Abstract:BackgroundObesity has been reported to lead to increased incidence of depression. Glycerol-3-phosphate acyltransferases 4 (GPAT4) is involved in triacylglycerol synthesis and plays an important role in the occurrence of obesity. GPAT4 is the only one of GPAT family expressed in the brain. The aim of this study is to investigate if central GPAT4 is associated with obesity-related depression and its underlying mechanism.ResultsA high-fat diet resulted in increased body weight and blood lipid. HFD induced depress… Show more
“…On the other hand, some pro‐inflammatory agents (IL‐8, TNF‐α, IL‐6, IL‐17, IL‐1β, and ICAM‐1) were found to be modulated by EP3 in this research. As we know, CREB could mediate the pro‐inflammatory cytokines 43,44 . Thus, it can be concluded that EP3 promoted the inflammatory responses through up‐regulation of CREB.…”
Aim
The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor‐3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis.
Methods and results
ApoE
−/−
mice were used to construct
in vivo
model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low‐density lipoprotein (ox‐LDL) to construct
in vitro
model of atherosclerosis. mRNA expressions were assessed by qRT‐PCR, and western blot was applied to assess the protein levels. CCK‐8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme‐linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis.
In vivo
experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L‐798106 (EP3 inhibitor) significantly inhibited the levels of pro‐inflammatory cytokines in atherosclerosis
in vivo
. EP3 inhibitor (L‐798106) significantly reversed ox‐LDL‐caused HASMCs injury via inhibiting the apoptosis and inflammatory responses (
P
< 0.05). The levels of interleukin‐17 (IL‐17) and intercellular adhesion molecule‐1 (ICAM‐1) in HASMCs were elevated by ox‐LDL, whereas L‐798106 or knockdown of cyclic AMP (cAMP) response element‐binding protein (CREB) notably restored this phenomenon (
P
< 0.05). EP3 overexpression further aggravated ox‐LDL‐induced inflammation in HASMCs, and EP3 up‐regulated the levels of IL‐17 and ICAM‐1 in ox‐LDL‐treated HASMCs (
P
< 0.05). EP3 up‐regulation promoted the inflammatory responses in ox‐LDL‐treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL‐17/ICAM‐1 axis (
P
< 0.05).
Conclusions
EP3 inhibitor alleviates ox‐LDL‐induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL‐17/ICAM‐1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis.
“…On the other hand, some pro‐inflammatory agents (IL‐8, TNF‐α, IL‐6, IL‐17, IL‐1β, and ICAM‐1) were found to be modulated by EP3 in this research. As we know, CREB could mediate the pro‐inflammatory cytokines 43,44 . Thus, it can be concluded that EP3 promoted the inflammatory responses through up‐regulation of CREB.…”
Aim
The progression of atherosclerosis can lead to the occurrence of multiple cardiovascular diseases (coronary heart disease, etc.). E prostanoid receptor‐3 (EP3) is known to participate in the progression of atherosclerosis. This study aimed to investigate the mechanism by which EP3 modulates the development of atherosclerosis.
Methods and results
ApoE
−/−
mice were used to construct
in vivo
model of atherosclerosis. Human aortic smooth muscle cells (HASMCs) were stimulated with oxidized low‐density lipoprotein (ox‐LDL) to construct
in vitro
model of atherosclerosis. mRNA expressions were assessed by qRT‐PCR, and western blot was applied to assess the protein levels. CCK‐8 assay was applied to assess the cell viability. The inflammatory cytokines levels were assessed by enzyme‐linked immunosorbent assay, and flow cytometry was applied to assess cell apoptosis.
In vivo
experiment was constructed to investigate the impact of EP3 in atherosclerosis development. L‐798106 (EP3 inhibitor) significantly inhibited the levels of pro‐inflammatory cytokines in atherosclerosis
in vivo
. EP3 inhibitor (L‐798106) significantly reversed ox‐LDL‐caused HASMCs injury via inhibiting the apoptosis and inflammatory responses (
P
< 0.05). The levels of interleukin‐17 (IL‐17) and intercellular adhesion molecule‐1 (ICAM‐1) in HASMCs were elevated by ox‐LDL, whereas L‐798106 or knockdown of cyclic AMP (cAMP) response element‐binding protein (CREB) notably restored this phenomenon (
P
< 0.05). EP3 overexpression further aggravated ox‐LDL‐induced inflammation in HASMCs, and EP3 up‐regulated the levels of IL‐17 and ICAM‐1 in ox‐LDL‐treated HASMCs (
P
< 0.05). EP3 up‐regulation promoted the inflammatory responses in ox‐LDL‐treated HASMCs through mediation of cAMP/protein kinase A (PKA)/CREB/IL‐17/ICAM‐1 axis (
P
< 0.05).
