PET Neuroimaging Reveals Serotonergic and Metabolic Dysfunctions in the Hippocampal Electrical Kindling Model of Epileptogenesis

: This review aims to focus the links existing between several aspects of the mother-child dyad in the intricate playground of obesity and Metabolic Syndrome (MetS), including its hepatic component, the Non- Alcoholic Fatty Liver Disease (NAFLD). In recent years human and animal model studies have shown that dietary interventions in mothers and offspring can be successful in reducing the risk of NAFLD development. Evidences also concern the new concept of a real intergenerational transmission of predisposition to metabolic disorders. Certain genes, such as SIRT1 and PNPLA3, and some epigenetic modifications, including micro RNAs function, seem to be responsible for fetal reprogramming in the setting of maternal obesity. These modifiers appear to be potential therapeutic targets to reduce the risk of future metabolic dysfunctions. : Controlling antepartum hyperglycemia, preventing gestational diabetes, and avoiding excessive weight gain during pregnancy can help reduce the relentless epidemic of childhood obesity and NAFLD. Also, the composition of the intestinal microbiota seems to be related to the development of metabolic disorders in the offspring. Several studies show that breastfed infants have a microbial signature different from formula-fed infants. Much interestingly, prolonged breastfeeding is beneficial not only for the newborn and his health in adult life, but also for the mothers’ health. Maternal benefits include reducing the risk of developing chronic diseases, such as diabetes mellitus, myocardial infarction and NAFLD as well. : In conclusion, all above mechanisms appear to intervene synergistically and may act as modifiable risk factors for infant and mother NAFLD.

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Therapeutic Potential of Agonists and Antagonists of A1, A2a, A2b and A3 Adenosine Receptors

Current Pharmaceutical Design ◽

10.2174/1381612825666190716112319 ◽

2019 ◽

Vol 25 (26) ◽

pp. 2892-2905 ◽

Cited By ~ 3

Author(s):

Sumit Jamwal ◽

Ashish Mittal ◽

Puneet Kumar ◽

Dana M. Alhayani ◽

Amal Al-Aboudi

Keyword(s):

Nervous System ◽

Therapeutic Potential ◽

The Body ◽

Membrane Receptors ◽

Physiological Importance ◽

Physiological Processes ◽

Central Nervous Systems ◽

Energy Consuming ◽

Metabolic Dysfunctions ◽

G Protein Coupled

Adenosine is a naturally occurring nucleoside and an essential component of the energy production and utilization systems of the body. Adenosine is formed by the degradation of adenosine-triphosphate (ATP) during energy-consuming processes. Adenosine regulates numerous physiological processes through activation of four subtypes of G-protein coupled membrane receptors viz. A1, A2A, A2B and A3. Its physiological importance depends on the affinity of these receptors and the extracellular concentrations reached. ATP acts as a neurotransmitter in both peripheral and central nervous systems. In the peripheral nervous system, ATP is involved in chemical transmission in sensory and autonomic ganglia, whereas in central nervous system, ATP, released from synaptic terminals, induces fast excitatory postsynaptic currents. ATP provides the energetics for all muscle movements, heart beats, nerve signals and chemical reactions inside the body. Adenosine has been traditionally considered an inhibitor of neuronal activity and a regulator of cerebral blood flow. Since adenosine is neuroprotective against excitotoxic and metabolic dysfunctions observed in neurological and ocular diseases, the search for adenosinerelated drugs regulating adenosine transporters and receptors can be important for advancement of therapeutic strategies against these diseases. This review will summarize the therapeutic potential and recent SAR and pharmacology of adenosine and its receptor agonists and antagonists.

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Treatment potential of LPCN 1144 on liver health and metabolic regulation in a non-genomic, high fat diet induced NASH rabbit model

Journal of Endocrinological Investigation ◽

10.1007/s40618-021-01522-7 ◽

2021 ◽

Author(s):

P. Comeglio ◽

E. Sarchielli ◽

S. Filippi ◽

I. Cellai ◽

G. Guarnieri ◽

...

Keyword(s):

Hepatic Fibrosis ◽

High Fat Diet ◽

Metabolic Regulation ◽

Therapeutic Potential ◽

Rabbit Model ◽

Free Testosterone ◽

Preclinical Model ◽

High Fat ◽

Liver Health ◽

Metabolic Dysfunctions

Abstract Purpose Low free testosterone (T) level in men is independently associated with presence and severity of Non-Alcoholic Steatohepatitis (NASH). The histological and molecular effects of oral testosterone prodrug LPCN 1144 treatment on hepatic fibrosis and NASH features are unknown. A metabolic syndrome-induced NASH model in rabbits consuming high fat diet (HFD) has been previously used to assess treatment effects of injectable T on hepatic fibrosis and NASH features. Here we present results on LPCN 1144 in this HFD-induced, NASH preclinical model. Methods Male rabbits were randomly assigned to five groups: regular diet (RD), HFD, HFD + 1144 vehicle (HFD + Veh), HFD + 1144 (1144), and HFD + 1144 + α-tocopherol (1144 + ALPHA). Rabbits were sacrificed after 12 weeks for liver histological, biochemical and genetic analyses. Histological scores were obtained through Giemsa (inflammation), Masson’s trichrome (steatosis and ballooning), and Picrosirius Red (fibrosis) staining. Results Compared to RD, HFD and HFD + Veh significantly worsened NASH features and hepatic fibrosis. Considering HFD and HFD + Veh arms, histological and biomarker features were not significantly different. Both 1144 and 1144 + ALPHA arms improved mean histological scores of NASH as compared to HFD arm. Importantly, percentage of fibrosis was improved in both 1144 (p < 0.05) and 1144 + ALPHA (p = 0.05) treatment arms vs. HFD. Both treatment arms also reduced HFD-induced inflammation and fibrosis mRNA markers. Furthermore, 1144 treatments significantly improved HFD-induced metabolic dysfunctions. Conclusions Histological and biomarker analyses demonstrate that LPCN 1144 improved HFD-induced hepatic fibrosis and NASH biochemical, biomolecular and histochemical features. These preclinical findings support a therapeutic potential of LPCN 1144 in the treatment of NASH and of hepatic fibrosis.

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