The alpha-7 nicotinic acetylcholine receptor agonist GTS-21 engages the glucagon-like peptide-1 incretin hormone axis to lower levels of blood glucose in db/db mice.

AIM: To establish if alpha-7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a blood glucose-lowering action in db/db mice, and to test if this action requires coordinate α7nAChR and GLP-1 receptor (GLP-1R) stimulation by GTS-21 and endogenous GLP-1, respectively. MATERIALS AND METHODS: Blood glucose levels were measured during an oral glucose tolerance test (OGTT) using db/db mice administered intraperitoneal GTS-21. Plasma GLP-1, peptide tyrosine tyrosine 1-36 (PYY1-36), glucose-dependent insulinotropic peptide (GIP), glucagon, and insulin levels were measured by ELISA. A GLP-1R-mediated action of GTS-21 that is secondary to α7nAChR stimulation was evaluated using α7nAChR and GLP-1R knockout (KO) mice, or by co-administration of GTS-21 with the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the GLP-1R antagonist, exendin (9-39). Insulin sensitivity was assessed in an insulin tolerance test. RESULTS: Single or multiple dose GTS-21 (0.5-8.0 mg/kg) acted in a dose-dependent manner to lower levels of blood glucose in the OGTT using 10-14 week-old male and female db/db mice. This action of GTS-21 was reproduced by the α7nAChR agonist, PNU-282987, was enhanced by sitagliptin, was counteracted by exendin (9-39), and was absent in α7nAChR and GLP-1R KO mice. Plasma GLP-1, PYY1-36, GIP, glucagon, and insulin levels increased in response to GTS-21, but insulin sensitivity, body weight, and food intake were unchanged. CONCLUSIONS: α7nAChR agonists improve oral glucose tolerance in db/db mice. This action is contingent to coordinate α7nAChR and GLP-1R stimulation. Thus α7nAChR agonists administered in combination with sitagliptin might serve as a new treatment for type 2 diabetes.

Galantamine improves glycemic control and diabetic nephropathy in Leprdb/db mice.

Galantamine, a centrally acting acetylcholinesterase inhibitor, has been shown to attenuate inflammation and insulin resistance in patients with metabolic syndrome. We investigated the effects of galantamine on glycemic control and development of diabetic nephropathy (DN) in Leprdb/db mice. Galantamine significantly reduced food intake, body weight, blood glucose and HbA1c levels. Insulin resistance (HOMA-IR, QUICKI), HOMA-ß and elevations in plasma inflammatory cytokine levels (TNF-α, IL-6 and HMGB-1) were all attenuated by galantamine. Galantamine also ameliorated diabetes-induced kidney injury as evidenced by improvements in renal function (BUN, creatinine, albuminuria), histologic injury and apoptosis. Improved glycemic control and nephropathy were associated with increased circulating GLP-1, decreased renal P-38 MAPK and caspase-1 activation and reduced SGLT-2 expression. These findings provide insights into the mechanisms by which galantamine improves glycemic control and attenuates DN in the Leprdb/db mouse model.

GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice.

Diabetic nephropathy (DN) is a serious complicating factor in human type 2 diabetes mellitus (T2DM), and it commonly results in end-stage renal disease (ESRD) that requires kidney dialysis. Here, we report that the α7 nicotinic acetylcholine receptor (α7nAChR) agonist GTS-21 exerts a novel anti-inflammatory action to ameliorate DN, as studied using an inbred strain of Leprdb/db mice in which hyperglycemia and obesity co-exist owing to defective leptin receptor (Lepr) signaling. For this analysis, GTS-21 was administered to 10-12 week-old male and female mice as a 4 mg/kg intraperitoneal injection, twice-a-day, for 8 weeks. Kidney function and injury owing to DN were monitored by determination of plasma levels of BUN, creatinine, KIM-1 and NGAL. Histologic analysis of glomerular hypertrophy and mesangial matrix expansion were also used to assess DN in these mice. Concurrently, renal inflammation was assessed by measuring IL-6 and HMGB1, while also quantifying renal cell apoptosis, and apoptotic signaling pathways. We found that Leprdb/db mice exhibited increased markers of BUN, creatinine, NGAL, KIM-1, IL-6, cytochrome C, and HMGB-1. These abnormalities were also accompanied by histologic kidney injury (mesangial matrix expansion and apoptosis). Remarkably, all such pathologies were significantly reduced by GTS-21. Collectively, our results provide new evidence that the α7nAChR agonist GTS-21 has the ability to attenuate diabetes-induced kidney injury. Additional studies are warranted to further investigate the involvement of the vagal cholinergic anti-inflammatory reflex pathway (CAP) in ameliorating diabetic nephropathy.

α7 Nicotinic Acetylcholine Receptor Agonists Regulate Inflammation and Growth Hormone Resistance in Sepsis.

ABSTRACT: During sepsis the normal induction of circulating insulin-like growth factor-I (IGF-I) by growth hormone (GH) action on liver is attenuated, a phenomenon called hepatic GH resistance. Hepatic GH resistance can be caused by cytokine-mediated activation of the NF-κB pathway which interferes with normal GH-signaling. The afferent and efferent fibers of the vagus nerve are integral to the cholinergic anti-inflammatory pathway (CAP) which attenuates hepatic TNFα production by activating the α7 nicotinic acetylcholine receptor (α7nAChR). We examined the effects of selective afferent vagotomy (SAV) and α7nAChR activation on sepsis-induced mortality, hepatic and systemic inflammation, the GH/IGF system and hepatic GH resistance using Sprague Dawley (SD) rats, C57BL/6 wild type (WT) mice, and α7nAChR knockout (KO) mice. Capsaicin was used to perform SAV and GTS-21 (α7nAChR agonist) was used to activate the α7nAChR. Sepsis-induced mortality, hepatic NF-κB activation, and plasma cytokine levels were increased in SAV rats and reduced in GTS-21-treated mice. The effects of sepsis on the GH/IGF-I system plasma IGF-I, IGF binding protein-1 (IGFBP-1), hepatic IGF-I, IGFBP-1, and GH receptor (GHR) mRNA and rhGH-responsiveness in mice were improved by GTS-21. Collectively these results confirm the protective effects of the anti-inflammatory CAP and α7nAChR activation in sepsis. They also provide evidence the CAP and α7nAChR activation could be used to attenuate hepatic GH resistance and anabolic failure in sepsis.

