scholarly journals Regulation of Glucagon Secretion at Low Glucose Concentrations: Evidence for Adenosine Triphosphate-Sensitive Potassium Channel Involvement

Endocrinology ◽  
2005 ◽  
Vol 146 (12) ◽  
pp. 5514-5521 ◽  
Author(s):  
Alvaro Muñoz ◽  
Min Hu ◽  
Khalid Hussain ◽  
Joseph Bryan ◽  
Lydia Aguilar-Bryan ◽  
...  
Keyword(s):  
Inverse Correlation ◽  
Glucagon Secretion ◽  
Katp Channels ◽  
Hepatic Glycogen ◽  
Glucagon Release ◽  
Cell Secretion ◽  
Cellular Mechanisms ◽  
Low Glucose

Glucagon is a potent counterregulatory hormone that opposes the action of insulin in controlling glycemia. The cellular mechanisms by which pancreatic α-cell glucagon secretion occurs in response to hypoglycemia are poorly known. SUR1/KIR6.2-type ATP-sensitive K+ (KATP) channels have been implicated in the glucagon counterregulatory response at central and peripheral levels, but their role is not well understood. In this study, we examined hypoglycemia-induced glucagon secretion in vitro in isolated islets and in vivo using Sur1KO mice lacking neuroendocrine-type KATP channels and paired wild-type (WT) controls. Sur1KO mice fed ad libitum have normal glucagon levels and mobilize hepatic glycogen in response to exogenous glucagon but exhibit a blunted glucagon response to insulin-induced hypoglycemia. Glucagon release from Sur1KO and WT islets is increased at 2.8 mmol/liter glucose and suppressed by increasing glucose concentrations. WT islets increase glucagon secretion approximately 20-fold when challenged with 0.1 mmol/liter glucose vs. approximately 2.7-fold for Sur1KO islets. Glucagon release requires Ca2+ and is inhibited by nifedipine. Consistent with a regulatory interaction between KATP channels and intra-islet zinc-insulin, WT islets exhibit an inverse correlation between β-cell secretion and glucagon release. Glibenclamide stimulated insulin secretion and reduced glucagon release in WT islets but was without effect on secretion from Sur1KO islets. The results indicate that loss of α-cell KATP channels uncouples glucagon release from inhibition by β-cells and reveals a role for KATP channels in the regulation of glucagon release by low glucose.

scholarly journals Multiple Molecular and Cellular Mechanisms of Action of Lycopene in Cancer Inhibition

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
Cristina Trejo-Solís ◽  
Jose Pedraza-Chaverrí ◽  
Mónica Torres-Ramos ◽  
Dolores Jiménez-Farfán ◽  
Arturo Cruz Salgado ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Cell Cycle Control ◽  
Inverse Correlation ◽  
Epidemiological Studies ◽  
Cellular Mechanisms ◽  
Low Incidence ◽  
Carcinogenic Process ◽  
Cancer Inhibition

Epidemiological studies suggest that including fruits, vegetables, and whole grains in regular dietary intake might prevent and reverse cellular carcinogenesis, reducing the incidence of primary tumours. Bioactive components present in food can simultaneously modulate more than one carcinogenic process, including cancer metabolism, hormonal balance, transcriptional activity, cell-cycle control, apoptosis, inflammation, angiogenesis and metastasis. Some studies have shown an inverse correlation between a diet rich in fruits, vegetables, and carotenoids and a low incidence of different types of cancer. Lycopene, the predominant carotenoid found in tomatoes, exhibits a high antioxidant capacity and has been shown to prevent cancer, as evidenced by clinical trials and studies in cell culture and animal models.In vitrostudies have shown that lycopene treatment can selectively arrest cell growth and induce apoptosis in cancer cells without affecting normal cells.In vivostudies have revealed that lycopene treatment inhibits tumour growth in the liver, lung, prostate, breast, and colon. Clinical studies have shown that lycopene protects against prostate cancer. One of the main challenges in cancer prevention is the integration of new molecular findings into clinical practice. Thus, the identification of molecular biomarkers associated with lycopene levels is essential for improving our understanding of the mechanisms underlying its antineoplastic activity.

