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Metabolism: Clinical and Experimental Jun 2024The molecular control of feeding after fasting is essential for maintaining energy homeostasis, while overfeeding usually leads to obesity. Identifying non-coding...
OBJECTIVE
The molecular control of feeding after fasting is essential for maintaining energy homeostasis, while overfeeding usually leads to obesity. Identifying non-coding microRNAs (miRNAs) that control food intake could reveal new oligonucleotide-based therapeutic targets for treating obesity and its associated diseases. This study aims to identify a miRNA modulating food intake and its mechanism in neuronal regulation of food intake and energy homeostasis.
METHODS
A comprehensive genome-wide miRNA screening in the arcuate nucleus of the hypothalamus (ARC) of fasted mice and ad libitum mice was performed. Through stereotactic virus injections, intracerebroventricular injections, and miRNA sponge technology, miR-7a-5p was inhibited specifically in AgRP neurons and the central nervous system, and metabolic phenotypes were monitored. Quantitative real-time PCR, Western blotting, immunofluorescence, whole-cell patch-clamp recording, and luciferase reporter assay were used to investigate the mechanisms underlying miR-7a-5p's regulation of food intake.
RESULTS
We found a significant increase in miR-7a-5p levels after fasting. miR-7a-5p was highly expressed in the ARC, and inhibition of miR-7a-5p specifically in AgRP neurons reduced food intake and body weight gain. miR-7a-5p inhibited S6K1 gene expression by binding to its 3'-UTR. Furthermore, the knockdown of ribosomal S6 kinase 1 (S6K1) in AgRP neurons can partially reverse the effects caused by miR-7a-5p inhibition. Importantly, intracerebroventricular administration of the miR-7a-5p inhibitor could also reduce food intake and body weight gain.
CONCLUSION
Our findings suggest that miR-7a-5p responds to energy deficit and regulates food intake by fine-tuning mTOR1/S6K1 signaling in the AgRP neurons, which could be a promising oligonucleotide-based therapeutic target for treating obesity and its associated diseases.
PubMed: 38942170
DOI: 10.1016/j.metabol.2024.155959 -
Metabolism: Clinical and Experimental Jun 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic conditions affect populations across economic strata. Nevertheless, there are...
Disparities in metabolic dysfunction-associated steatotic liver disease and cardiometabolic conditions in low and lower middle-income countries: systematic analysis from the global burden of disease study 2019.
OBJECTIVE
Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic conditions affect populations across economic strata. Nevertheless, there are limited epidemiological studies addressing these diseases in low (LICs) and lower-middle-income countries (lower MICs). Therefore, an analysis of the trend of MASLD and cardiometabolic conditions in these countries is necessary.
METHODS
From 2000 to 2019, jointpoint regression analysis was employed to calculate the prevalence, mortality, and disability-adjusted life years (DALYs) for cardiometabolic conditions including MASLD, type 2 diabetes mellitus (T2DM), dyslipidemia (DLP), hypertension (HTN), obesity, peripheral artery disease (PAD), atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), stroke, and chronic kidney disease from HTN and T2DM, in LICs and lower MICs (according to the World Bank Classification 2019) using the Global Burden of Disease 2019 data.
RESULTS
Among the eleven cardiometabolic conditions, MASLD (533.65 million), T2DM (162.96 million), and IHD (76.81 million) had the highest prevalence in LICs and Lower MICs in 2019. MASLD represented the largest proportion of global prevalence in these countries (43 %). From 2000 to 2019, mortality in LICs and lower MICs increased in all cardiometabolic conditions, with obesity-related mortality having the highest increase (+134 %). During this timeframe, there were increased age-standardized death rates (ASDR) from obesity, PAD, and AF/AFL. From all conditions, the DALYs-to-prevalence ratio was higher in LICs and lower MICs than the global average.
CONCLUSION
The burden of MASLD and cardiometabolic conditions is increasing worldwide, with LICs and lower MICs experiencing higher disability per prevalence. As these conditions are preventable, counteracting these trends requires not only the modification of ongoing actions but also the strategizing of immediate interventions.
