Pharmaceuticals

31 pages, 3989 KiB

Open AccessReview

Fluoroquinolones and Biofilm: A Narrative Review

by Nicholas Geremia, Federico Giovagnorio, Agnese Colpani, Andrea De Vito, Alexandru Botan, Giacomo Stroffolini, Dan-Alexandru Toc, Verena Zerbato, Luigi Principe, Giordano Madeddu, Roberto Luzzati, Saverio Giuseppe Parisi and Stefano Di Bella

Pharmaceuticals 2024, 17(12), 1673; https://doi.org/10.3390/ph17121673 - 11 Dec 2024

Abstract

Background: Biofilm-associated infections frequently span multiple body sites and represent a significant clinical challenge, often requiring a multidisciplinary approach involving surgery and antimicrobial therapy. These infections are commonly healthcare-associated and frequently related to internal or external medical devices. The formation of biofilms [...] Read more.

Background: Biofilm-associated infections frequently span multiple body sites and represent a significant clinical challenge, often requiring a multidisciplinary approach involving surgery and antimicrobial therapy. These infections are commonly healthcare-associated and frequently related to internal or external medical devices. The formation of biofilms complicates treatment, as they create environments that are difficult for most antimicrobial agents to penetrate. Fluoroquinolones play a critical role in the eradication of biofilm-related infections. Numerous studies have investigated the synergistic potential of combining fluoroquinolones with other chemical agents to augment their efficacy while minimizing potential toxicity. Comparative research suggests that the antibiofilm activity of fluoroquinolones is superior to that of beta-lactams and glycopeptides. However, their activity remains less effective than that of minocycline and fosfomycin. Noteworthy combinations include fluoroquinolones with fosfomycin and aminoglycosides for enhanced activity against Gram-negative organisms and fluoroquinolones with minocycline and rifampin for more effective treatment of Gram-positive infections. Despite the limitations of fluoroquinolones due to the intrinsic characteristics of this antibiotic, they remain fundamental in this setting thanks to their bioavailability and synergisms with other drugs. Methods: A comprehensive literature search was conducted using online databases (PubMed/MEDLINE/Google Scholar) and books written by experts in microbiology and infectious diseases to identify relevant studies on fluoroquinolones and biofilm. Results: This review critically assesses the role of fluoroquinolones in managing biofilm-associated infections in various clinical settings while also exploring the potential benefits of combination therapy with these antibiotics. Conclusions: The literature predominantly consists of in vitro studies, with limited in vivo investigations. Although real world data are scarce, they are in accordance with fluoroquinolones’ effectiveness in managing early biofilm-associated infections. Also, future perspectives of newer treatment options to be placed alongside fluoroquinolones are discussed. This review underscores the role of fluoroquinolones in the setting of biofilm-associated infections, providing a comprehensive guide for physicians regarding the best use of this class of antibiotics while highlighting the existing critical issues. Full article

(This article belongs to the Special Issue Fluoroquinolones)

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22 pages, 6760 KiB

Open AccessReview

Exploring the Therapeutic Potential, Ethnomedicinal Values, and Phytochemistry of Helianthus tuberosus L.: A Review

by Ruvimbo Faith Tapera, Xavier Siwe-Noundou, Leshweni Jeremia Shai and Shoeshoe Mokhele

Pharmaceuticals 2024, 17(12), 1672; https://doi.org/10.3390/ph17121672 - 11 Dec 2024

Abstract

Helianthus tuberosus L. (Jerusalem artichoke) tubers and aerial parts possess both nutritional and therapeutic properties. The Jerusalem artichoke has been utilized for various applications, including its use as a functional food source, a reservoir of bioactive compounds, and a raw material to produce [...] Read more.

Helianthus tuberosus L. (Jerusalem artichoke) tubers and aerial parts possess both nutritional and therapeutic properties. The Jerusalem artichoke has been utilized for various applications, including its use as a functional food source, a reservoir of bioactive compounds, and a raw material to produce biofuels. Moreover, the Jerusalem artichoke is a rich source of an indigestible polysaccharide called inulin, which serves as a prebiotic that improves gastrointestinal health. This plant has been used globally throughout history as a dietary supplement, for pain treatment, to reduce swelling, and to boost the immune system, as well as to treat skin wounds in folk medicine. It is an abundant source of bioactive compounds, such as phenolic acids, coumarins, and flavonoids, which are known to exert pharmacological activities, including antioxidant, antimicrobial, and anti-inflammatory properties. The literature on its potential as an antidiabetic, anticancer, anti-fungistatic, antiviral, and anti-obesity agent, among others, is scanty. This review aims to provide a comprehensive overview of Helianthus tuberosus L.’s traditional uses, nutritional properties, secondary bioactive compounds, and pharmacological properties to further explore its health benefits. Full article