scholarly journals Molecular and Cellular Mechanisms of Metformin in Cervical Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2545
Author(s):  
Ya-Hui Chen ◽  
Po-Hui Wang ◽  
Pei-Ni Chen ◽  
Shun-Fa Yang ◽  
Yi-Hsuan Hsiao
Keyword(s):  
Cervical Cancer ◽  
Potential Role ◽  
Treatment Options ◽  
Cellular Mechanisms ◽  
Anticancer Effects ◽  
Clinical Benefits ◽  
Underlying Mechanisms

Cervical cancer is one of the major gynecologic malignancies worldwide. Treatment options include chemotherapy, surgical resection, radiotherapy, or a combination of these treatments; however, relapse and recurrence may occur, and the outcome may not be favorable. Metformin is an established, safe, well-tolerated drug used in the treatment of type 2 diabetes; it can be safely combined with other antidiabetic agents. Diabetes, possibly associated with an increased site-specific cancer risk, may relate to the progression or initiation of specific types of cancer. The potential effects of metformin in terms of cancer prevention and therapy have been widely studied, and a number of studies have indicated its potential role in cancer treatment. The most frequently proposed mechanism underlying the diabetes–cancer association is insulin resistance, which leads to secondary hyperinsulinemia; furthermore, insulin may exert mitogenic effects through the insulin-like growth factor 1 (IGF-1) receptor, and hyperglycemia may worsen carcinogenesis through the induction of oxidative stress. Evidence has suggested clinical benefits of metformin in the treatment of gynecologic cancers. Combining current anticancer drugs with metformin may increase their efficacy and diminish adverse drug reactions. Accumulating evidence is indicating that metformin exerts anticancer effects alone or in combination with other agents in cervical cancer in vitro and in vivo. Metformin might thus serve as an adjunct therapeutic agent for cervical cancer. Here, we reviewed the potential anticancer effects of metformin against cervical cancer and discussed possible underlying mechanisms.

Pomegranate, its Components and Modern Deliverable Formulations as Potential Botanicals in the Prevention and Treatment of Various Cancers

2021 ◽  
Vol 18 ◽  
Author(s):  
Laila Hussein ◽  
Mostafa Gouda ◽  
Harpal S. Buttar
Keyword(s):  
Side Effects ◽  
Biological Tissues ◽  
Pomegranate Juice ◽  
In Vivo Studies ◽  
Lifestyle Modifications ◽  
Cellular Mechanisms ◽  
Double Blind ◽  
Prevention And Treatment

Abstract: Cancer is a global multifactorial disease consisting of over 200 types of cancers. It is well recognized that primary prevention is an effective way to fight cancers by using natural polyphenolic anticancer foods, vegetables and fruits, avoiding exposure to carcinogenic environment, smoking cessation, and through lifestyle modifications. The present review provides up to date information on the effects and functions of pomegranate juice and its bioactive components on the most widespread six cancer types. Pomegranate contains important polyphenolic compounds such as ellagitannins and punicalagin, with strong antioxidant ability for scavenging free radicals and producing metal-chelates in the biological tissues. The in vitro and in vivo studies suggests that antioxidant and anti-inflammation properties of pomegranate constitute have major antimutagenic and antiproliferative activities for regulating gene expression, modulating cellular mechanisms, and limiting the ability of cancers to metastasize. A limited number of clinical studies have suggested that pomegranate ingredients have the potential for the prevention and treatment of cancer, especially colorectal and prostate cancer. In cancer therapy, it remains a clinical dilemma to hit the right target without inducing side effects. The costly anticancer chemotherapies are often associated with drug resistance and serious side effects in vital organs, and noncancerous neighboring cells. It appears that the pomegranate based phytotherapies would be affordable and cost-effective for next generation non-pharmacologic anticancer remedies with lesser side effects. However, well-designed, randomized, double-blind, and multi-center studies are needed to establish the long-term safety, efficacy and dose schedules for orally deliverable pomegranate formulations.