PubMed: 38942169
DOI: 10.1016/j.metabol.2024.155958 -
The Journal of Heart and Lung... Jun 2024Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that...
BACKGROUND
Right ventricular (RV) imaging has not a definite role in risk stratification of pulmonary arterial hypertension (PAH) patients. We tested the hypothesis that echocardiography-derived phenotypes, depicting different degrees of RV remodeling and dysfunction, may provide additional prognostic information to current risk stratification tools.
METHODS
Consecutive incident PAH patients aged ≥ 18 years, diagnosed between January 2005 and December 2021, underwent clinical assessment, right heart catheterization, standard echocardiography. Simple echocardiographic variables were combined in order to define a priori four phenotypes representing different degrees of RV dilatation and RV-pulmonary arterial (PA) coupling: Phenotype 1 with mildy dilated right ventricle and preserved RV-PA coupling (n=152 patients); phenotype 2 with mildly dilated right ventricle and poor RV-PA coupling (n=143 patients); phenotype 3 with severely dilated right ventricle and preserved RV-PA coupling (n=201 patients); phenotype 4 with severely dilated right ventricle and poor RV-PA coupling, with or without severe tricuspid regurgitation (n=519 patients). Risk stratification was based on on the ESC/ERS 3-strata model and REVEAL 2.0 score.
RESULTS
These phenotypes were present in all risk groups. Notably, regardless of the ESC/ERS risk stratum assigned to the patient, phenotype 4 was associated with a 2-fold increase of the odds of death (HR 2.1, 95% C.I. 1.6-2.8, p<0.001), while phenotype 1 was associated with a 71% reduction in the odds of dying (HR 0.29, 95% C.I. 0.18-0.47, p<0.001).
CONCLUSIONS
Echocardiography-derived phenotypes describing RV remodeling and dysfunction may provide prognostic information which is independent of and additional to the clinically defined risk in incident PAH patients.
PubMed: 38942159
DOI: 10.1016/j.healun.2024.06.003 -
Journal of Ethnopharmacology Jun 2024The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms...
ETHNOPHARMACOLOGICAL RELEVANCE
The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated.
AIM OF THE STUDY
This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement.
MATERIALS AND METHODS
The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aβ) aggregation was detected via immunostaining, while the quantification of Aβ and Aβ was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aβ metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot.
RESULTS
A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY.
CONCLUSION
QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.
PubMed: 38942156
DOI: 10.1016/j.jep.2024.118497 -
Neurotoxicology Jun 2024There is a propensity for synthetic cannabinoid abuse to spread worldwide. CP-55,940, a synthetic cannabinoid having the ability to activate both CB1 and CB2 receptors,...
There is a propensity for synthetic cannabinoid abuse to spread worldwide. CP-55,940, a synthetic cannabinoid having the ability to activate both CB1 and CB2 receptors, has been shown to induce cell death in neurons as well as other cells. Here we investigate molecular events underling the adverse effects of CP-55,940 on neuronal cells. Exposure of mouse neuroblastoma Neuro2a cells to 10-50µM CP-55,940 results in concentration-dependent cell death that is not accompanied by an induction of apoptosis. CP-55,940 also stimulates autophagy, but the stimulation is not followed by an increase in autophagic degradation. Transcriptome analysis using DNA microarray revealed the increased expression of genes for the cholesterol biosynthesis pathway that is associated with the activation of SREBP-2, the master transcriptional regulator of cholesterol biosynthesis. However, free cholesterol is localized mainly to cytoplasmic structures, although it is localized to the plasma membrane in healthy cells. Thus, cellular trafficking of cholesterol seems to be somewhat disrupted in CP-55,940 stimulated cells. These results show for the first time that CP-55,940 stimulates autophagy as well as cholesterol biosynthesis, although not all the processes involved in the cellular response to CP-55,940 seem to be complete in these cells.
PubMed: 38942151
DOI: 10.1016/j.neuro.2024.06.013 -
Antiviral Research Jun 2024The SARS-CoV-2 Spike glycoprotein (S) utilizes a unique trimeric conformation to interact with the ACE2 receptor on host cells, making it a prime target for inhibitors...
