scholarly journals Preclinical and Clinical Studies of p38α MAP kinase inhibition to Treat Basal Forebrain Cholinergic Dysfunction and Degeneration

2021 ◽  
Author(s):  
John Alam ◽  
Ralph Nixon ◽  
Ying Jiang ◽  
Stephen Gomperts ◽  
Paul Maruff ◽  
...  
Keyword(s):  
Basal Forebrain ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Lewy Bodies ◽  
Cholinergic Neurons ◽  
Novel Approach ◽  
Primary Driver ◽  
Preclinical And Clinical Studies ◽  
Pathological Disease ◽  
P38α Kinase

Abstract The endosome-associated protein Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α kinase is a Rab-5 activator, we hypothesized that inhibition of this kinase held potential as an approach to treat diseases associated with BFCN loss. Herein we report that treatment with an oral small molecule p38α kinase inhibitor reversed pathological disease progression in the basal forebrain in a mouse model that develops BFCN degeneration. Further, the preclinical results were successfully translated to the clinic, with improvement of clinical outcomes associated with cholinergic function in a clinical study in dementia with Lewy bodies (DLB), a disease in which BFCN dysfunction and degeneration is the primary driver of disease expression. The findings both advances a novel approach to treating DLB and validates the translational platform that provided the mechanistic rationale for advancing that approach.

scholarly journals Targeting SRC Family Kinases in Mesothelioma: Time to Upgrade

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1866
Author(s):  
Paola Indovina ◽  
Iris Maria Forte ◽  
Francesca Pentimalli ◽  
Antonio Giordano
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Current Treatment ◽  
Src Family Kinases ◽  
Oncogenic Pathways ◽  
History Of ◽  
Cancer Types ◽  
Preclinical And Clinical Studies ◽  
Lost In Translation

Malignant mesothelioma (MM) is a deadly tumor mainly caused by exposure to asbestos. Unfortunately, no current treatment is able to change significantly the natural history of the disease, which has a poor prognosis in the majority of patients. The non-receptor tyrosine kinase SRC and other SRC family kinase (SFK) members are frequently hyperactivated in many cancer types, including MM. Several works have indeed suggested that SFKs underlie MM cell proliferation, survival, motility, and invasion, overall affecting multiple oncogenic pathways. Consistently, SFK inhibitors effectively counteracted MM cancerous features at the preclinical level. Dasatinib, a multi-kinase inhibitor targeting SFKs, was also assessed in clinical trials either as second-line treatment for patients with unresectable MM or, more recently, as a neoadjuvant agent in patients with resectable MM. Here, we provide an overview of the molecular mechanisms implicating SFKs in MM progression and discuss possible strategies for a more successful clinical application of SFK inhibitors. Our aim is to stimulate discussion and further consideration of these agents in better designed preclinical and clinical studies to make the most of another class of powerful antitumoral drugs, which too often are lost in translation when applied to MM.

Urtica dioica in the Management of Benign Prostate Hyperplasia (BPH)

2020 ◽  
Vol 10 (5) ◽  
pp. 535-542
Author(s):  
Mohaddese Mahboubi
Keyword(s):  
Molecular Mechanisms ◽  
Life Quality ◽  
Urtica Dioica ◽  
Urinary Flow ◽  
Prostate Hyperplasia ◽  
Long Time ◽  
Tract Infections ◽  
Preclinical And Clinical Studies ◽  
Benign Prostate ◽  
Maximum Urinary Flow

Background:: Benign Prostatic hyperplasia (BPH) is known as a disease prevalent in men after the age of 50 years old. Ninety percent of men with the age of 80 years and over have BPH. BPH is associated with functional problems like dysuria, nocturia, polyuria, urinary incontinence and recurrent urinary tract infections. Urtica dioica or nettle is a popular medicinal plant for management of BPH in men. Objective:: This article evaluates the efficacy and safety of nettle and its related possible mechanisms in the management of BPH. Methods:: For the preparation of this manuscript, all the information was gathered from accessible and inaccessible resources (Web, Books, Thesis, etc.). Results:: The results of preclinical and clinical studies confirmed the efficacy of nettle roots extracts (methanol, ethanol, and petroleum ether) in the improvement of BPH in term of IPSS score, and patient's life quality. An increase in mean and maximum urinary flow rates and a reduction in prostate volume and residual urine level were observed after treatment with nettle extract. Nettle roots should be used for 6-12 months as its use is possible for a long time without any serious adverse effects. Conclusion:: Designing the clinical trials to compare the efficacy of different extracts from roots or leaves and investigation of molecular mechanisms of action could be the approaches for future.

A Comprehensive Review on Pharmacology and Toxicology of Bioactive Compounds of Lagerstroemia Speciosa (L.) Pers.

