Potential molecular targets of Leishmania pathways in developing novel antileishmanials

2021 ◽  
Author(s):  
Dandugudumula Ramu ◽  
Shailja Singh
Keyword(s):  
Drug Resistance ◽  
Molecular Targets ◽  
Molecular Pathways ◽  
Parasitic Disease ◽  
Comprehensive Overview ◽  
Drug Candidates ◽  
New Class ◽  
The Way

The illness known as leishmaniasis has not become a household name like malaria, although it stands as the second-largest parasitic disease, surpassed only by malaria. As no licensed vaccine is available, treatment for leishmaniasis mostly relies on chemotherapy. Inefficiency and drug resistance are the major impediments in current therapeutics. In this scenario, identification of novel molecular drug candidates is indispensable to develop robust antileishmanials. The exploration of structure-based drugs to target enzymes/molecules of Leishmania which differ structurally/functionally from their equivalents in mammalian hosts not only helps in developing a new class of antileishmanials, but also paves the way to understand Leishmania biology. This review provides a comprehensive overview on possible drug candidates relating to various Leishmania molecular pathways.

Chemistry of antimony-based drugs in biological systems and studies of their mechanism of action

2013 ◽  
Vol 33 (1) ◽  
pp. 1-12 ◽  
Author(s):  
Frédéric Frézard ◽  
Cynthia Demicheli ◽  
Kelly C. Kato ◽  
Priscila G. Reis ◽  
Edgar H. Lizarazo-Jaimes
Keyword(s):  
Molecular Structure ◽  
Drug Resistance ◽  
Mechanism Of Action ◽  
Biological Systems ◽  
Molecular Targets ◽  
Pharmacological Action ◽  
Trypanothione Reductase ◽  
Parasitic Disease ◽  
First Line ◽  
Pentavalent Antimony

AbstractAntimonial drugs have been used for a century in the therapy of the parasitic disease leishmaniasis. Even though pentavalent antimonials are still first-line drugs, they exhibit several limitations, including severe side effects, the need for daily parenteral administration and drug resistance. The molecular structure of pentavalent antimonials, their metabolism and mechanism of action, are still being investigated. Previous studies suggest that pentavalent antimony acts as a prodrug which is converted to the active and more toxic trivalent antimony. Other works support the direct involvement of pentavalent antimony. Recent data indicate that thiols and ribose-containing biomolecules may mediate the pharmacological action of these drugs. Trypanothione reductase and zinc-finger proteins were identified as possible molecular targets. This review summarizes the progress achieved to date on the chemistry of antimonial drugs in biological systems.

scholarly journals Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1292 ◽  
Author(s):  
Shirin Hafezi ◽  
Mohamed Rahmani
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Targeted Therapies ◽  
Single Agent ◽  
Therapeutic Agents ◽  
Malignant Cells ◽  
Future Perspectives ◽  
Comprehensive Overview ◽  
Antiapoptotic Proteins ◽  
Preclinical And Clinical Studies

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.

scholarly journals Viruses and Type 1 Diabetes: From Enteroviruses to the Virome

2021 ◽  
Vol 9 (7) ◽  
pp. 1519
Author(s):  
Sonia R. Isaacs ◽  
Dylan B. Foskett ◽  
Anna J. Maxwell ◽  
Emily J. Ward ◽  
Clare L. Faulkner ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Virus Detection ◽  
Detection Methods ◽  
Islet Autoimmunity ◽  
Comprehensive Overview ◽  
Drug Candidates

For over a century, viruses have left a long trail of evidence implicating them as frequent suspects in the development of type 1 diabetes. Through vigorous interrogation of viral infections in individuals with islet autoimmunity and type 1 diabetes using serological and molecular virus detection methods, as well as mechanistic studies of virus-infected human pancreatic β-cells, the prime suspects have been narrowed down to predominantly human enteroviruses. Here, we provide a comprehensive overview of evidence supporting the hypothesised role of enteroviruses in the development of islet autoimmunity and type 1 diabetes. We also discuss concerns over the historical focus and investigation bias toward enteroviruses and summarise current unbiased efforts aimed at characterising the complete population of viruses (the “virome”) contributing early in life to the development of islet autoimmunity and type 1 diabetes. Finally, we review the range of vaccine and antiviral drug candidates currently being evaluated in clinical trials for the prevention and potential treatment of type 1 diabetes.

scholarly journals MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance

Cells ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 39
Author(s):  
Crescenzo Massaro ◽  
Elham Safadeh ◽  
Giulia Sgueglia ◽  
Hendrik G. Stunnenberg ◽  
Lucia Altucci ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Hormone Signaling ◽  
Cancer Resistance ◽  
Comprehensive Overview ◽  
Substantial Progress

Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.

scholarly journals Antidiabetic Effects of Resveratrol: The Way Forward in Its Clinical Utility

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Omolola R. Oyenihi ◽  
Ayodeji B. Oyenihi ◽  
Anne A. Adeyanju ◽  
Oluwafemi O. Oguntibeju
Keyword(s):  
Diabetes Mellitus ◽  
Clinical Utility ◽  
Therapeutic Agent ◽  
Molecular Targets ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Antidiabetic Drug ◽  
Near Future ◽  
Antidiabetic Effects ◽  
The Way

Despite recent advances in the understanding and management ofdiabetes mellitus, the prevalence of the disease is increasing unabatedly with resulting disabling and life-reducing consequences to the global human population. The limitations and side effects associated with current antidiabetic therapies have necessitated the search for novel therapeutic agents. Due to the multipathogenicity ofdiabetes mellitus,plant-derived compounds with proven multiple pharmacological actions have been postulated to “hold the key” in the search for an affordable, efficacious, and safer therapeutic agent in the treatment of the disease and associated complications. Resveratrol, a phytoalexin present in few plant species, has demonstrated beneficial antidiabetic effects in animals and humans through diverse mechanisms and multiple molecular targets. However, despite the enthusiasm and widespread successes achieved with the use of resveratrol in animal models ofdiabetes mellitus, there are extremely limited clinical data to confirm the antidiabetic qualities of resveratrol. This review presents an update on the mechanisms of action and protection of resveratrol indiabetes mellitus, highlights challenges in its clinical utility, and suggests the way forward in translating the promising preclinical data to a possible antidiabetic drug in the near future.