Sparstolonin B: A Unique Anti-Inflammatory Agent.

Toll-like receptors are transmembrane proteins which sense and transmit infectious and inflammatory responses to the cells expressing them. Therapeutic strategies for the blockade of excessive Toll-like receptor signaling are being actively pursued for several diseases. Recently, Sparstolonin B, isolated from Chinese herb, which suppresses selectively Toll-like receptors has been studied in various inflammatory models. The objective of this review is to summarize the current literature regarding the use of Sparstolonin B in various in vitro and in vivo studies and to provide an overview regarding the potential use of this agent in different inflammatory diseases. Additionally, the current knowledge regarding the role of Toll-like receptors in inflammatory disease and the usage of various Toll-like receptor antagonists will be summarized. Based on our review, we believe Sparstolonin B could serve as a potential therapeutic agent for treatment of Toll-like receptor-mediated inflammatory disorders.

High-grade malignant pancreatic neoplasm with sarcomatoid features.

Sarcomatoid carcinoma is a rare and aggressive form that occur at diverse locations in the body such as upper respiratory tract, upper and lower digestive tracts, genitourinary tract, breast and thyroid glands. However, its occurrence in pancreas has been rarely reported. Sarcomatoid carcinoma of pancreas (SCP) is a high-grade epithelial malignancy composed predominantly of spindle cells often having features suggestive of epithelial derivation without features indicative of a specific line of mesenchymal differentiation. Its pathogenesis has not been elucidated. Microscopically, SCP comprises mostly anaplastic cells and is strikingly sarcoma-like in appearance. Confirmation of this disease is often based on the pathological diagnosis. We report a case that was incidentally found after a CT was done for worsening chronic back pain and the patient was found to have a pancreatic mass and a liver lesion. Endoscopic ultrasound (EUS)-guided liver biopsy revealed high grade malignant pancreatic neoplasm with sarcomatoid features. Further CT chest revealed bilateral lung nodules and PET scan revealed prominent bony metastases within vertebral bodies at L1, L2, and L3. The patient refused definitive treatment and succumbed to illness within 3 months.

Osteoclast-like giant cell tumor of the pancreas-an unusual presentation in a patient with large mantle cell lymphoma.

Osteoclast-like giant cell tumor of the pancreas is very rare. We report a 78-year-old male who was previously treated for large mantle cell lymphoma, was found to have an increased uptake in a peri-pancreatic node from his restaging PET scan. Endoscopic ultrasound-directed fine-needle aspiration of the mass and lymph node revealed an undifferentiated carcinoma with osteoclast-like giant cells. Osteoclast-like giant cell tumors of the pancreas are frequently found to be unresectable at diagnosis due to their large size (>5 cm). In our patient, due to its small size (<3 cm) sub-total pancreatectomy was performed. Three years from the surgery, the patient is doing well without recurrence. This case report intends to increase provider awareness that in the setting of new pancreatic lesions in a patient with previous history of lymphoma, a high index of suspicion for a primary pancreatic lesion should be included in the differential diagnosis.

Risk factors for in-hospital shunt thrombosis and mortality in patients weighing less than 3 kg with functionally univentricular heart undergoing a modified Blalock-Taussig shunt.

OBJECTIVES: To determine the association between several perioperative variables and in-hospital shunt thrombosis and mortality in patients weighing less than 3 kg with functional univentricular heart (UVH) who underwent modified Blalock-Taussig shunt. METHODS: Between January 2006 and February 2016, 85 patients who weighed less than 3 kg with functional UVH and underwent modified Blalock-Taussig shunt were reviewed. In-hospital shunt thrombosis and mortality were the primary outcomes. The associations between perioperative variables and outcomes were assessed with univariate and multivariate analyses. RESULTS: In-hospital shunt thrombosis was 14% (12 of 85). Hospital mortality was 18% (15 of 85), which resulted in an 82% discharge survival rate. Shunt thrombosis was significantly associated with in-hospital mortality (odds ratio 18.9, 95% confidence interval 4.5-78.9). There were no statistically significant associations between weight, specific diagnosis of functional UVH and shunt thrombosis or mortality. Multivariate analysis identified delayed initiation of anticoagulant (P < 0.01) and postoperative cardiac arrest (P < 0.01) as risk factors of shunt thrombosis, while intraoperative bradycardia (P < 0.01), high postoperative haemoglobin (P = 0.03) and shunt thrombosis (P < 0.01) were risk factors for hospital mortality. CONCLUSIONS: In this high-risk group of patients who weighed less than 3 kg with functional UVH and who underwent modified Blalock-Taussig shunt, in-hospital mortality was strongly associated with the occurrence of shunt thrombosis. Our study highlighted the perioperative variables of delayed postoperative initiation of anticoagulant, cardiac arrest and the occurrence of intraoperative bradycardia that were significant risk factors for shunt thrombosis and mortality. Achieving better quality of perioperative care potentially improves outcomes.