Elucidating Potential Profibrotic Mechanisms of Emerging Biomarkers for Early Prognosis of Hepatic Fibrosis

Hepatic fibrosis has been associated with a series of pathophysiological processes causing excessive accumulation of extracellular matrix proteins. Several cellular processes and molecular mechanisms have been implicated in the diseased liver that augments fibrogenesis, fibrogenic cytokines and associated liver complications. Liver biopsy remains an essential diagnostic tool for histological evaluation of hepatic fibrosis to establish a prognosis. In addition to being invasive, this methodology presents with several limitations including poor cost-effectiveness, prolonged hospitalizations, and risks of peritoneal bleeding, while the clinical use of this method does not reveal underlying pathogenic mechanisms. Several alternate noninvasive diagnostic strategies have been developed, to determine the extent of hepatic fibrosis, including the use of direct and indirect biomarkers. Immediate diagnosis of hepatic fibrosis by noninvasive means would be more palatable than a biopsy and could assist clinicians in taking early interventions timely, avoiding fatal complications, and improving prognosis. Therefore, we sought to review some common biomarkers of liver fibrosis along with some emerging candidates, including the oxidative stress-mediated biomarkers, epigenetic and genetic markers, exosomes, and miRNAs that needs further evaluation and would have better sensitivity and specificity. We also aim to elucidate the potential role of cardiotonic steroids (CTS) and evaluate the pro-inflammatory and profibrotic effects of CTS in exacerbating hepatic fibrosis. By understanding the underlying pathogenic processes, the efficacy of these biomarkers could allow for early diagnosis and treatment of hepatic fibrosis in chronic liver diseases, once validated.

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Adhesion Receptors in Health and Disease

Critical Reviews in Oral Biology & Medicine ◽

10.1177/10454411990100030601 ◽

1999 ◽

Vol 10 (3) ◽

pp. 337-358 ◽

Cited By ~ 23

Author(s):

A.I. Rojas ◽

A.R. Ahmed

Keyword(s):

Cell Adhesion ◽

Potential Role ◽

Therapeutic Agents ◽

Global Perspective ◽

Matrix Proteins ◽

Immunoglobulin Superfamily ◽

Cell Binding ◽

Cellular Processes ◽

Health And Disease

Cell adhesion molecules have been recognized to play a major role in a variety of physiological and pathological phenomena. They determine the specificity of cell-cell binding and the interactions between cells and extracellular matrix proteins Some of them may also function as receptors that trigger intracellular pathways and participate in cellular processes like migration, proliferation, differentiation, and cell death. The receptors that mediate adhesion between epithelial cells that are discussed in this review include integrins, selectins, the immunoglobulin superfamily members, and cadherins. The intent of this review is to inform the reader about recent advances in cellular and molecular functions of certain receptors specifically those that are considered important in cell adhesion. We have deliberately not provided all-inclusive detailed information on every molecule, but instead, have presented a generalized overview in order to give the reader a global perspective. This information will be useful in enhancing the reader's understanding of the molecular pathology of diseases and recognizing the potential role of these receptors and ligands as therapeutic agents.

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E6 and E7 oncoproteins: Potential targets of cervical cancer

Current Medicinal Chemistry ◽

10.2174/0929867327666201111145546 ◽

2020 ◽

Vol 27 ◽

Author(s):

Ramarao Malla ◽

Mohammad Amjad Kamal

Keyword(s):

Cervical Cancer ◽

Drug Resistance ◽

Host Cell ◽

Molecular Mechanisms ◽

Immune Therapy ◽

Cervical Lesions ◽

Diagnostic Strategies ◽

E6 And E7 Oncoproteins ◽

E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

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Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

Journal of Personalized Medicine ◽

10.3390/jpm11060513 ◽

2021 ◽

Vol 11 (6) ◽

pp. 513

Author(s):

Zheng Zhang ◽

Meng Gu ◽

Zhongze Gu ◽

Yan-Ru Lou

Keyword(s):

Molecular Mechanisms ◽

Neurological Diseases ◽

Cellular Processes ◽

Dna And Rna ◽

Chemotherapeutic Response ◽

Non Coding Rna ◽

Response To Chemotherapy ◽

Personalized Oncology ◽

Long Non Coding Rna

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments.