Conclusions
EP3 inhibitor alleviates ox‐LDL‐induced HASMC inflammation via mediation of cAMP/PKA/CREB/IL‐17/ICAM‐1 axis. Our study might shed new lights on discovering novel strategies against atherosclerosis.
“…The former is targeted by three drugs with antineoplastic activity which decrease its expression: doxorubicin 52 , 59 , orlistat 60 , 61 , and paclitaxel 60 , 62 . GPAT4 is the only gene of the GPAT family expressed in the brain, and it has recently been identified as a potential drug target for treating obesity-associated depression 63 . Figure 4 Comparison of genes of interest identified in this study against published works: ( A ) Larsson et al 56 , which highlighted essential genes for models for high and low survival, ( B ) Richards et al 9 , where the list of marker genes comprises the top 50 genes for each one of the 86 intra-GSC clusters, ( C ) Wang et al 54 , where upregulated genes for outer RG-like and ventricular RG-like (UP ORG and UP VRG, respectively) were considered, and ( D ) Liu et al 67 , where “targets” comprise both genes and miRNAs.…”
The manifestation of intra- and inter-tumor heterogeneity hinders the development of ubiquitous cancer treatments, thus requiring a tailored therapy for each cancer type. Specifically, the reprogramming of cellular metabolism has been identified as a source of potential drug targets. Drug discovery is a long and resource-demanding process aiming at identifying and testing compounds early in the drug development pipeline. While drug repurposing efforts (i.e., inspecting readily available approved drugs) can be supported by a mechanistic rationale, strategies to further reduce and prioritize the list of potential candidates are still needed to facilitate feasible studies. Although a variety of ‘omics’ data are widely gathered, a standard integration method with modeling approaches is lacking. For instance, flux balance analysis is a metabolic modeling technique that mainly relies on the stoichiometry of the metabolic network. However, exploring the network’s topology typically neglects biologically relevant information. Here we introduce Transcriptomics-Informed Stoichiometric Modelling And Network analysis (TISMAN) in a recombinant innovation manner, allowing identification and validation of genes as targets for drug repurposing using glioblastoma as an exemplar.
“…Additionally, depressive mood may occur in adolescents with obesity due to biochemical changes caused by metabolic disturbances, including expanded cerebrospinal fluid space and diminished white matter volume [ 27 ]. Furthermore, neurodegeneration and structural remodeling may impair emotion, study and memory through brain inflammation [ 40 ], and mostly affected the hippocampus [ 40 ]. A major component of the MUHO definition consisted of inflammation in the majority of previous studies.…”
Objectives
It has been suggested that obesity phenotypes are related to mental health problems and health-related quality of life (HRQoL). However, there is no certain consensus. This systematic review aimed to evaluate the association between different obesity phenotypes with common psychiatric symptoms and HRQoL.
Methods
Electronic databases i.e. PubMed, Scopus, EMBASE, and google scholar were searched until September 2021, to identify studies that investigated associations between the obesity phenotypes with psychiatric symptoms and/or mental and physical HRQoL. Two researchers independently checked titles and abstracts, evaluated full-text studies, extracted data, and appraised their quality using the Newcastle–Ottawa Scale.
Results
Eighteen studies, with a total of 3,929,203 participants, were included. Of the studies included in this systematic review, 10 articles evaluated the association between obesity phenotypes and psychiatric symptoms, while six papers investigated the association between HRQoL and obesity phenotypes, and two studies assessed both. As a whole, the findings of these studies suggest that obese individuals with a favorable metabolic profile have a slightly higher risk of mental health problems and poor quality of life, however, the risk becomes larger when obesity is combined with an adverse metabolic profile. So, metabolically healthy obesity may not be a completely benign condition in relation to mental disorders and poor quality of life.
Conclusion
According to published research, obesity is likely to increase the risk of mental health problems and poor quality of life when metabolic disturbances are present.
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