(This article belongs to the Special Issue Natural Products for Therapeutic Potential)

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21 pages, 2965 KiB

Open AccessArticle

Antinociceptive Potential of Ximenia americana L. Bark Extract and Caffeic Acid: Insights into Pain Modulation Pathways

by Renata Torres Pessoa, Lucas Yure Santos da Silva, Isabel Sousa Alcântara, Tarcísio Mendes Silva, Eduardo dos Santos Silva, Roger Henrique Sousa da Costa, Aparecida Barros da Silva, Jaime Ribeiro-Filho, Anita Oliveira Brito Pereira Bezerra Martins, Henrique Douglas Melo Coutinho, Jean Carlos Pereira Sousa, Andréa Rodrigues Chaves, Ricardo Neves Marreto and Irwin Rose Alencar de Menezes

Pharmaceuticals 2024, 17(12), 1671; https://doi.org/10.3390/ph17121671 - 11 Dec 2024

Abstract

Background/Objectives: This study evaluated the antinociceptive effect of the Ximenia americana L. bark extract (HEXA) and its primary component, caffeic acid (CA), through in vivo assays. Methods: The antinociceptive properties were assessed using abdominal writhing, hot plate, and Von Frey tests. Additionally, [...] Read more.

Background/Objectives: This study evaluated the antinociceptive effect of the Ximenia americana L. bark extract (HEXA) and its primary component, caffeic acid (CA), through in vivo assays. Methods: The antinociceptive properties were assessed using abdominal writhing, hot plate, and Von Frey tests. Additionally, the study investigated the modulation of various pain signaling pathways using a pharmacological approach. Results: The results demonstrated that all doses of the HEXA significantly increased latency in the hot plate test, decreased the number of abdominal contortions, reduced hyperalgesia in the Von Frey test, and reduced both phases of the formalin test. Caffeic acid reduced licking time in the first phase of the formalin test at all doses, with the highest dose showing significant effects in the second phase. The HEXA potentially modulated α₂-adrenergic (52.99%), nitric oxide (57.77%), glutamatergic (33.66%), vanilloid (39.84%), cyclic guanosine monophosphate (56.11%), and K⁺ATP channel-dependent pathways (38.70%). Conversely, CA influenced the opioid, glutamatergic (53.60%), and vanilloid (34.42%) pathways while inhibiting nitric oxide (52.99%) and cyclic guanosine monophosphate (38.98%). Conclusions: HEXA and CA exhibit significant antinociceptive effects due to their potential interference in multiple pain signaling pathways. While the molecular targets remain to be fully investigated, HEXA and CA demonstrate significant potential for the development of new analgesic drugs. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals — Multi-Targeted Natural Products as Therapeutics)

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12 pages, 6805 KiB

Open AccessArticle

Development of a PET Probe Targeting Bromodomain and Extra-Terminal Proteins for In Vitro and In Vivo Visualization

by Yongle Wang, Yanli Wang, Yulong Xu, Hua Cheng, Tewodros Mulugeta Dagnew, Leyi Kang, Darcy Tocci, Iris Z. Shen, Can Zhang and Changning Wang

Pharmaceuticals 2024, 17(12), 1670; https://doi.org/10.3390/ph17121670 - 11 Dec 2024

Abstract

Background: Bromodomain and extra-terminal (BET) proteins are critical regulators of gene transcription, as they recognize acetylated lysine residues. The BD1 bromodomain of BRD4, a member of the BET family, has emerged as a promising therapeutic target for various diseases. This study aimed to [...] Read more.

Background: Bromodomain and extra-terminal (BET) proteins are critical regulators of gene transcription, as they recognize acetylated lysine residues. The BD1 bromodomain of BRD4, a member of the BET family, has emerged as a promising therapeutic target for various diseases. This study aimed to develop and evaluate a novel C-11 labeled PET radiotracer, [¹¹C]YL10, for imaging the BD1 bromodomain of BRD4 in vivo. Methods: [¹¹C]YL10 was synthesized and evaluated for its ability to bind to the BD1 bromodomain selectively. PET imaging studies were conducted in mice to assess brain penetration, pharmacokinetics, and selectivity. In vitro autoradiography and blocking experiments were performed to confirm the tracer’s specificity for the BD1 domain. Results: [¹¹C]YL10 demonstrated good brain penetration, high selectivity for the BD1 bromodomain, and favorable pharmacokinetics in initial PET imaging studies. In vitro autoradiography and blocking experiments confirmed the specific binding of [¹¹C]YL10 to the BD1 domain of BRD4, further validating its potential as a targeted radiotracer. Conclusions: The development of [¹¹C]YL10 provides a new tool for studying BRD4 bromodomains using PET imaging technology. This radiotracer offers potential advancement in the diagnosis and research of neurodegenerative diseases and related disorders involving BRD4 dysregulation. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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24 pages, 3290 KiB