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Structure, Function, Involvement in Diseases and Targeting of 14-3-3 Proteins: An Update

Current Medicinal Chemistry ◽

10.2174/0929867324666170426095015 ◽

2018 ◽

Vol 25 (1) ◽

pp. 5-21 ◽

Cited By ~ 25

Author(s):

Ylenia Cau ◽

Daniela Valensin ◽

Mattia Mori ◽

Sara Draghi ◽

Maurizio Botta

Keyword(s):

Protein Interactions ◽

Molecular Mechanisms ◽

Physiological Role ◽

Specific Protein ◽

Protein Protein Interactions ◽

Cellular Processes ◽

Protein Partners ◽

High Sequence Homology ◽

Small Molecule Modulators

14-3-3 is a class of proteins able to interact with a multitude of targets by establishing protein-protein interactions (PPIs). They are usually found in all eukaryotes with a conserved secondary structure and high sequence homology among species. 14-3-3 proteins are involved in many physiological and pathological cellular processes either by triggering or interfering with the activity of specific protein partners. In the last years, the scientific community has collected many evidences on the role played by seven human 14-3-3 isoforms in cancer or neurodegenerative diseases. Indeed, these proteins regulate the molecular mechanisms associated to these diseases by interacting with (i) oncogenic and (ii) pro-apoptotic proteins and (iii) with proteins involved in Parkinson and Alzheimer diseases. The discovery of small molecule modulators of 14-3-3 PPIs could facilitate complete understanding of the physiological role of these proteins, and might offer valuable therapeutic approaches for these critical pathological states.

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Autophagy is activated in the ovarian tissue of polycystic ovary syndrome

Reproduction ◽

10.1530/rep-17-0499 ◽

2018 ◽

Vol 155 (1) ◽

pp. 85-92 ◽

Cited By ~ 16

Author(s):

Da Li ◽

Yue You ◽

Fang-Fang Bi ◽

Tie-Ning Zhang ◽

Jiao Jiao ◽

...

Keyword(s):

Polycystic Ovary Syndrome ◽

Potential Role ◽

Polycystic Ovary ◽

Ovarian Tissue ◽

Ovary Syndrome ◽

Cellular Processes ◽

Transmission Electron ◽

Wide Range ◽

Response To Stress

The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1, TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.

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Clinical Importance of Wnt5a in the Pathogenesis of Colorectal Cancer

Journal of Oncology ◽

10.1155/2021/3136508 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Mehran Pashirzad ◽

Thozhukat Sathyapalan ◽

Amirhossein Sahebkar

Keyword(s):

Colorectal Cancer ◽

Molecular Mechanisms ◽

Potential Role ◽

Clinical Importance ◽

Signaling Cascades ◽

Cancer Type ◽

Invasion And Metastasis ◽

Cellular Processes ◽

Wnt5a Expression ◽

Noncanonical Signaling

Wnt5a is one of the potent signaling molecules that initiates responses involved in cancer through activation of both canonical and noncanonical signaling cascades. Wnt5a both directly and indirectly triggers cancer-associated signaling pathways based on the cancer type. In colorectal cancer (CRC), altering Wnt5a expression can influence several cellular processes of tumor cells, including proliferation, differentiation, migration, invasion, and metastasis. This review summarizes the molecular mechanisms and clinical importance of Wnt5a in the pathogenesis of CRC for better understanding the pathogenesis and its potential role as a prognostic marker and as an appropriate therapeutic target in the treatment of this disease in the future.

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Neuroinflammation and Its Impact on the Pathogenesis of COVID-19

Frontiers in Medicine ◽

10.3389/fmed.2021.745789 ◽

2021 ◽

Vol 8 ◽

Author(s):

Mohammed M. Almutairi ◽

Farzane Sivandzade ◽

Thamer H. Albekairi ◽

Faleh Alqahtani ◽

Luca Cucullo

Keyword(s):

Immune System ◽

Molecular Mechanisms ◽

Potential Role ◽

Immune Cell ◽

Clinical Manifestations ◽

Cell Infiltration ◽

Cellular Mechanisms ◽

Cytokine Levels

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The clinical manifestations of COVID-19 include dry cough, difficult breathing, fever, fatigue, and may lead to pneumonia and respiratory failure. There are significant gaps in the current understanding of whether SARS-CoV-2 attacks the CNS directly or through activation of the peripheral immune system and immune cell infiltration. Although the modality of neurological impairments associated with COVID-19 has not been thoroughly investigated, the latest studies have observed that SARS-CoV-2 induces neuroinflammation and may have severe long-term consequences. Here we review the literature on possible cellular and molecular mechanisms of SARS-CoV-2 induced-neuroinflammation. Activation of the innate immune system is associated with increased cytokine levels, chemokines, and free radicals in the SARS-CoV-2-induced pathogenic response at the blood-brain barrier (BBB). BBB disruption allows immune/inflammatory cell infiltration into the CNS activating immune resident cells (such as microglia and astrocytes). This review highlights the molecular and cellular mechanisms involved in COVID-19-induced neuroinflammation, which may lead to neuronal death. A better understanding of these mechanisms will help gain substantial knowledge about the potential role of SARS-CoV-2 in neurological changes and plan possible therapeutic intervention strategies.