Control of dorsoventral pattern in vertebrate neural development: induction and polarizing properties of the floor plate

Development ◽  
1991 ◽  
Vol 113 (Supplement_2) ◽  
pp. 105-122 ◽  
Author(s):  
Marysia Placzek ◽  
Toshiya Yamada ◽  
Marc Tessier-Lavigne ◽  
Thomas Jessell ◽  
Jane Dodd
Keyword(s):  
Neural Tube ◽  
Neural Development ◽  
Cell Types ◽  
Floor Plate ◽  
Neural Cells ◽  
Dorsoventral Patterning ◽  
Cellular Mechanisms ◽  
Cell Position

Distinct classes of neural cells differentiate at specific locations within the embryonic vertebrate nervous system. To define the cellular mechanisms that control the identity and pattern of neural cells we have used a combination of functional assays and antigenic markers to examine the differentiation of cells in the developing spinal cord and hindbrain in vivo and in vitro. Our results suggest that a critical step in the dorsoventral patterning of the embryonic CNS is the differentiation of a specialized group of midline neural cells, termed the floor plate, in response to local inductive signals from the underlying notochord. The floor plate and notochord appear to control the pattern of cell types that appear along the dorsoventral axis of the neural tube. The fate of neuroepithelial cells in the ventral neural tube may be defined by cell position with respect to the ventral midline and controlled by polarizing signals that originate from the floor plate and notochord.

scholarly journals Pancreatic tumor cell metastasis is restricted by MT1-MMP binding protein MTCBP-1

2018 ◽  
Vol 218 (1) ◽  
pp. 317-332 ◽  
Author(s):  
Li Qiang ◽  
Hong Cao ◽  
Jing Chen ◽  
Shaun G. Weller ◽  
Eugene W. Krueger ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Pancreatic Tumor ◽  
Binding Protein ◽  
Critical Role ◽  
Inverse Correlation ◽  
Pancreatic Tumors ◽  
Matrix Remodeling ◽  
Peripheral Tissues

The process by which tumor cells mechanically invade through surrounding stroma into peripheral tissues is an essential component of metastatic dissemination. The directed recruitment of the metalloproteinase MT1-MMP to invadopodia plays a critical role in this invasive process. Here, we provide mechanistic insight into MT1-MMP cytoplasmic tail binding protein 1 (MTCBP-1) with respect to invadopodia formation, matrix remodeling, and invasion by pancreatic tumor cells. MTCBP-1 localizes to invadopodia and interacts with MT1-MMP. We find that this interaction displaces MT1-MMP from invadopodia, thereby attenuating their number and function and reducing the capacity of tumor cells to degrade matrix. Further, we observe an inverse correlation between MTCBP-1 and MT1-MMP expression both in cultured cell lines and human pancreatic tumors. Consistently, MTCBP-1–expressing cells show decreased ability to invade in vitro and metastasize in vivo. These findings implicate MTCBP-1 as an inhibitor of the metastatic process.

The influence of the haematocrit on primary haemostasis in vitro

2005 ◽  
Vol 94 (12) ◽  
pp. 1213-1218 ◽  
Author(s):  
Marco Eugster ◽  
Walter H. Reinhart
Keyword(s):  
Platelet Function ◽  
Type I Collagen ◽  
Inverse Correlation ◽  
Type I ◽  
Membrane Pore ◽  
Closure Time ◽  
Function Analyzer ◽  
Platelet Function Analyzer

SummaryPrimary haemostasis consists of platelet adhesion to subendothelial collagen, their activation and aggregation and finally the formation of a platelet plug. Erythrocytes are involved in this process because they flow in the center of the vessel and push platelets towards the site of action on the vessel wall and enhance shear forces, which activate platelets. In the platelet function analyzer PFA-100® (Dade Behring, Düdingen, Switzerland), the in vivo situation is simulated in vitro with blood being aspirated at high shear rates (5000s-1) through a capillary into a membrane pore with a diameter of 150 μm coated with type I collagen and either epinephrine or adenosine diphosphate. Aggregating platelets plug the pore and stop the flow, which is measured as the closure time. We analysed the influence of erythrocytes on platelet function analyzer measurements by systematic variation of the haematocrit (20,30,40,and 50%) at constant platelet counts of 289±61 ×103/μl plasma, or 152±30 ×103/μl blood, 96±9 ×103/μl blood and 54±5 ×103/μl blood, respectively. An inverse correlation was found between haematocrit and closure time under all circumstances. A decrease of the platelet count by 50 ×103 /μl could be compensated for by a 10% increase in haematocrit. The haematocrit must, therefore, be taken into consideration for the correct interpretation of PFA-100® measurements. Our data also provide a pathophysiological rationale to reduce the risk of bleeding in patients with thrombocytopenia and anaemia by normalizing the haematocrit with erythrocyte transfusions.