Open AccessReview

Targeting Iron Responsive Elements (IREs) of APP mRNA into Novel Therapeutics to Control the Translation of Amyloid-β Precursor Protein in Alzheimer’s Disease

by Mateen A. Khan

Pharmaceuticals 2024, 17(12), 1669; https://doi.org/10.3390/ph17121669 - 11 Dec 2024

Abstract

The hallmark of Alzheimer’s disease (AD) is the buildup of amyloid-β (Aβ), which is produced when the amyloid precursor protein (APP) misfolds and deposits as neurotoxic plaques in the brain. A functional iron responsive element (IRE) RNA stem loop is encoded by the [...] Read more.

The hallmark of Alzheimer’s disease (AD) is the buildup of amyloid-β (Aβ), which is produced when the amyloid precursor protein (APP) misfolds and deposits as neurotoxic plaques in the brain. A functional iron responsive element (IRE) RNA stem loop is encoded by the APP 5′-UTR and may be a target for regulating the production of Alzheimer’s amyloid precursor protein. Since modifying Aβ protein expression can give anti-amyloid efficacy and protective brain iron balance, targeted regulation of amyloid protein synthesis through modulation of 5′-UTR sequence function is a novel method for the prospective therapy of Alzheimer’s disease. Numerous mRNA interference strategies target the 2D RNA structure, even though messenger RNAs like tRNAs and rRNAs can fold into complex, three-dimensional structures, adding even another level of complexity. The IRE family is among the few known 3D mRNA regulatory elements. This review seeks to describe the structural and functional aspects of IREs in transcripts, including that of the amyloid precursor protein, that are relevant to neurodegenerative diseases, including AD. The mRNAs encoding the proteins involved in iron metabolism are controlled by this family of similar base sequences. Like ferritin IRE RNA in their 5′-UTR, iron controls the production of APP in their 5′-UTR. Iron misregulation by iron regulatory proteins (IRPs) can also be investigated and contrasted using measurements of the expression levels of tau production, Aβ, and APP. The development of AD is aided by iron binding to Aβ, which promotes Aβ aggregation. The development of small chemical therapeutics to control IRE-modulated expression of APP is increasingly thought to target messenger RNAs. Thus, IRE-modulated APP expression in AD has important therapeutic implications by targeting mRNA structures. Full article

(This article belongs to the Special Issue New Insights into Therapy for Alzheimer’s and Other Neurodegenerative Diseases)

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17 pages, 2212 KiB

Open AccessArticle

In Vitro Screening of an In-House Library of Structurally Distinct Chemotypes Towards the Identification of Novel SARS-CoV-2 Inhibitors

by Michele Tonelli, Anna Sparatore, Ivan Bassanini, Valeria Francesconi, Fabio Sparatore, Kevin K. Maina, Serena Delbue, Sarah D’Alessandro, Silvia Parapini and Nicoletta Basilico

Pharmaceuticals 2024, 17(12), 1668; https://doi.org/10.3390/ph17121668 - 11 Dec 2024

Abstract

Background/Objectives: Four years after the COVID-19 pandemic, a very limited number of drugs has been marketed; thus, the search for new medications still represents a compelling need. In our previous work on antiviral, antiparasitic, and antiproliferative agents, we described several compounds (1 [...] Read more.

