ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL

AbstractUnderstanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight the therapeutic potential of targeting this axis to treat metastatic melanoma.

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Medicinal Plants and Bioactive Compounds for Diabetes Management: Important Advances for Drug Discovery

Current Pharmaceutical Design ◽

10.2174/1381612826666200928160357 ◽

2020 ◽

Vol 26 ◽

Author(s):

Kondeti Ramudu Shanmugam ◽

Bhasha Shanmugam ◽

Gangigunta Venkatasubbaiah ◽

Sahukari Ravi ◽

Kesireddy Sathyavelu Reddy

Keyword(s):

Herbal Medicine ◽

Medicinal Plants ◽

Bioactive Compounds ◽

Diabetes Management ◽

Therapeutic Potential ◽

Public Health Problem ◽

In Vivo Studies ◽

Major Public Health Problem

Background : Diabetes is a major public health problem in the world. It affects each and every part of the human body and also leads to organ failure. Hence, great progress made in the field of herbal medicine and diabetic research. Objectives: Our review will focus on the effect of bioactive compounds of medicinal plants which are used to treat diabetes in India and other countries. Methods: Information regarding diabetes, oxidative stress, medicinal plants and bioactive compounds were collected from different search engines like Science direct, Springer, Wiley online library, Taylor and francis, Bentham Science, Pubmed and Google scholar. Data was analyzed and summarized in the review. Results and Conclusion: Anti-diabetic drugs that are in use have many side effects on vital organs like heart, liver, kidney and brain. There is an urgent need for alternative medicine to treat diabetes and their disorders. In India and other countries herbal medicine was used to treat diabetes. Many herbal plants have antidiabetic effects. The plants like ginger, phyllanthus, curcumin, aswagandha, aloe, hibiscus and curcuma showed significant anti-hyperglycemic activities in experimental models and humans. The bioactive compounds like Allicin, azadirachtin, cajanin, curcumin, querceitin, gingerol possesses anti-diabetic, antioxidant and other pharmacological properties. This review focuses on the role of bioactive compounds of medicinal plants in prevention and management of diabetes. Conclusion: Moreover, our review suggests that bioactive compounds have the potential therapeutic potential against diabetes. However, further in vitro and in vivo studies are needed to validate these findings.

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ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02415-19 ◽

2020 ◽

Vol 64 (6) ◽

Cited By ~ 3

Author(s):

Ørjan Samuelsen ◽

Ove Alexander Høgmoen Åstrand ◽

Christopher Fröhlich ◽

Adam Heikal ◽

Susann Skagseth ◽

...

Keyword(s):

Active Site ◽

Therapeutic Potential ◽

Treatment Options ◽

Carbapenem Resistance ◽

Functional Space ◽

Bactericidal Effect ◽

Gram Negative ◽

Content Type

ABSTRACT Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound.

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Natural products with therapeutic potential in melanoma metastasis

Natural Product Reports ◽

10.1039/c4np00130c ◽

2015 ◽

Vol 32 (8) ◽

pp. 1170-1182 ◽

Cited By ~ 41

Author(s):

A. AlQathama ◽

J. M. Prieto

Keyword(s):

Natural Products ◽

Cancer Treatment ◽

Therapeutic Potential ◽

Melanoma Cells ◽

Mechanisms Of Action ◽

Melanoma Metastasis ◽

Pharmacological Effects ◽

Cytotoxic Compounds

Natural products continue to provide lead cytotoxic compounds for cancer treatment but less attention has been given to antimigratory compounds. We here systematically and critically survey more than 30 natural products with direct in vitro and in vivo pharmacological effects on migration and/or metastasis of melanoma cells and chart the mechanisms of action for this underexploited property.

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The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

Cells ◽

10.3390/cells10113088 ◽

2021 ◽

Vol 10 (11) ◽

pp. 3088

Author(s):

Mariana Matias ◽

Jacinta O. Pinho ◽

Maria João Penetra ◽

Gonçalo Campos ◽

Catarina Pinto Reis ◽

...

Keyword(s):

Therapeutic Potential ◽

Drug Evaluation ◽

Three Dimensional ◽

Experimental Models ◽

In Vivo Studies ◽

Murine Models ◽

In Vivo Experiments ◽

Novel Therapeutic Strategies

Melanoma is recognized as the most dangerous type of skin cancer, with high mortality and resistance to currently used treatments. To overcome the limitations of the available therapeutic options, the discovery and development of new, more effective, and safer therapies is required. In this review, the different research steps involved in the process of antimelanoma drug evaluation and selection are explored, including information regarding in silico, in vitro, and in vivo experiments, as well as clinical trial phases. Details are given about the most used cell lines and assays to perform both two- and three-dimensional in vitro screening of drug candidates towards melanoma. For in vivo studies, murine models are, undoubtedly, the most widely used for assessing the therapeutic potential of new compounds and to study the underlying mechanisms of action. Here, the main melanoma murine models are described as well as other animal species. A section is dedicated to ongoing clinical studies, demonstrating the wide interest and successful efforts devoted to melanoma therapy, in particular at advanced stages of the disease, and a final section includes some considerations regarding approval for marketing by regulatory agencies. Overall, considerable commitment is being directed to the continuous development of optimized experimental models, important for the understanding of melanoma biology and for the evaluation and validation of novel therapeutic strategies.