Mechanisms of neocortical epileptogenesis in vitro

1982 ◽  
Vol 48 (6) ◽  
pp. 1321-1335 ◽  
Author(s):  
M. J. Gutnick ◽  
B. W. Connors ◽  
D. A. Prince
Keyword(s):  
Reversal Potential ◽  
Excitatory Input ◽  
Short Latency ◽  
Resting Potential ◽  
Excitatory Postsynaptic Potential ◽  
Cellular Mechanisms ◽  
Voltage Dependent ◽  
Intact Cortex

1. The cellular mechanisms underlying interictal epileptogenesis have been examined in an in vitro slice preparation of guinea pig neocortex. Penicillin or bicuculline was applied to the tissue, and intracellular recordings were obtained from neurons and glia. 2. Following convulsant application, stimulation could elicit a short-latency excitatory postsynaptic potential (EPSP) and a large, longer latency depolarization shift (DS) in single neurons. DSs in neurons of the slice were very similar to those evoked in neurons of neocortex in vivo in that they displayed an all-or-none character, large shifts in latency during repetitive stimuli, long afterpotentials, and a prolonged refractory period. In contrast to epileptogenesis produced by penicillin in intact cortex, neither spontaneous DSs nor ictal episodes were observed in neocortical slices. 3. In simultaneous recordings from pairs of neurons within the same cortical column, DS generation and latency shifts were invariably synchronous. DS generation in neurons was also coincident with large, paroxysmal increases of extracellular [K+], as indicated by simultaneous recordings from glia. 4. When polarizing currents were applied to neurons injected with the local anesthetic QX-314, the DS amplitude varied monotonically and had an extrapolated reversal potential near 0 mV. In neurons injected with the K+-current blocker Cs+, large displacements of membrane potential were possible, and both the short-latency EPSP and the peak of the DS diminished completely at about 0 mV. At potentials positive to this, the short-latency EPSP was reversed, and the DS was replaced by a paroxysmal hyperpolarization whose rise time and peak latency were prolonged compared to the DS evoked at resting potential. The paroxysmal hyperpolarization probably represents the prolonged activation of the impaled neuron by EPSPs. 5. Voltage-dependent components, including slow spikes, appeared to contribute to generation of the DS at resting potential in Cs+-filled cells, and these components were blocked during large depolarizations. 6. The results suggest that DS generation in single neocortical neurons occurs during synchronous synaptic activation of a large group of cells. DS onset in a given neuron is determined by the timing of a variable-latency excitatory input that differs from the short-latency EPSP. The DS slow envelope appears to be generated by long-duration excitatory synaptic currents and may be modulated by intrinsic voltage-dependent membrane conductances. 7. We present a hypothesis for the initiation of the DS, based on the anatomical and physiological organization of the intrinsic neocortical circuits.

scholarly journals Cellular adaptations in fat tissue of exercise-trained miniature swine: role of excess energy intake

2000 ◽  
Vol 88 (3) ◽  
pp. 881-887 ◽  
Author(s):  
Gale B. Carey
Keyword(s):  
Adipose Tissue ◽  
Energy Intake ◽  
Excess Energy ◽  
Fat Tissue ◽  
Cellular Mechanisms ◽  
Miniature Swine ◽  
Extracellular Adenosine

This study examined the influence of energy expenditure and energy intake on cellular mechanisms regulating adipose tissue metabolism. 1 Twenty-four swine were assigned to restricted-fed sedentary, restricted-fed exercise-trained, full-fed sedentary, or full-fed exercise-trained groups. After 3 mo of treatment, adipocytes were isolated and adipocyte size, adenosine A1 receptor characteristics, and lipolytic sensitivity were measured. Swine were infused with epinephrine during which adipose tissue extracellular adenosine, plasma fatty acids, and plasma glycerol were measured. Results revealed that adipocytes isolated from restricted-fed exercised swine had a smaller diameter, a lower number of A1 receptors, and a greater sensitivity to lipolytic stimulation, compared with adipocytes from full-fed exercised swine. Extracellular adenosine levels were transiently increased on infusion of epinephrine in adipose tissue of restricted-fed exercised but not full-fed exercised swine. These results suggest a role for adenosine in explaining the discrepancy between in vitro and in vivo lipolysis findings and underscore the notion that excess energy intake dampens the lipolytic sensitivity of adipocytes to β-agonists and adenosine, even if accompanied by exercise training.

