An Integrative Pharmacology-Based Pattern to Uncover the Pharmacological Mechanism of Ginsenoside H Dripping Pills in the Treatment of Depression

Objectives: To evaluate the pharmacodynamical effects and pharmacological mechanism of Ginsenoside H dripping pills (GH) in chronic unpredictable mild stress (CUMS) model rats.Methods: First, the CUMS-induced rat model was established to assess the anti-depressant effects of GH (28, 56, and 112 mg/kg) by the changes of the behavioral indexes (sucrose preference, crossing score, rearing score) and biochemical indexes (serotonin, dopamine, norepinephrine) in Hippocampus. Then, the components of GH were identified by ultra-performance liquid chromatography-iron trap-time of flight-mass spectrometry (UPLC/IT-TOF MS). After network pharmacology analysis, the active ingredients of GH were further screened out based on OB and DL, and the PPI network of putative targets of active ingredients of GH and depression candidate targets was established based on STRING database. The PPI network was analyzed topologically to obtain key targets, so as to predict the potential pharmacological mechanism of GH acting on depression. Finally, some major target proteins involved in the predictive signaling pathway were validated experimentally.Results: The establishment of CUMS depression model was successful and GH has antidepressant effects, and the middle dose of GH (56 mg/kg) showed the best inhibitory effects on rats with depressant-like behavior induced by CUMS. Twenty-eight chemical components of GH were identified by UPLC/IT-TOF MS. Subsequently, 20(S)-ginsenoside Rh2 was selected as active ingredient and the PPI network of the 43 putative targets of 20(S)-ginsenoside Rh2 containing in GH and the 230 depression candidate targets, was established based on STRING database, and 47 major targets were extracted. Further network pharmacological analysis indicated that the cAMP signaling pathway may be potential pharmacological mechanism regulated by GH acting on depression. Among the cAMP signaling pathway, the major target proteins, namely, cAMP, PKA, CREB, p-CREB, BDNF, were used to verify in the CUMS model rats. The results showed that GH could activate the cAMP-PKA-CREB-BDNF signaling pathway to exert antidepressant effects.Conclusions: An integrative pharmacology-based pattern was used to uncover that GH could increase the contents of DA, NE and 5-HT, activate cAMP-PKA-CREB-BDNF signaling pathway exert antidepressant effects.

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cAMP-signaling pathway acts in selective synergism with glucose or tolbutamide to increase cytosolic Ca2+ in rat pancreatic beta-cells

Diabetes ◽

10.2337/diabetes.45.3.295 ◽

1996 ◽

Vol 45 (3) ◽

pp. 295-301 ◽

Cited By ~ 8

Author(s):

K. Yaekura ◽

M. Kakei ◽

T. Yada

Keyword(s):

Signaling Pathway ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Camp Signaling ◽

Camp Signaling Pathway

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Role of cAMP in Double Switch of Glucagon Secretion

Cells ◽

10.3390/cells10040896 ◽

2021 ◽

Vol 10 (4) ◽

pp. 896

Author(s):

Jan Zmazek ◽

Vladimir Grubelnik ◽

Rene Markovič ◽

Marko Marhl

Keyword(s):

Glucose Metabolism ◽

Signaling Pathway ◽

Cell Model ◽

Dominant Role ◽

Glucagon Secretion ◽

Camp Signaling ◽

Independent Manner ◽

Metabolic Switch ◽

Camp Signaling Pathway ◽

Double Switch

Glucose metabolism plays a crucial role in modulating glucagon secretion in pancreatic alpha cells. However, the downstream effects of glucose metabolism and the activated signaling pathways influencing glucagon granule exocytosis are still obscure. We developed a computational alpha cell model, implementing metabolic pathways of glucose and free fatty acids (FFA) catabolism and an intrinsically activated cAMP signaling pathway. According to the model predictions, increased catabolic activity is able to suppress the cAMP signaling pathway, reducing exocytosis in a Ca2+-dependent and Ca2+ independent manner. The effect is synergistic to the pathway involving ATP-dependent closure of KATP channels and consequent reduction of Ca2+. We analyze the contribution of each pathway to glucagon secretion and show that both play decisive roles, providing a kind of “secure double switch”. The cAMP-driven signaling switch plays a dominant role, while the ATP-driven metabolic switch is less favored. The ratio is approximately 60:40, according to the most recent experimental evidence.

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Assessment of cellular mechanisms contributing to cAMP compartmentalization in pulmonary microvascular endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00361.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. C839-C852 ◽

Cited By ~ 38

Author(s):

Wei P. Feinstein ◽

Bing Zhu ◽

Silas J. Leavesley ◽

Sarah L. Sayner ◽

Thomas C. Rich

Keyword(s):

Endothelial Cells ◽

Adenylyl Cyclase ◽

Signaling Pathway ◽

Camp Signaling ◽

Microvascular Endothelial Cells ◽

Camp Production ◽

Barrier Integrity ◽

Pulmonary Microvascular Endothelial Cells ◽

Camp Signaling Pathway ◽

Microvascular Endothelial

Cyclic AMP signals encode information required to differentially regulate a wide variety of cellular responses; yet it is not well understood how information is encrypted within these signals. An emerging concept is that compartmentalization underlies specificity within the cAMP signaling pathway. This concept is based on a series of observations indicating that cAMP levels are distinct in different regions of the cell. One such observation is that cAMP production at the plasma membrane increases pulmonary microvascular endothelial barrier integrity, whereas cAMP production in the cytosol disrupts barrier integrity. To better understand how cAMP signals might be compartmentalized, we have developed mathematical models in which cellular geometry as well as total adenylyl cyclase and phosphodiesterase activities were constrained to approximate values measured in pulmonary microvascular endothelial cells. These simulations suggest that the subcellular localizations of adenylyl cyclase and phosphodiesterase activities are by themselves insufficient to generate physiologically relevant cAMP gradients. Thus, the assembly of adenylyl cyclase, phosphodiesterase, and protein kinase A onto protein scaffolds is by itself unlikely to ensure signal specificity. Rather, our simulations suggest that reductions in the effective cAMP diffusion coefficient may facilitate the formation of substantial cAMP gradients. We conclude that reductions in the effective rate of cAMP diffusion due to buffers, structural impediments, and local changes in viscosity greatly facilitate the ability of signaling complexes to impart specificity within the cAMP signaling pathway.

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