a major pathogen that causes severe lower respiratory tract infection in infants, the elderly and the immunocompromised worldwide. At present no approved specific drugs or vaccines are available to treat this pathogen. Recently, several promising candidates targeting RSV entry and multiplication steps are under investigation. However, it is possible to lead to drug resistance under the long-term treatment. Therapeutic combinations constitute an alternative to prevent resistance and reduce antiviral doses. Therefore, we tested in vitro two-drug combinations of fusion inhibitors (GS5806, Ziresovir and BMS433771) and RNA-dependent RNA polymerase complex (RdRp) inhibitors (ALS8176, RSV604, and Cyclopamine). The statistical program MacSynergy II was employed to determine synergism, additivity or antagonism between drugs. From the result, we found that combinations of ALS8176 and Ziresovir or GS5806 exhibit additive effects against RSV in vitro, with interaction volume of 50 µM2% and 31 µM2% at 95% confidence interval, respectively. On the other hand, all combinations between fusion inhibitors showed antagonistic effects against RSV in vitro, with volume of antagonism ranging from −50 µM2 % to −176 µM2 % at 95% confidence interval. Over all, our results suggest the potentially therapeutic combinations in combating RSV in vitro could be considered for further animal and clinical evaluations.

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Development of a Bioartificial Vascular Pancreas

Journal of Tissue Engineering ◽

10.1177/20417314211027714 ◽

2021 ◽

Vol 12 ◽

pp. 204173142110277

Author(s):

Edward X Han ◽

Juan Wang ◽

Mehmet Kural ◽

Bo Jiang ◽

Katherine L Leiby ◽

...

Keyword(s):

Type 1 Diabetes ◽

Pancreatic Islets ◽

Vascular Graft ◽

Term Treatment ◽

Diffusion Limitations ◽

Human Scale ◽

Arterial Blood ◽

Long Term Treatment

Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.

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Long-term treatment of acromegaly with the slow-release somatostatin analogue lanreotide

Acta Endocrinologica ◽

10.1530/eje.0.1310020 ◽

1994 ◽

Vol 131 (1) ◽

pp. 20-26 ◽

Cited By ~ 42

Author(s):

Josef Marek ◽

Václav Hána ◽

Michal Kršek ◽

Vlasta Justová ◽

France Catus ◽

...

Keyword(s):

Blood Glucose ◽

Slow Release ◽

Serum Levels ◽

Term Treatment ◽

Somatostatin Analogue ◽

Tumour Mass ◽

Long Term Treatment ◽

Active Acromegaly ◽

One Year

Marek J, Hána V. Kršek M. Justová V, Catus F, Thomas F. Long-term treatment of acromegaly with the slow-release somatostatin analogue lanreotide. Eur J Endocrinol 1994;131:20–6. ISSN 0804–4643 Thirteen patients with active acromegaly despite previous surgery were treated with 30 mg lanreotide im twice a month for 9 months. In 10 subjects the treatment continued to 19 months. GH serum levels of all patients decreased significantly from an initial value of 32.0 (29.4) μg/l [median (standard error of median)] to 10.0 (3.6) and 19.1 (5.7) after 3 and 9 months of treatment, respectively. In the 10 patients with the treatment longer than one year the decrease in GH was from 46.8 (29.4) μg/l to 12.5 (5.0) and 16.1 (5.3) after 13 and 19 months, respectively. IGF-I serum levels decreased significantly from 1193 (73)μg/l to 782 (99) and 621 (103) after 3 and 9 months, respectively, and were normalized in 3 patients. In the 10 patients treated for longer than one year, levels decreased significantly from 1318 (74)μg/l to 653 (170) and 742 (180) after 13 and 19 months, respectively. IGF BP-3 levels were reduced to the normal range in 6 patients and decreased from 8.7 (1.5)mg/l to 6.4 (0.8) and to 5.4 (1.0) after 3 and 9 months, respectively. In the patients with the 19 months treatment the decrease was from 9.3 (1.6) mg/l to 3.9 (0.9) and 4.8 (0.9) after 13 and 19 months, respectively. The IGF BP-3 to IFG I ratio increased in 7 patients. This elevation significantly correlated with the decrease in bioassayable somatomedin. Prolactin serum levels fell in all patients with increased prolactin secretion. Testosterone plasma levels increased in 4 out of 5 men without replacement therapy. Clinical improvement was observed in all patients. A reduction of tumour mass was observed in five patients and complete disappearance of the tumour in one subject. All patients complained of mild abdominal pain and softened stools for several days following the injections. However, these side effects never required interruption of treatment. Asymptomatic microlithiasis was seen in only one patient after 13 months, which led to treatment being suspended for a period of 3 months after which it was resumed. Fasting serum insulin and insulin area under the curve (AUC) after oral glucose tolerance test (OGTT) fell in all patients. Fasting blood glucose, fructosamine and glucose AUC after OGTT slightly increased during the treatment, but all blood glucose levels (fasting and during OGTT) remained within normal ranges. Lanreotide appears to be a safe and effective treatment in patients with active acromegaly unresolved by surgery. The long-acting formulation avoids the drawbacks associated with either repeated daily injections or continuous infusions of somatostatin analogues. Josef Marek, Third Department of Medicine, Charles University, U nemocnice 1, 128 21 Praha 2, The Czech Republic