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Potential role of viral infections in miscarriage and insights into the underlying molecular mechanisms

Congenital Anomalies ◽

10.1111/cga.12458 ◽

2021 ◽

Author(s):

Zahra Heydarifard ◽

Sevrin Zadheidar ◽

Jila Yavarian ◽

Somayeh Shatizadeh Malekshahi ◽

Shirin Kalantari ◽

...

Keyword(s):

Molecular Mechanisms ◽

Potential Role ◽

Viral Infections

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Functional Interactomes of Genes Showing Association with Type-2 Diabetes and Its Intermediate Phenotypic Traits Point towards Adipo-Centric Mechanisms in Its Pathophysiology

Biomolecules ◽

10.3390/biom10040601 ◽

2020 ◽

Vol 10 (4) ◽

pp. 601

Author(s):

Aditya Saxena ◽

Nitin Wahi ◽

Anshul Kumar ◽

Sandeep Kumar Mathur

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Network Analysis ◽

Potential Role ◽

Phenotypic Traits ◽

Protein Protein Interaction ◽

Cellular Processes ◽

Antidiabetic Treatment

The pathogenic mechanisms causing type 2 diabetes (T2D) are still poorly understood; a greater awareness of its causation can lead to the development of newer and better antidiabetic drugs. In this study, we used a network-based approach to assess the cellular processes associated with protein–protein interaction subnetworks of glycemic traits—HOMA-β and HOMA-IR. Their subnetworks were further analyzed in terms of their overlap with the differentially expressed genes (DEGs) in pancreatic, muscle, and adipose tissue in diabetics. We found several DEGs in these tissues showing an overlap with the HOMA-β subnetwork, suggesting a role of these tissues in β-cell failure. Many genes in the HOMA-IR subnetwork too showed an overlap with the HOMA-β subnetwork. For understanding the functional theme of these subnetworks, a pathway-to-pathway complementary network analysis was done, which identified various adipose biology-related pathways, containing genes involved in both insulin secretion and action. In conclusion, network analysis of genes showing an association between T2D and its intermediate phenotypic traits suggests their potential role in beta cell failure. These genes enriched the adipo-centric pathways and were expressed in both pancreatic and adipose tissue and, therefore, might be one of the potential targets for future antidiabetic treatment.

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Natural Sulfur-Containing Compounds: An Alternative Therapeutic Strategy against Liver Fibrosis

Cells ◽

10.3390/cells8111356 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1356 ◽

Cited By ~ 13

Author(s):

Milito ◽

Brancaccio ◽

D’Argenio ◽

Castellano

Keyword(s):

Extracellular Matrix ◽

Growth Factor ◽

Liver Fibrosis ◽

Hepatic Fibrosis ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Sulfur Containing ◽

Sulfur Containing Compounds

Liver fibrosis is a pathophysiologic process involving the accumulation of extracellular matrix proteins as collagen deposition. Advanced liver fibrosis can evolve in cirrhosis, portal hypertension and often requires liver transplantation. At the cellular level, hepatic fibrosis involves the activation of hepatic stellate cells and their transdifferentiation into myofibroblasts. Numerous pro-fibrogenic mediators including the transforming growth factor-β1, the platelet-derived growth factor, endothelin-1, toll-like receptor 4, and reactive oxygen species are key players in this process. Knowledge of the cellular and molecular mechanisms underlying hepatic fibrosis development need to be extended to find novel therapeutic strategies. Antifibrotic therapies aim to inhibit the accumulation of fibrogenic cells and/or prevent the deposition of extracellular matrix proteins. Natural products from terrestrial and marine sources, including sulfur-containing compounds, exhibit promising activities for the treatment of fibrotic pathology. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans are largely unknown. This review aims to provide a reference collection on experimentally tested natural anti-fibrotic compounds, with particular attention on sulfur-containing molecules. Their chemical structure, sources, mode of action, molecular targets, and pharmacological activity in the treatment of liver disease will be discussed.

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