scholarly journals Molecular mechanisms of liver carcinogenesis related to metabolic syndrome

Author(s):  
Claudia Campani ◽  
Jean-Charles Nault

Global prevalence of non-alcoholic fatty liver disease (NAFLD) and of NAFLD-hepatocellular carcinoma (HCC) is estimated to grow in the next years. The burden of NAFLD and the evidence that NAFLD-HCC arises also in non-cirrhotic patients, explain the urgent need of a better characterization of the molecular mechanisms involved in NAFLD progression. Obesity and diabetes cause a chronic inflammatory state which favors changes in serum cytokines and adipokines, an increase in oxidative stress, DNA damage, and the activation of multiple signaling pathways involved in cell proliferation. Moreover, a role in promoting NAFLD-HCC has been highlighted in the innate and adaptive immune system, dysbiosis, and alterations in bile acids metabolism. Several dietary, genetic, or combined mouse models have been used to study nonalcoholic steatohepatitis (NASH) development and its progression to HCC, but models that fully recapitulate the biological and prognostic features of human NASH are still lacking. In humans, four single nucleotide polymorphisms (PNPLA3, TM6SF2, GCKR, and MBOAT7) have been linked to the development of both NASH and HCC in cirrhotic and non-cirrhotic patients, whereas HSD17B13 polymorphism has a protective effect. In addition, higher rates of somatic ACVR2A mutations and a novel mutational signature have been recently discovered in NASH-HCC patients. The knowledge of the molecular pathogenesis of NAFLD-HCC will be helpful to personalized screening programs and allow for primary and secondary chemopreventive treatments for NAFLD patients who are more likely to progress to HCC.

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.


2021 ◽  
Author(s):  
Zhilin Yuan ◽  
Irina S. Druzhinina ◽  
John G. Gibbons ◽  
Zhenhui Zhong ◽  
Yves Van de Peer ◽  
...  

AbstractUnderstanding how organisms adapt to extreme living conditions is central to evolutionary biology. Dark septate endophytes (DSEs) constitute an important component of the root mycobiome and they are often able to alleviate host abiotic stresses. Here, we investigated the molecular mechanisms underlying the beneficial association between the DSE Laburnicola rhizohalophila and its host, the native halophyte Suaeda salsa, using population genomics. Based on genome-wide Fst (pairwise fixation index) and Vst analyses, which compared the variance in allele frequencies of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs), respectively, we found a high level of genetic differentiation between two populations. CNV patterns revealed population-specific expansions and contractions. Interestingly, we identified a ~20 kbp genomic island of high divergence with a strong sign of positive selection. This region contains a melanin-biosynthetic polyketide synthase gene cluster linked to six additional genes likely involved in biosynthesis, membrane trafficking, regulation, and localization of melanin. Differences in growth yield and melanin biosynthesis between the two populations grown under 2% NaCl stress suggested that this genomic island contributes to the observed differences in melanin accumulation. Our findings provide a better understanding of the genetic and evolutionary mechanisms underlying the adaptation to saline conditions of the L. rhizohalophila–S. salsa symbiosis.


2021 ◽  
Vol 24 (4) ◽  
pp. 120
Author(s):  
T.S. Sall ◽  
E.S. Shcherbakova ◽  
S.I. Sitkin ◽  
T.Ya. Vakhitov ◽  
I.G. Bakulin ◽  
...  

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3055
Author(s):  
Megan A. Opichka ◽  
Matthew W. Rappelt ◽  
David D. Gutterman ◽  
Justin L. Grobe ◽  
Jennifer J. McIntosh

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.


Author(s):  
Oliver Selmoni ◽  
Gaël Lecellier ◽  
Hélène Magalon ◽  
Laurent Vigliola ◽  
Francesca Benzoni ◽  
...  

AbstractAnomalous heat waves are causing a major decline of hard corals around the world and threatening the persistence of coral reefs. There are, however, reefs that had been exposed to recurrent thermal stress over the years and whose corals appeared tolerant against heat. One of the mechanisms that could explain this phenomenon is local adaptation, but the underlying molecular mechanisms are poorly known.In this work, we applied a seascape genomics approach to study heat stress adaptation in three coral species of New Caledonia (southwestern Pacific) and to uncover molecular actors potentially involved. We used remote sensing data to characterize the environmental trends across the reef system, and sampled corals living at the most contrasted sites. These samples underwent next generation sequencing to reveal single-nucleotide-polymorphisms (SNPs) of which frequencies associated with heat stress gradients. As these SNPs might underpin an adaptive role, we characterized the functional roles of the genes located in their genomic neighborhood.In each of the studied species, we found heat stress associated SNPs notably located in proximity of genes coding for well-established actors of the cellular responses against heat. Among these, we can mention proteins involved in DNA damage-repair, protein folding, oxidative stress homeostasis, inflammatory and apoptotic pathways. In some cases, the same putative molecular targets of heat stress adaptation recurred among species.Together, these results underscore the relevance and the power of the seascape genomics approach for the discovery of adaptive traits that could allow corals to persist across wider thermal ranges.


