Neurodegeneration in the Pathogenesis of Diabetic Retinopathy: Molecular Mechanisms and Therapeutic Implications

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽

10.3390/cells10061548 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1548

Author(s):

Mustafa N. Mithaiwala ◽

Danielle Santana-Coelho ◽

Grace A. Porter ◽

Jason C. O’Connor

Keyword(s):

Molecular Mechanisms ◽

Treatment Options ◽

Treatment Strategies ◽

Kynurenine Pathway ◽

Economic Problem ◽

Cns Disease ◽

Therapeutic Implications ◽

Efficacious Treatment ◽

The Central Nervous System ◽

Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

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Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00454-7 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Yuefei Jin ◽

Wangquan Ji ◽

Haiyan Yang ◽

Shuaiyin Chen ◽

Weiguo Zhang ◽

...

Keyword(s):

Molecular Mechanisms ◽

Endothelial Activation ◽

World Health ◽

Therapeutic Approaches ◽

Inflammatory Reactions ◽

Angiotensin Converting Enzyme 2 ◽

Therapeutic Implications ◽

Endothelial Inflammation ◽

The World ◽

Health Organization

AbstractOn 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

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Network pharmacology and molecular docking study on the active ingredients of qidengmingmu capsule for the treatment of diabetic retinopathy

Scientific Reports ◽

10.1038/s41598-021-86914-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mingxu Zhang ◽

Jiawei Yang ◽

Xiulan Zhao ◽

Ying Zhao ◽

Siquan Zhu

Keyword(s):

Diabetic Retinopathy ◽

Molecular Docking ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Enrichment Analysis ◽

Docking Study ◽

Network Pharmacology ◽

Biological Processes ◽

Active Ingredients ◽

Molecular Docking Study

AbstractDiabetic retinopathy (DR) is a leading cause of irreversible blindness globally. Qidengmingmu Capsule (QC) is a Chinese patent medicine used to treat DR, but the molecular mechanism of the treatment remains unknown. In this study, we identified and validated potential molecular mechanisms involved in the treatment of DR with QC via network pharmacology and molecular docking methods. The results of Ingredient-DR Target Network showed that 134 common targets and 20 active ingredients of QC were involved. According to the results of enrichment analysis, 2307 biological processes and 40 pathways were related to the treatment effects. Most of these processes and pathways were important for cell survival and were associated with many key factors in DR, such as vascular endothelial growth factor-A (VEGFA), hypoxia-inducible factor-1A (HIF-1Α), and tumor necrosis factor-α (TNFα). Based on the results of the PPI network and KEGG enrichment analyses, we selected AKT1, HIF-1α, VEGFA, TNFα and their corresponding active ingredients for molecular docking. According to the molecular docking results, several key targets of DR (including AKT1, HIF-1α, VEGFA, and TNFα) can form stable bonds with the corresponding active ingredients of QC. In conclusion, through network pharmacology methods, we found that potential biological mechanisms involved in the alleviation of DR by QC are related to multiple biological processes and signaling pathways. The molecular docking results also provide us with sound directions for further experiments.

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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Cancers ◽

10.3390/cancers13184550 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4550

Author(s):

Laura Gramantieri ◽

Catia Giovannini ◽

Fabrizia Suzzi ◽

Ilaria Leoni ◽

Francesca Fornari

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Anticancer Agents ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Driving Forces ◽

Predictive Biomarkers ◽

Molecular Classification ◽

Circulating Biomarkers ◽

Therapeutic Implications

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.

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Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

eLife ◽

10.7554/elife.68039 ◽

2021 ◽

Vol 10 ◽

Author(s):

Jenny I Aguilar ◽

Mary Hongying Cheng ◽

Josep Font ◽

Alexandra C Schwartz ◽

Kaitlyn Ledwitch ◽

...

Keyword(s):

High Speed ◽

Molecular Mechanisms ◽

Motor Coordination ◽

Neurodegenerative Disorder ◽

Expression System ◽

Distinct Type ◽

Underlying Disease ◽

Deficiency Syndrome ◽

Motor Deficits ◽

Therapeutic Implications

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

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Molecular mechanisms and therapeutic implications of the carbon monoxide/hmox1 and the hydrogen sulfide/CSE pathways in the prevention of pre-eclampsia and fetal growth restriction

Pregnancy Hypertension ◽

10.1016/j.preghy.2014.04.013 ◽

2014 ◽

Vol 4 (3) ◽

pp. 243-244 ◽

Cited By ~ 12

Author(s):

Asif Ahmed

Keyword(s):

Carbon Monoxide ◽

Hydrogen Sulfide ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Molecular Mechanisms ◽

Growth Restriction ◽

Therapeutic Implications

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Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Medicines ◽

10.3390/medicines6030082 ◽

2019 ◽

Vol 6 (3) ◽

pp. 82 ◽

Cited By ~ 12

Author(s):

Ugo Testa ◽

Germana Castelli ◽

Elvira Pelosi

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Intraepithelial Neoplasia ◽

Cancer Development ◽

Initial Development ◽

Therapeutic Implications ◽

Cancer Pathways ◽

Signaling Axis ◽

Prostate Cancer Development ◽

Prostate Cancers

Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2019-00980 ◽

2019 ◽

Vol 104 (11) ◽

pp. 5431-5444 ◽

Cited By ~ 9

Author(s):

Gian Paolo Fadini ◽

Mattia Albiero ◽

Benedetta Maria Bonora ◽

Angelo Avogaro

Keyword(s):

English Language ◽

Molecular Mechanisms ◽

Evidence Synthesis ◽

Clinical Manifestations ◽

Vascular Complications ◽

Peripheral Circulation ◽

Clinical Aspects ◽

Therapeutic Implications ◽

Diabetes Onset ◽

Increased Risk

Abstract Context Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. Evidence Acquisition The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. Evidence Synthesis Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in abnormal angiogenesis can explain the well-known association between microangiopathy and macroangiopathy. Impaired angiogenesis can also affect endocrine islet and adipose tissue function, providing a link to diabetes onset. Exposure to high glucose itself directly affects angiogenic/vasculogenic processes, and the mechanisms include defective responses to hypoxia and proangiogenic factors, impaired nitric oxide bioavailability, shortage of proangiogenic cells, and loss of pericytes. Conclusions Dissecting the molecular drivers of tissue-specific alterations of angiogenesis/vasculogenesis is an important challenge to devise new therapeutic approaches. Angiogenesis-modulating therapies should be carefully evaluated in view of their potential off-target effects. At present, glycemic control remains the most reasonable therapeutic strategy to normalize angiogenesis in diabetes.

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