Carbonic Anhydrase Inhibitors as Novel Drugs against Mycobacterial β-Carbonic Anhydrases: An Update on In Vitro and In Vivo Studies

Mycobacteria cause a variety of diseases, such as tuberculosis, leprosy, and opportunistic diseases in immunocompromised people. The treatment of these diseases is problematic, necessitating the development of novel treatment strategies. Recently, β-carbonic anhydrases (β-CAs) have emerged as potential drug targets in mycobacteria. The genomes of mycobacteria encode for three β-CAs that have been cloned and characterized from Mycobacterium tuberculosis (Mtb) and the crystal structures of two of the enzymes have been determined. Different classes of inhibitor molecules against Mtb β-CAs have subsequently been designed and have been shown to inhibit these mycobacterial enzymes in vitro. The inhibition of these centrally important mycobacterial enzymes leads to reduced growth of mycobacteria, lower virulence, and impaired biofilm formation. Thus, the inhibition of β-CAs could be a novel approach for developing drugs against the severe diseases caused by pathogenic mycobacteria. In the present article, we review the data related to in vitro and in vivo inhibition studies in the field.

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Pathogenesis of Keratinocyte Carcinomas and the Therapeutic Potential of Medicinal Plants and Phytochemicals

Molecules ◽

10.3390/molecules26071979 ◽

2021 ◽

Vol 26 (7) ◽

pp. 1979

Author(s):

Andrea Jess Josiah ◽

Danielle Twilley ◽

Sreejarani Kesavan Pillai ◽

Suprakas Sinha Ray ◽

Namrita Lall

Keyword(s):

Cell Carcinoma ◽

Therapeutic Potential ◽

Treatment Strategies ◽

In Vivo Studies ◽

Contributing Factors ◽

Alternative Approach ◽

Transdermal Drug Delivery Systems ◽

Novel Treatment Strategies

Keratinocyte carcinoma (KC) is a form of skin cancer that develops in keratinocytes, which are the predominant cells present in the epidermis layer of the skin. Keratinocyte carcinoma comprises two sub-types, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This review provides a holistic literature assessment of the origin, diagnosis methods, contributing factors, and current topical treatments of KC. Additionally, it explores the increase in KC cases that occurred globally over the past ten years. One of the principal concepts highlighted in this article is the adverse effects linked to conventional treatment methods of KC and how novel treatment strategies that combine phytochemistry and transdermal drug delivery systems offer an alternative approach for treatment. However, more in vitro and in vivo studies are required to fully assess the efficacy, mechanism of action, and safety profile of these phytochemical based transdermal chemotherapeutics.

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Mycobacterium tuberculosis β-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs

International Journal of Molecular Sciences ◽

10.3390/ijms20205153 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5153 ◽

Cited By ~ 5

Author(s):

Aspatwar ◽

Kairys ◽

Rala ◽

Parikka ◽

Bozdag ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Pathogenic Bacteria ◽

Bacterial Species ◽

In Vivo Studies ◽

Close Relative ◽

Carbonic Anhydrases ◽

In Vitro Inhibition ◽

Inhibition Studies

The genome of Mycobacterium tuberculosis (Mtb) encodes three β-carbonic anhydrases (CAs, EC 4.2.1.1) that are crucial for the life cycle of the bacterium. The Mtb β-CAs have been cloned and characterized, and the catalytic activities of the enzymes have been studied. The crystal structures of two of the enzymes have been resolved. In vitro inhibition studies have been conducted using different classes of carbonic anhydrase inhibitors (CAIs). In vivo inhibition studies of pathogenic bacteria containing β-CAs showed that β-CA inhibitors effectively inhibited the growth of pathogenic bacteria. The in vitro and in vivo studies clearly demonstrated that β-CAs of not only mycobacterial species, but also other pathogenic bacteria, can be targeted for developing novel antimycobacterial agents for treating tuberculosis and other microbial infections that are resistant to existing drugs. In this review, we present the molecular and structural data on three β-CAs of Mtb that will give us better insights into the roles of these enzymes in pathogenic bacterial species. We also present data from both in vitro inhibition studies using different classes of chemical compounds and in vivo inhibition studies focusing on M. marinum, a model organism and close relative of Mtb.

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Molecular mechanisms underpinning sarcomas and implications for current and future therapy

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00647-8 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Victoria Damerell ◽

Michael S. Pepper ◽

Sharon Prince

Keyword(s):

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Treatment Strategies ◽

Mesenchymal Transition ◽

Mesenchymal To Epithelial Transition ◽

Cells Of Origin ◽

Novel Treatment Strategies ◽

Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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A Mini Review on Antidiabetic Properties of Fermented Foods

Nutrients ◽

10.3390/nu10121973 ◽

2018 ◽

Vol 10 (12) ◽

pp. 1973 ◽

Cited By ~ 8

Author(s):

Bhagavathi Sivamaruthi ◽

Periyanaina Kesika ◽

Mani Prasanth ◽

Chaiyavat Chaiyasut

Keyword(s):