2020 ◽  
Vol 06 ◽  
Author(s):  
Surya Kant Tripathi ◽  
Sunayna Behera ◽  
Munmun Panda ◽  
Gokhan Zengin ◽  
Bijesh K. Biswal
Keyword(s):  
Molecular Mechanisms ◽  
Biological Activities ◽  
Health Benefit ◽  
Biologically Active ◽  
Pharmacological Properties ◽  
Lagerstroemia Speciosa ◽  
Novel Drugs ◽  
Corosolic Acid ◽  
Current Article ◽  
Preclinical And Clinical Studies

Background: Lagerstroemia speciosa (L.) Pers is one of the most valuable plants due to its ornamental and pharmacological relevance. It is known for its anti-diabetic activity with proved potent blood sugar-lowering activity. The anti-diabetic activity is due to presence of its biologically active component corosolic acid. Moreover, L. speciosa and its novel purified compounds are also well-known for its several biological activities with beneficial health benefit on the human being. Objectives: This review provides a summary of pharmacokinetics, toxicity, and pharmacological properties of L. speciosa and its purified phytochemicals which may help researchers for building up new researches in near future. Methods: The current article is prepared by collecting through various online and offline databases. Preliminary source of study and data collection for outlining the review was research articles and reviews that have been already published by many reputed publishers, including Springer, Elsevier, Taylor & Francis imprints, BMC, Willy, The Norwegian Academy of Science and Letters, Environmental health prospective (EHP), and PLOS One. Result: The available studies results suggested that the L. speciosa and its phytochemicals showed antidiabetic, anticancer, anti-inflammatory, antimicrobial, antioxidant, antiviral, anti-obesity, and cardio-protective activities. Pharmacokinetic stud-ies suggested the low bioavailability of its purified compounds. However, nano-encapsulation can improve the bioavaila-bility related issue and effectively potentiate the medicinal properties of its constituents. Conclusion: Considering the worthy pharmacological properties, L. speciosa is considered as a potent source of several novel drugs. Though, still preclinical and clinical studies are needed to reveal the targets, molecular mechanisms, bioavail-ability, and toxicity of its constituents.

scholarly journals HSP90-dependent PUS7 overexpression facilitates the metastasis of colorectal cancer cells by regulating LASP1 abundance

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Dan Song ◽  
Ming Guo ◽  
Shuai Xu ◽  
Xiaotian Song ◽  
Bin Bai ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Intellectual Development ◽  
Molecular Mechanisms ◽  
Hsp90 Inhibitor ◽  
Pseudouridine Synthase ◽  
Novel Approach ◽  
Cell Metastasis ◽  
Underlying Mechanisms

Abstract Background Pseudouridine synthase (PUS) 7 is a member of the PUS family that catalyses pseudouridine formation. It has been shown to be involved in intellectual development and haematological malignancies. Nevertheless, the role and the underlying molecular mechanisms of PUS7 in solid tumours, such as colorectal cancer (CRC), remain unexplored. This study elucidated, for the first time, the role of PUS7 in CRC cell metastasis and the underlying mechanisms. Methods We conducted immunohistochemistry, qPCR, and western blotting to quantify the expression of PUS7 in CRC tissues as well as cell lines. Besides, diverse in vivo and in vitro functional tests were employed to establish the function of PUS7 in CRC. RNA-seq and proteome profiling analysis were also applied to identify the targets of PUS7. PUS7-interacting proteins were further uncovered using immunoprecipitation and mass spectrometry. Results Overexpression of PUS7 was observed in CRC tissues and was linked to advanced clinical stages and shorter overall survival. PUS7 silencing effectively repressed CRC cell metastasis, while its upregulation promoted metastasis, independently of the PUS7 catalytic activity. LASP1 was identified as a downstream effector of PUS7. Forced LASP1 expression abolished the metastasis suppression triggered by PUS7 silencing. Furthermore, HSP90 was identified as a client protein of PUS7, associated with the increased PUS7 abundance in CRC. NMS-E973, a specific HSP90 inhibitor, also showed higher anti-metastatic activity when combined with PUS7 repression. Importantly, in line with these results, in human CRC tissues, the expression of PUS7 was positively linked to the expression of HSP90 and LASP1, and patients co-expressing HSP90/PUS7/LASP1 showed a worse prognosis. Conclusions The HSP90-dependent PUS7 upregulation promotes CRC cell metastasis via the regulation of LASP1. Thus, targeting the HSP90/PUS7/LASP1 axis may be a novel approach for the treatment of CRC.

scholarly journals Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

2021 ◽  
Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Lewy Body ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Subsequent Development ◽  
Lewy Body Dementia ◽  
Anterior Cingulate ◽  
Lewy Body Diseases

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

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