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Long-Term Treatment with Pivmecillinam in Patients with Recurrent Bacteriuria

Journal of International Medical Research ◽

10.1177/030006058201000307 ◽

1982 ◽

Vol 10 (3) ◽

pp. 179-182

Author(s):

B Bresky ◽

K Lincoln

Keyword(s):

Escherichia Coli ◽

Adverse Effect ◽

Renal Function ◽

Term Treatment ◽

The Body ◽

End Of Treatment ◽

Long Term Treatment ◽

Tract Infections

Thirty out-patients with chronic recurrent urinary tract infections, who had failed to respond to 10 days treatment with either pivmecillinam and/or amoxycillin, received a 3-month course of pivmecillinam at a dose of 200 mg, three times daily. Twenty-seven patients had bacteriuria due to Enterobacteriaceae, mainly Escherichia coli, sensitive to mecillinam in vitro. Pivmecillinam eradicated all the initial urinary pathogens. Reinfections occurred during treatment in three patients, who remained asymptomatic. Four subjects complained of gastro-intestinal side-effects, and therapy was withdrawn in three instances. Another three patients described unusual adverse events towards the end of the course of treatment, described as an odd sensation in the body and a desire for salt. The sensation disappeared a few days after the end of treatment. Treatment with pivmecillinam had no adverse effect on haematopoietic, hepatic or renal function.

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Free fatty acids normalize a rosiglitazone-induced visfatin release

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00109.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. E885-E890 ◽

Cited By ~ 22

Author(s):

Dominik G. Haider ◽

Friedrich Mittermayer ◽

Georg Schaller ◽

Michaela Artwohl ◽

Sabina M. Baumgartner-Parzer ◽

...

Keyword(s):

Fatty Acids ◽

Free Fatty Acids ◽

Term Treatment ◽

Double Blind ◽

Lipid Infusion ◽

Major Mechanism ◽

Insulin Mimetic ◽

Long Term Treatment ◽

Plasma Ffa

The detrimental effect of elevated free fatty acids (FFAs) on insulin sensitivity can be improved by thiazolidinediones (TZDs) in patients with type 2 diabetes mellitus. It is unknown whether this salutary action of TZD is associated with altered release of the insulin-mimetic adipocytokine visfatin. In this study, we investigated whether visfatin concentrations are altered by FFA and TZD treatment. In a randomized, double-blind, placebo-controlled, parallel-group study 16 healthy volunteers received an infusion of triglycerides/heparin to increase plasma FFA after 3 wk of treatment with rosiglitazone (8 mg/day, n = 8) or placebo ( n = 8), and circulating plasma visfatin was measured. As a corollary, human adipocytes were incubated with synthetic fatty acids and rosiglitazone to assess visfatin release in vitro. The results were that rosiglitazone treatment increased systemic plasma visfatin concentrations from 0.6 ± 0.1 to 1.7 ± 0.2 ng/ml ( P < 0.01). Lipid infusion caused a marked elevation of plasma FFA but had no effect on circulating visfatin in controls. In contrast, elevated visfatin concentrations in subjects receiving rosiglitazone were normalized by lipid infusion. In isolated adipocytes, visfatin was released into supernatant medium by acute addition and long-term treatment of rosiglitazone. This secretion was blocked by synthetic fatty acids and by inhibition of phosphatidylinositol 3-kinase or Akt. In conclusion, release of the insulin-mimetic visfatin may represent a major mechanism of metabolic TZD action. The presence of FFA antagonizes this action, which may have implications for visfatin bioactivity.

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