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Anti-Inflammatory Potential of Daturaolone from Datura innoxia Mill.: In Silico, In Vitro and In Vivo Studies

Pharmaceuticals ◽

10.3390/ph14121248 ◽

2021 ◽

Vol 14 (12) ◽

pp. 1248

Author(s):

Muhammad Waleed Baig ◽

Humaira Fatima ◽

Nosheen Akhtar ◽

Hidayat Hussain ◽

Mohammad K. Okla ◽

...

Keyword(s):

In Silico ◽

Therapeutic Potential ◽

In Vivo Studies ◽

Metabolic Reaction ◽

Datura Innoxia ◽

In Vivo Models ◽

Immobility Time ◽

Anti Inflammatory

Exploration of leads with therapeutic potential in inflammatory disorders is worth pursuing. In line with this, the isolated natural compound daturaolone from Datura innoxia Mill. was evaluated for its anti-inflammatory potential using in silico, in vitro and in vivo models. Daturaolone follows Lipinski’s drug-likeliness rule with a score of 0.33. Absorption, distribution, metabolism, excretion and toxicity prediction show strong plasma protein binding; gastrointestinal absorption (Caco-2 cells permeability = 34.6 nm/s); no blood–brain barrier penetration; CYP1A2, CYP2C19 and CYP3A4 metabolism; a major metabolic reaction, being aliphatic hydroxylation; no hERG inhibition; and non-carcinogenicity. Predicted molecular targets were mainly inflammatory mediators. Molecular docking depicted H-bonding interaction with nuclear factor kappa beta subunit (NF-κB), cyclooxygenase-2, 5-lipoxygenase, phospholipase A2, serotonin transporter, dopamine receptor D1 and 5-hydroxy tryptamine. Its cytotoxicity (IC50) value in normal lymphocytes was >20 µg/mL as compared to cancer cells (Huh7.5; 17.32 ± 1.43 µg/mL). Daturaolone significantly inhibited NF-κB and nitric oxide production with IC50 values of 1.2 ± 0.8 and 4.51 ± 0.92 µg/mL, respectively. It significantly reduced inflammatory paw edema (81.73 ± 3.16%), heat-induced pain (89.47 ± 9.01% antinociception) and stress-induced depression (68 ± 9.22 s immobility time in tail suspension test). This work suggests a possible anti-inflammatory role of daturaolone; however, detailed mechanistic studies are still necessary to corroborate and extrapolate the findings.

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Click Activated Protodrugs Against Cancer Increase the Therapeutic Potential of Chemotherapy through Local Capture and Activation

10.26434/chemrxiv.13087715 ◽

2020 ◽

Author(s):

Kui Wu ◽

Nathan Yee ◽

Sangeetha Srinivasan ◽

Amir Mahmoodi ◽

Michael Zakharian ◽

...

Keyword(s):

Therapeutic Potential ◽

Unmet Need ◽

Sodium Hyaluronate ◽

Maximum Tolerated Dose ◽

The Body ◽

In Vivo Studies ◽

Tumor Biomarker ◽

Tumor Site

<div> <div> <div> <p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)- modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer, SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated dose of conventional doxorubicin with greatly reduced systemic toxicity. </p> </div> </div> </div>

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Effect of Low-Immunogenic Yogurt Drinks and Probiotic Bacteria on Immunoreactivity of Cow’s Milk Proteins and Tolerance Induction—In Vitro and In Vivo Studies

Nutrients ◽

10.3390/nu12113390 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3390

Author(s):

Barbara Wróblewska ◽

Anna Kaliszewska-Suchodoła ◽

Ewa Fuc ◽

Lidia Hanna Markiewicz ◽

Anna Maria Ogrodowczyk ◽

...

Keyword(s):