Structure–function analysis of full-length midkine reveals novel residues important for heparin binding and zebrafish embryogenesis

2013 ◽  
Vol 451 (3) ◽  
pp. 407-415 ◽  
Author(s):  
Jackwee Lim ◽  
Sheng Yao ◽  
Martin Graf ◽  
Christoph Winkler ◽  
Daiwen Yang
Keyword(s):  
Function Analysis ◽  
Structural Features ◽  
Full Length ◽  
Domain Growth ◽  
Heparin Binding ◽  
Cellular Mechanisms ◽  
The Individual ◽  
Zebrafish Embryogenesis

Midkine is a heparin-binding di-domain growth factor, implicated in many biological processes as diverse as angiogenesis, neurogenesis and tumorigenesis. Elevated midkine levels reflect poor prognosis for many carcinomas, yet the molecular and cellular mechanisms orchestrating its activity remain unclear. At the present time, the individual structures of isolated half domains of human midkine are known and its functionally active C-terminal half domain remains a popular therapeutic target. In the present study, we determined the structure of full-length zebrafish midkine and show that it interacts with fondaparinux (a synthetic highly sulfated pentasaccharide) and natural heparin through a previously uncharacterized, but highly conserved, hinge region. Mutating six consecutive residues in the conserved hinge to glycine strongly abates heparin binding and midkine embryogenic activity. In contrast with previous in vitro studies, we found that the isolated C-terminal half domain is not active in vivo in embryos. Instead, we have demonstrated that the N-terminal half domain is needed to enhance heparin binding and mediate midkine embryogenic activity surprisingly in both heparin-dependent and -independent manners. Our findings provide new insights into the structural features of full-length midkine relevant for embryogenesis, and unravel additional therapeutic routes targeting the N-terminal half domain and conserved hinge.

scholarly journals Vascular-dependent effects of elevated glucose on postganglionic sympathetic neurons

2011 ◽  
Vol 300 (4) ◽  
pp. H1386-H1392 ◽  
Author(s):  
Deborah H. Damon
Keyword(s):  
Vascular Function ◽  
Sympathetic Neurons ◽  
Vascular Complications ◽  
Sympathetic Nerves ◽  
T Test ◽  
Neuronal Cultures ◽  
Elevated Glucose ◽  
Low Glucose

Perivascular sympathetic nerves are important determinants of vascular function that are likely to contribute to vascular complications associated with hyperglycemia and diabetes. The present study tested the hypothesis that glucose modulates perivascular sympathetic nerves by studying the effects of 7 days of hyperglycemia on norepinephrine (NE) synthesis [tyrosine hydroxylase (TH)], release, and uptake. Direct and vascular-dependent effects were studied in vitro in neuronal and neurovascular cultures. Effects were also studied in vivo in rats made hyperglycemic (blood glucose >296 mg/dl) with streptozotocin (50 mg/kg). In neuronal cultures, TH and NE uptake measured in neurons grown in high glucose (HG; 25 mM) were less than that in neurons grown in low glucose (LG; 5 mM) ( P < 0.05; n = 4 and 6, respectively). In neurovascular cultures, elevated glucose did not affect TH or NE uptake, but it increased NE release. Release from neurovascular cultures grown in HG (1.8 ± 0.2%; n = 5) was greater than that from cultures grown in LG (0.37 ± 0.28%; n = 5; P < 0.05; unpaired t-test). In vivo, elevated glucose did not affect TH or NE uptake, but it increased NE release. Release in hyperglycemic animals (9.4 + 1.1%; n = 6) was greater than that in control animals (5.39 + 1.1%; n = 6; P < 0.05; unpaired t-test). These data identify a novel vascular-dependent effect of elevated glucose on postganglionic sympathetic neurons that is likely to affect the function of perivascular sympathetic nerves and thereby affect vascular function.

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