Author(s):  
Samar F. Miski ◽  
Mai A. Alim A. Sattar Ahmad ◽  
Ahmed Esmat

Aim: To determine the potential hepatoprotective effect of Agmatine (AGM) on NAFLD-induced by Type 2 diabetes mellitus (T2DM) in rats. Study design:  Forty male Wistar rats weighing from (200 -250 g) were distributed at random into five groups (8 rats per group): group 1 as control; group 2 as untreated-T2DM; groups 3 & 4 as T2DM cotreated with AGM (40 & 80 mg/kg/d), while group 5 T2DM cotreated with Silymarin (100 mg/kg/d). Place and duration of study: Department of Pharmacology, Faculty of Medicine, king Abdul-Aziz University; between October 2020 and January 2021. Methodology: A rat model of T2DM with NAFLD complication was established by feeding rats with 10% fructose in drinking water and intraperitoneally injecting them with a single low dose of streptozotocin (STZ) (45mg/kg). The fasting blood glucose was detected, serum levels of hepatic biomarkers were all assessed. Moreover, histopathological examination was performed by hematoxylin and eosin (H&E) staining. Results: STZ induced T2DM in rats causes a significant (p<0.05, n=8) rise in serum levels of FBG, ALT, AST, TB, TC, TG, and LDL in comparison with the corresponding control group. Co-treatment with AGM (40 & 80 mg/kg) and silymarin significantly alleviated hyperglycemia and amended hepatic biomarkers that was reflected on improved histopathological changes. Conclusion: The current data suggest that oral AGM co-treatment could have a hepatoprotective effect against T2DM associated with NAFLD in rats. Further investigations are recommended to elucidate molecular mechanisms accountable for the useful effects of AGM on hepatocytes.


2019 ◽  
Author(s):  
Hongzhu Cui ◽  
Suhas Srinivasan ◽  
Dmitry Korkin

AbstractProgress in high-throughput -omics technologies moves us one step closer to the datacalypse in life sciences. In spite of the already generated volumes of data, our knowledge of the molecular mechanisms underlying complex genetic diseases remains limited. Increasing evidence shows that biological networks are essential, albeit not sufficient, for the better understanding of these mechanisms. The identification of disease-specific functional modules in the human interactome can provide a more focused insight into the mechanistic nature of the disease. However, carving a disease network module from the whole interactome is a difficult task. In this paper, we propose a computational framework, DIMSUM, which enables the integration of genome-wide association studies (GWAS), functional effects of mutations, and protein-protein interaction (PPI) network to improve disease module detection. Specifically, our approach incorporates and propagates the functional impact of non-synonymous single nucleotide polymorphisms (nsSNPs) on PPIs to implicate the genes that are most likely influenced by the disruptive mutations, and to identify the module with the greatest impact. Comparison against state-of-the-art seed-based module detection methods shows that our approach could yield modules that are biologically more relevant and have stronger association with the studied disease. We expect for our method to become a part of the common toolbox for disease module analysis, facilitating discovery of new disease markers.


2021 ◽  
Vol 11 ◽  
Author(s):  
Joyce Bernardi ◽  
Kelly A. Aromolaran ◽  
Hua Zhu ◽  
Ademuyiwa S. Aromolaran

Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.


2008 ◽  
Vol 115 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Paola Loria ◽  
Amedeo Lonardo ◽  
Giovanni Targher

NAFLD (non-alcoholic fatty liver disease) encompasses the spectrum of fatty liver disease in insulin-resistant individuals who often display T2DM (Type 2 diabetes mellitus) and obesity. The present review highlights the pathophysiological basis and clinical evidence for a possible causal linkage between NAFLD and CVD (cardiovascular disease). The role of traditional and non-traditional CVD risk factors in the pathophysiology of NAFLD is considered in the first part of the review, with the basic science shared by atherogenesis and hepatic steatogenesis discussed in depth in the second part. In conclusion, NAFLD is not an innocent bystander, but a major player in the development and progression of CVD. NAFLD and CVD also share similar molecular mechanisms and targeted treatment strategies. On the research side, studies should focus on interventions aimed at restoring energy homoeostasis in lipotoxic tissues and at improving hepatic (micro)vascular blood supply.


Sign in / Sign up

Export Citation Format

Share Document