Therapeutic Potential ◽

Tolerance Induction ◽

Milk Proteins ◽

In Vivo Studies ◽

Cow’S Milk ◽

Milk Allergy ◽

Cow's Milk ◽

Safe Product

There is no effective therapy for milk allergy. The role of lactic acid bacteria (LAB) and probiotics in protection against allergy-related outcomes is still under investigation. The aim of the study was to evaluate the immunomodulative and therapeutic potential of yogurt drinks in cow’s milk allergy (CMA) management. We compared immunoreactivity of α-casein (α-CN), β-casein (β-CN), κ-casein (κ-CN), α-lactalbumin (α-LA), and β-lactoglobulin (β-LG) in 27 yogurt drinks fermented with different basic yogurt cultures, or yogurt cultures enriched with Lactobacillus plantarum and/or Bifidobacterium lactis strains, by competitive ELISA assay. Drinks with the lowest antigenic potential were used as allergoids for CMA therapy. BALB/c mice were sensitized via intraperitoneal injection of α-CN + β-LG mixture with aluminum adjuvant, and gavaged with increasing doses of selected low-immunogenic drinks (YM—basic, or YM-LB—enriched with L. plantarum and B. lactis) to induce tolerance. Milk- or phosphate-buffered saline (PBS)-dosed mice served as controls. Compared to milk, the immunoreactivity of proteins in drinks increased or decreased, depending on the bacterial sets applied for fermentation. Only a few sets acted synergistically in reducing immunoreactivity. The selected low-immunogenic drinks stimulated allergic mice for profiling Th2 to Th1 response and acquire tolerance, and the effect was greater with YM-LB drink, which during long-lasting interventional feeding strongly increased the secretion of regulatory cytokines, i.e., IL-10 and TGF-β, and IgA and decreased IL-4, IgE, and anti-(α-CN + β-LG) IgG1. The studies revealed variations in the potency of yogurt bacteria to change allergenicity of milk proteins and the need for their strict selection to obtain a safe product for allergy sufferers. The YM-LB drink with reduced antigenic potential may be a source of allergoids used in the immunotherapy of IgE mediated CMA, but further clinical or volunteer studies are required.

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Safety and Utility of Chloroquine/ Hydroxychloroquine in Palliative Care Patients

American Journal of Hospice and Palliative Medicine® ◽

10.1177/1049909120952773 ◽

2020 ◽

pp. 104990912095277

Author(s):

Eric Prommer

Keyword(s):

Palliative Care ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Symptom Control ◽

In Vivo Studies ◽

Advanced Illness ◽

Know How ◽

Seriously Ill

The coronavirus disease 2019 (COVID-19) pandemic represents a significant healthcare challenge for the world. Many drugs have therapeutic potential. The aminoquinolones, hydroxychloroquine, and chloroquine are undergoing evaluation as a potential therapy against COVID -19. In vitro and in vivo studies suggest that these drugs affect viral adherence and modify inflammatory responses, which may provide some impact on the symptoms associated with COVID. As palliative care specialists encounter more COVID positive patients, palliative care specialists need to know how these drugs work, and importantly how they interact with palliative care drugs used for symptom control. At the same time, there is a need to reduce polypharmacy in any seriously ill patient population. The goals of this paper are to identify whether or not hydroxychloroquine/chloroquine improves symptoms in palliative care patients and whether or not these drugs are safe to use in the advanced illness population who have COVID.

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Oncostatin M-induced astrocytic tissue inhibitor of metalloproteinases-1 drives remyelination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1912910117 ◽

2020 ◽

Vol 117 (9) ◽

pp. 5028-5038 ◽

Cited By ~ 5

Author(s):

Evelien Houben ◽

Kris Janssens ◽

Doryssa Hermans ◽

Jennifer Vandooren ◽

Chris Van den Haute ◽

...

Keyword(s):

Therapeutic Potential ◽

Treatment Options ◽

Oncostatin M ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor ◽

Human Value ◽

Demyelinating Disorders ◽

Downstream Mediator

The brain’s endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRβ knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRβ KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

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The Therapeutic Potential of Naringenin: A Review of Clinical Trials

Pharmaceuticals ◽

10.3390/ph12010011 ◽

2019 ◽

Vol 12 (1) ◽

pp. 11 ◽

Cited By ~ 93

Author(s):

Bahare Salehi ◽

Patrick Fokou ◽

Mehdi Sharifi-Rad ◽

Paolo Zucca ◽

Raffaele Pezzani ◽

...

Keyword(s):

Therapeutic Potential ◽

Biological Activities ◽

In Vivo Studies ◽

Citrus Fruits ◽

Delivery Methods ◽

Cardioprotective Effects ◽

Compromised Patients ◽

Cardioprotective Action

Naringenin is a flavonoid belonging to flavanones subclass. It is widely distributed in several Citrus fruits, bergamot, tomatoes and other fruits, being also found in its glycosides form (mainly naringin). Several biological activities have been ascribed to this phytochemical, among them antioxidant, antitumor, antiviral, antibacterial, anti-inflammatory, antiadipogenic and cardioprotective effects. Nonetheless, most of the data reported have been obtained from in vitro or in vivo studies. Although some clinical studies have also been performed, the main focus is on naringenin bioavailability and cardioprotective action. In addition, these studies were done in compromised patients (i.e., hypercholesterolemic and overweight), with a dosage ranging between 600 and 800 μM/day, whereas the effect on healthy volunteers is still debatable. In fact, naringenin ability to improve endothelial function has been well-established. Indeed, the currently available data are very promising, but further research on pharmacokinetic and pharmacodynamic aspects is encouraged to improve both available production and delivery methods and to achieve feasible naringenin-based clinical formulations.

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