The SARS-CoV-2 Spike glycoprotein (S) utilizes a unique trimeric conformation to interact with the ACE2 receptor on host cells, making it a prime target for inhibitors that block viral entry. We have previously identified a novel proteinaceous cavity within the Spike protein homotrimer that could serve as a binding site for small molecules. However, it is not known whether these molecules would inhibit, stimulate, or have no effect on viral replication. To address this, we employed structural-based screening to identify small molecules that dock into the trimer cavity and assessed their impact on viral replication. Our findings show that a cohort of identified small molecules binding to the Spike trimer cavity effectively reduces the replication of various SARS-CoV-2 variants. These molecules exhibited inhibitory effects on B.1 (European original, D614G, EDB2) and B.1.617.2 (δ) variants, while showing moderate activity against the B.1.1.7 (α) variant. We further categorized these molecules into distinct groups based on their structural similarities. Our experiments demonstrated a dose-dependent viral replication inhibitory activity of these compounds, with some, like BCC0040453 exhibiting no adverse effects on cell viability even at high concentrations. Further investigation revealed that pre-incubating virions with compounds like BCC0031216 at different temperatures significantly inhibited viral replication, suggesting their specificity towards the S protein. Overall, our study highlights the inhibitory impact of a diverse set of chemical molecules on the biological activity of the Spike protein. These findings provide valuable insights into the role of the trimer cavity in the viral replication cycle and aid drug discovery programs aimed at targeting the coronavirus family.
PubMed: 38942150
DOI: 10.1016/j.antiviral.2024.105949 -
Cancer Letters Jun 2024Aberrant expression of G protein-coupled receptor class C group 5 member A (GPRC5A) has been reported in multiple cancers and is closely related to patient prognosis....
Aberrant expression of G protein-coupled receptor class C group 5 member A (GPRC5A) has been reported in multiple cancers and is closely related to patient prognosis. However, the mechanistic role of GPRC5A in gallbladder cancer (GBC) remains unclear. Here, we determined tumor expression levels of GPRC5A and the molecular mechanisms by which GPRC5A regulates gallbladder cancer metastasis. We found that GPRC5A was significantly upregulated in GBC, correlating with poorer patient survival. Knocking down GPRC5A inhibited GBC cell metastasis both in vitro and in vivo. GRPRC5A knockdown resulted in downregulation of TNS4 expression through the JAK2-STAT3 axis. Clinically, GPRC5A expression positively correlated with TNS4. Finally, STAT3 bound to TNS4's promoter region, inducing its expression. Overall, GPRC5A showed high expression in GBC tissues, associated with poor patient prognosis. Our findings first demonstrate that the GPRC5A-JAK2-STAT3-TNS4 pathway promotes GBC cell metastasis, suggesting potential therapy targets.
PubMed: 38942137
DOI: 10.1016/j.canlet.2024.217067 -
Journal of Microbiological Methods Jun 2024Sepsis is a major health concern globally, and identification of the causative organism usually takes several days. Furthermore, molecular amplification using whole...
Sepsis is a major health concern globally, and identification of the causative organism usually takes several days. Furthermore, molecular amplification using whole blood from patients with sepsis remains challenging because of primer cross-reactivity with human DNA, which can delay appropriate clinical intervention. To address these concerns, we designed primers that could reduce cross-reactivity. By evaluating these primers against human DNA, we confirmed that the cross-reactivity observed with conventional primers was notably absent. In silico PCR further demonstrated the specificity and efficiency of the designed primers across 23 bacterial species that are often associated with sepsis. When tested using blood samples from sepsis patients, the designed primers showed moderate sensitivity and high specificity. Surprisingly, our method identified bacteria even in samples that were detected at other sites but tested negative using conventional blood culture methods. Although we identified some challenges, such as contamination with Acetobacter aceti due to the saponin pretreatment of samples, the developed method demonstrates remarkable potential for rapid identification of the causative organisms of sepsis and provides a new avenue for diagnosis in clinical practice.