Natural products targeting cancer stem cells: a revisit

2021 ◽  
Vol 28 ◽  
Author(s):  
Jiahua Cui ◽  
Jiajun Qian ◽  
Larry Ming-Cheung Chow ◽  
Jinping Jia
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Biologically Active ◽  
Cellular Targets ◽  
Drug Candidates ◽  
Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

scholarly journals Redox Modulation at Work: Natural Phytoprotective Polysulfanes From Alliums Based on Redox-Active Sulfur

2018 ◽  
Vol 4 (5) ◽  
pp. 397-407 ◽  
Author(s):  
Awais Anwar ◽  
Emma Gould ◽  
Ryan Tinson ◽  
Javaid Iqbal ◽  
Chris Hamilton
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
Antimicrobial Properties ◽  
Molecular Targets ◽  
Cancer Cell Lines ◽  
Special Focus ◽  
Anticancer Activities ◽  
Comprehensive Overview ◽  
Anticancer Properties

Abstract Purpose of review This article provides a brief overview of natural phytoprotective products of allium with a special focus on the therapeutic potential of diallyl polysulfanes from garlic, their molecular targets and their fate in the living organisms. A comprehensive overview of antimicrobial and anticancer properties of published literature is presented for the reader to understand the effective concentrations of polysulfanes and their sensitivity towards different human pathogenic microbes, fungi, and cancer cell lines. Recent findings The article finds polysulfanes potentials as new generation novel antibiotics and chemo preventive agent. The effective dose rates of polysulfanes for antimicrobial properties are in the range of 0.5–40 mg/L and for anticancer 20–100 μM. The molecular targets for these redox modulators are mainly cellular thiols as well as inhibition and/or activation of certain cellular proteins in cancer cell lines. Summary Antimicrobial and anticancer activities of polysulfanes published in the literature indicate that with further development, they could be promising candidates for cancer prevention due to their selectivity towards abnormal cells.

scholarly journals STRONGYLS BENZIMIDAZOLE RESISTANCE IN EQUINE FROM ZOO

2009 ◽  
Vol 15 (1) ◽  
pp. 63-68
Author(s):  
Mihai CERNEA ◽  
Cristina CERNEA
Keyword(s):  
Drug Resistance ◽  
Drug Combinations ◽  
Drug Resistant ◽  
Time Treatment ◽  
Benzimidazole Resistance ◽  
Baia Mare ◽  
Significant Pathology ◽  
The Way

The research in view of establishing the development and the way in which antihelmintical treatment influences epidemiological indexes, was carried out between October 2008 and May 2009 in equine species from zoos. In the zoo located Targu Mures it was noticed am strongyls intensity of 2300 EPG - 8700 LPG in horses, and 700 EPG - 1400 LPG in ponies. In vitro effectiveness of bemzimidazoles (BZ) being low in both horses and ponies. In the zoo located in Turda the intensity of the strongyl parasitism reached the level of 900 EPG - 2300 LPG in horses and 2400EPG - 2800 LPG in ponies, the effectiveness of the benzimidazoles being low. In the zoo located in Baia Mare the intensity of strongyls infestation was of 900 EPG - 1600 LPG in horses, 1900 EPG – 2600 LPG in ponies, 900 EPG -1500 LPG in donkeys benzimidazoles treatment being proven effective. Cyathostomum species are considered as having the most significant pathology in equines. Worldwide, anthelmintical treatment, especially in strongylatosis, faces an ever-increasing phenomenon of drug resistance, to phenotiazin, thiabendazole as well as other BZ and ProBZ, in the strongyls population. The lack of success in treatment using drug combinations (piperazin and phenotiazin; triclorfon and phenotiazin; diclorfos and morantel) have spurred the development of new substances to which strongyls have not developed resistance. Tong time treatment with the same substance leads to the development of drug-resistant strongyl population, thus a low effectiveness, below the desired level.

scholarly journals Ancient Characters and Contemporary Readers: A Response to Elizabeth E. Shively & Jan Rüggemeier and Cornelis Bennema

2021 ◽  
Vol 29 (4-5) ◽  
pp. 452-466
Author(s):  
Suzanne Keen
Keyword(s):  
Final Section ◽  
Comprehensive Overview ◽  
Good Samaritan ◽  
Introductory Essay ◽  
The Way

Abstract In this response essay, which culminates with an application of my theory of narrative empathy to the Parable of the Good Samaritan, I comment on an article by Cornelis Bennema and engage with the ideas in the framing, introductory essay by Jan Rüggemeier and Elizabeth E. Shively. In the course of carrying out these tasks, I also offer what I hope will be broadly useful comments on fictional and nonfictional contexts for character construction, on characters and characterization, and on the way diverse actual readers engage with characters. This essay concludes with some thoughts on narrative empathy, responding to the final section of Rüggemeier and Shively’s essay, which offers comprehensive overview of empathy and sympathy as aspects of emotional reading.

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