Functional Properties ◽

Antioxidant Properties ◽

Treatment Strategies ◽

In Vivo Studies ◽

Fermented Foods ◽

Gastrointestinal Health ◽

Randomized Controlled Clinical Trials ◽

The Government

In general, fermented foods (FFs) are considered as functional foods. Since the awareness about the health benefits of FFs has increased, the consumption of FF also improved significantly in recent decades. Diabetes is one of the leading threats of the health span of an individual. The present manuscript details the general methods of the production of FFs, and the results of various studies (in vitro, in vivo, and clinical studies) on the antidiabetic properties of FFs. The fermentation method and the active microbes involved in the process play a crucial role in the functional properties of FFs. Several in vitro and in vivo studies have been reported on the health-promoting properties of FFs, such as anti-inflammation, anticancer, antioxidant properties, improved cognitive function and gastrointestinal health, and the reduced presence of metabolic disorders. The studies on the functional properties of FFs by randomized controlled clinical trials using human volunteers are very limited for several reasons, including ethical reasons, safety concerns, approval from the government, etc. Several scientific teams are working on the development of complementary and alternative medicines to improve the treatment strategies for hyperglycemia.

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Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Parasitology ◽

10.1017/s0031182020000955 ◽

2020 ◽

Vol 147 (11) ◽

pp. 1216-1228

Author(s):

Cristina Fonseca-Berzal ◽

Cristiane França da Silva ◽

Denise da Gama Jaen Batista ◽

Gabriel Melo de Oliveira ◽

José Cumella ◽

...

Keyword(s):

Trypanosoma Cruzi ◽

Positive Impact ◽

Cardiac Cells ◽

In Vivo Studies ◽

Drug Resistant ◽

Activity Profile ◽

Reference Drug ◽

Novel Drugs

AbstractIn previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.

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Therapeutic Effects of Curcumin—From Traditional Past to Present and Future Clinical Applications

International Journal of Molecular Sciences ◽

10.3390/ijms20153757 ◽

2019 ◽

Vol 20 (15) ◽

pp. 3757 ◽

Cited By ~ 6

Author(s):

Beatrice Bachmeier ◽

Dieter Melchart

Keyword(s):

Molecular Mechanisms ◽

Malignant Tumors ◽

Scientific Evidence ◽

Treatment Strategies ◽

Therapeutic Effects ◽

Microbial Infection ◽

Therapeutic Benefits ◽

Novel Treatment Strategies

The efficacy of the plant-derived polyphenol curcumin, in various aspects of health and wellbeing, is matter of public interest. An internet search of the term “Curcumin” displays about 12 million hits. Among the multitudinous information presented on partly doubtful websites, there are reports attracting the reader with promises ranging from eternal youth to cures for incurable diseases. Unfortunately, many of these reports are not based on scientific evidence, but they feed the desideratum of the reader for a “miracle cure”. This circumstance makes it very difficult for researchers, who work in a scientifically sound and evidence-based manner on the therapeutic benefits (or side effects) of curcumin, to demarcate their results from sensational reports that circulate in the web and in other media. This is only one of many obstacles making it difficult to pave curcumin’s way into clinical application; others are its nonpatentability and low economic usability. A further impediment comes from scientists who never worked with curcumin or any other natural plant-derived compound in their own labs. They have never tested these compounds in any scientific assay, neither in vitro nor in vivo; however, they claim, in a sometimes polemic manner, that everything that has so far been published on curcumin’s molecular effects is based on artefacts. The here presented Special Issue comprises a collection of five scientifically sound articles and nine reviews reporting on the therapeutic benefits and the molecular mechanisms of curcumin or of chemically modified curcumin in various diseases ranging from malignant tumors to chronic diseases, microbial infection, and even neurodegenerative diseases. The excellent results of the scientific projects that underlie the five original papers give reason to hope that curcumin will be part of novel treatment strategies in the near future—either as monotherapy or in combination with other drugs or therapeutic applications.

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MicroRNAs in the Atherosclerotic Plaque

Clinical Chemistry ◽

10.1373/clinchem.2013.204917 ◽

2013 ◽

Vol 59 (12) ◽

pp. 1708-1721 ◽

Cited By ~ 51

Author(s):

Emma Raitoharju ◽

Niku Oksala ◽

Terho Lehtimäki

Keyword(s):