PubMed: 38942122
DOI: 10.1016/j.mimet.2024.106982 -
Free Radical Biology & Medicine Jun 2024Aerobic glycolysis has been recognized as a hallmark of human cancer. G protein pathway suppressor 2 (GPS2) is a negative regulator of the G protein-MAPK pathway and a...
Aerobic glycolysis has been recognized as a hallmark of human cancer. G protein pathway suppressor 2 (GPS2) is a negative regulator of the G protein-MAPK pathway and a core subunit of the NCoR/SMRT transcriptional co-repressor complex. However, how its biological properties intersect with cellular metabolism in breast cancer (BC) development remains poorly elucidated. Here, we report that GPS2 is low expressed in BC tissues and negatively correlated with poor prognosis. Both in vitro and in vivo studies demonstrate that GPS2 suppresses malignant progression of BC. Moreover, GPS2 suppresses aerobic glycolysis in BC cells. Mechanistically, GPS2 destabilizes HIF-1α to reduce the transcription of its downstream glycolytic regulators (PGK1, PGAM1, ENO1, PKM2, LDHA, PDK1, PDK2, and PDK4), and then suppresses cellular aerobic glycolysis. Notably, receptor for activated C kinase 1 (RACK1) is identified as a key ubiquitin ligase for GPS2 to promote HIF-1α degradation. GPS2 stabilizes the binding of HIF-1α to RACK1 by directly binding to RACK1, resulting in polyubiquitination and instability of HIF-1α. Furthermore, amino acid residues 70-92 aa of the GPS2 N-terminus bind RACK1. A 23-amino-acid-long GPS2-derived peptide was developed based on this N-terminal region, which promotes the interaction of RACK1 with HIF-1α, downregulates HIF-1α expression and significantly suppresses BC tumorigenesis in vitro and in vivo. In conclusion, our findings indicate that GPS2 decreases the stability of HIF-1α, which in turn suppresses aerobic glycolysis and tumorigenesis in BC, suggesting that targeting HIF-1α degradation and treating with peptides may be a promising approach to treat BC.
PubMed: 38942092
DOI: 10.1016/j.freeradbiomed.2024.06.021 -
Behavioural Brain Research Jun 2024The central route of streptozotocin (STZ) administration has been introduced as a rat model of sporadic Alzheimer's disease (AD). Curcumin was suggested to possess...
The central route of streptozotocin (STZ) administration has been introduced as a rat model of sporadic Alzheimer's disease (AD). Curcumin was suggested to possess possible neuroprotective effects, which may be profitable in AD. However, the low bioavailability of curcumin hinders its beneficial effects in clinical studies. Earlier studies suggested that a bovine serum albumin-based nanocurcumin, produces superior neuroprotective effects compared to natural curcumin. In the present study, the protective effect of nanocurcumin in rat model of central STZ induced memory impairment was assessed. In addition, due to the importance of the hippocampus in memory, the amounts of hippocampal active caspase-3, Akt, and CaMKII-α were evaluated. Adult male Wistar rats weighing 250-300g were used. STZ (icv) was injected during days 1 and 3 (3mg/kg in divided), and nanocurcumin or curcumin 50mg/kg/oral gavage was administered daily during days 4-14. Morris water maze training was performed on days 15-17, and the retention memory test was achieved on the 18th day. Following memory assessment, the rats were sacrificed and the hippocampi were used to assess caspase-3 cleavage, Akt, and CaMKII-α signaling. The findings revealed that nanocurcumin ingestion (but not natural curcumin) in the dose of 50mg/kg was capable to prevent the impairment of water maze learning and memory induced by central STZ. Molecular assessments indicated that STZ treatment increased the caspase-3 cleavage in the hippocampus while deactivating Akt and CaMKII-α. Nanocurcumin reduced caspase-3 cleavage to a non-significant level compared to control group and restored Akt and CaMKII-α within the hippocampus while natural curcumin exerted no significant effect. These findings might suggest that nanocurcumin can restore memory deficit, hippocampal apoptosis as well as Akt and CaMKII-α signaling disruption associated with brain insulin resistance.
PubMed: 38942084
DOI: 10.1016/j.bbr.2024.115129