Atherosclerotic Plaque ◽

Mirna Expression ◽

Drug Targets ◽

Human Peripheral Blood ◽

Expression Profiles ◽

Mirna Profile ◽

In Vivo Studies ◽

Atherosclerotic Plaques

BACKGROUND MicroRNAs (miRNA, miR) are noncoding RNAs that regulate gene expression by hindering translation. miRNA expression profiles have been shown to differ in vivo and in vitro in many cellular processes associated with cardiovascular diseases (CVDs). The progression of CVDs has also been shown to alter the blood miRNA profile in humans. CONTENT We summarize the results of animal and cell experiments concerning the miRNA profile in the atherosclerotic process and the changes which occur in the blood miRNA profile of individuals with CVD. We also survey the relationship of these CVD-related miRNAs and their expression in the human advanced atherosclerotic plaque, thereby providing more insight into miRNA function in human atherosclerotic lesions. The miRNAs miR-126, -134, -145, -146a, -198, -210, -340*, and -92a were found to be expressed differently in the blood of individuals affected and unaffected by CVD. These differences paralleled those seen in tissue comparisons of miRNA expression in advanced atherosclerotic plaques and healthy arteries. Furthermore, several miRNAs associated with atherosclerosis in in vitro studies (such as miR-10a, -126, -145, -146a/b, -185, -210, and -326) were expressed in plaques in a similar pattern as was predicted by the in vitro experiments. The clinical implications of miRNAs in atherosclerosis as biomarkers and as possible drug targets are also reviewed. SUMMARY miRNA profiles in in vitro and in vivo studies as well as in human peripheral blood are quite representative of the miRNA expression in human atherosclerotic plaques. miRNAs appear promising in terms of future clinical applications.

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Fabrication and Biological Assessment of Antidiabetic α-Mangostin Loaded Nanosponges: In Vitro, In Vivo, and In Silico Studies

Molecules ◽

10.3390/molecules26216633 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6633

Author(s):

Faisal Usman ◽

Hamid Saeed Shah ◽

Sumera Zaib ◽

Sirikhwan Manee ◽

Jahanzeb Mudassir ◽

...

Keyword(s):

Microvascular Complications ◽

Treatment Strategies ◽

Biological Assessment ◽

In Vivo Studies ◽

Hydrodynamic Diameter ◽

Scanning Calorimetry ◽

Ligand Complex ◽

In Silico Studies

Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic β-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively.

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Autophagy and salivary gland cancer: A putative target for salivary gland tumors

Tumor Biology ◽

10.1177/1010428320980568 ◽

2020 ◽

Vol 42 (12) ◽

pp. 101042832098056

Author(s):

Evangelos Koustas ◽

Panagiotis Sarantis ◽

Margarita Theodorakidou ◽

Michalis V Karamouzis ◽

Stamatios Theocharis

Keyword(s):

Salivary Gland ◽

Current Knowledge ◽

Treatment Options ◽

Treatment Strategies ◽

In Vivo Studies ◽

Salivary Gland Cancer ◽

Number Of Patients ◽

Salivary Gland Carcinomas

Salivary gland carcinomas are a group of heterogeneous tumors of different histological subtypes, presenting relatively low incidence but the entire variable of types. Although novel treatment options for salivary gland carcinomas patients’ outcomes have improved, the treatment of this type of cancer is still not standardized. In addition, a significant number of patients, with a lack of optimal treatment strategies, have reduced survival. In the last two decades, a plethora of evidence pointed to the importance of autophagy, an essential catabolic process of cytoplasmatic component digestion, in cancer. In vitro and in vivo studies highlight the importance of autophagy in salivary gland carcinomas development as a tumor suppressor or promoter mechanism. Despite the potential of autophagy in salivary gland carcinomas development, no therapies are currently available that specifically focus on autophagy modulation in salivary gland carcinomas. In this review, we summarize current knowledge and clinical trials in regard to the interplay between autophagy and the development of salivary gland carcinomas. Autophagy manipulation may be a putative therapeutic strategy for salivary gland carcinomas patients.

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Epigenetic roles of PIWI proteins and piRNAs in lung cancer

Cell & Bioscience ◽

10.1186/s13578-019-0368-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 4

Author(s):

Hadis Fathizadeh ◽

Zatollah Asemi

Keyword(s):

Lung Cancer ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

High Mobility ◽

P Element ◽

In Vivo Studies ◽

Cancer Pathogenesis ◽

Non Coding Rnas

AbstractLung cancer is one of very important malignancies which are related to high mobility and mortality in the world. Despite several efforts for improving diagnosis and treatment strategies of lung cancer, finding and developing new and effective therapeutic and diagnostic are needed. A variety of internal and external factors could be involved in lung cancer pathogenesis. Among internal factors, epigenetic mechanisms have been emerged as very important players in the lung cancer. Non-coding RNAs is known as one of epigenetic regulators which exert their effects on a sequence of cellular and molecular mechanisms. P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs or piR) is one of small non-coding RNAs that the deregulation of these molecules is associated with initiation and progression of different cancers such as lung cancer. Several activities are related to PIWI/piRNA pathway such as suppression of transposons and mobile genetic elements. In vitro and in vivo studies demonstrated the upregulation or downregulation of PIWI proteins and piRNAs could lead to the increasing of cell proliferation, apoptosis reduction and promoting tumor growth in the lung cancer. Hence, PIWI proteins and piRNA could be introduced as new diagnostic and therapeutic biomarkers in the lung cancer therapy. Herein, we have focused on PIWI proteins and piRNA functions and their impact on the progression of lung cancer.

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