Background/Objectives: Four years after the COVID-19 pandemic, a very limited number of drugs has been marketed; thus, the search for new medications still represents a compelling need. In our previous work on antiviral, antiparasitic, and antiproliferative agents, we described several compounds (1–13 and 16–20) structurally related to clofazimine, chloroquine, and benzimidazole derivatives. Thus, we deemed it worthwhile to test them against the replication of SARS-CoV-2, together with a few other compounds (14, 15 and 21–25), which showed some analogy to miscellaneous anti-coronavirus agents. Methods: Twenty-five structurally assorted compounds were evaluated in vitro for cytotoxicity against Vero E6 and for their ability to inhibit SARS-CoV-2 replication. Results: Several compounds (2, 3, 10, 11, 13–15, 18–20) demonstrated antiviral activity (IC₅₀ range 1.5–28 µM) and six of them exhibited an interesting selectivity index in the range 4.5–20. The chloroquine analogs 10 and 11 were more potent than the reference chloroquine itself and doubled its SI value (20 versus 11). Also, the benzimidazole ring emerged as a valuable scaffold, originating several compounds (13–15 and 18–20) endowed with anti-SARS-CoV-2 activity. Despite the modest activity, the cytisine and the arylamino enone derivatives 23 and 25, respectively, also deserve further consideration as model compounds. Conclusions: The investigated chemotypes may represent valuable hit compounds, deserving further in-depth biological studies to define their mechanisms of action. The derived information will guide the subsequent chemical optimization towards the development of more efficient anti-SARS-CoV-2 agents. Full article

(This article belongs to the Section Medicinal Chemistry)

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30 pages, 4182 KiB

Open AccessArticle

Design, Synthesis and Molecular Modeling of Pyrazolo[1,5-a]pyrimidine Derivatives as Dual Inhibitors of CDK2 and TRKA Kinases with Antiproliferative Activity

by Mohamed H. Attia, Deena S. Lasheen, Nermin Samir, Azza T. Taher, Hatem A. Abdel-Aziz and Dalal A. Abou El Ella

Pharmaceuticals 2024, 17(12), 1667; https://doi.org/10.3390/ph17121667 - 10 Dec 2024

Abstract

Background: The increasing prevalence of drug resistance in cancer therapy underscores the urgent need for novel therapeutic approaches. Dual enzyme inhibitors, targeting critical kinases such as CDK2 and TRKA, represent a promising strategy. The goal of this investigation was to design, synthesize, and [...] Read more.

Background: The increasing prevalence of drug resistance in cancer therapy underscores the urgent need for novel therapeutic approaches. Dual enzyme inhibitors, targeting critical kinases such as CDK2 and TRKA, represent a promising strategy. The goal of this investigation was to design, synthesize, and evaluate a set of pyrazolo[1,5-a]pyrimidine derivatives for their dual inhibition potential toward CDK2 and TRKA kinases, along with their potential antiproliferative against cancer cell lines. Methods: A set of pyrazolo[1,5-a]pyrimidine derivatives (6a–t, 11a–g, and 12) was synthesized and subjected to in vitro enzymatic assays to determine their inhibitory activity against CDK2 and TRKA kinases. Selected compounds were further assessed for antiproliferative effects across the set of 60 cell lines from the NCI, representing various human cancer types. Additionally, simulations of molecular docking were conducted to explore the modes of binding for the whole active compounds and compare them with known inhibitors. Results: Compounds 6t and 6s exhibited potent dual inhibitory activity, showing an IC₅₀ = 0.09 µM and 0.23 µM against CDK2, and 0.45 µM against TRKA, respectively. These results were comparable to reference inhibitors ribociclib (CDK2, IC₅₀ = 0.07 µM) and larotrectinib (TRKA, IC₅₀ = 0.07 µM). Among the studied derivatives, compound 6n displayed a notable broad-spectrum anticancer activity, achieving a mean growth inhibition (GI%) of 43.9% across 56 cell lines. Molecular docking simulations revealed that the synthesized compounds adopt modes of binding similar to those of the lead inhibitors. Conclusions: In this study, prepared pyrazolo[1,5-a]pyrimidine derivatives demonstrated significant potential as dual CDK2/TRKA inhibitors, and showed potent anticancer activity toward diverse cancer cell lines. These findings highlight their potential as key compounds for the design of novel anticancer therapeutics. Full article

(This article belongs to the Section Medicinal Chemistry)

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20 pages, 9545 KiB

Open AccessArticle

FDA-Approved Hydrogel-Mediated In Situ Sonodynamic and Chemotherapeutic Therapy for Pancreatic Cancer

by Jian Wang, Nianhui Yu, Yunpeng Tang, Yingsheng Cheng and Hui Li

Pharmaceuticals 2024, 17(12), 1666; https://doi.org/10.3390/ph17121666 - 10 Dec 2024

Abstract

Background: Albumin-bound paclitaxel (nab-PTX) nanoparticles have been proven effective in treating advanced pancreatic cancer. However, the clinical application of nab-PTX nanoparticles is often associated with suboptimal outcomes and severe side effects due to its non-specific distribution and rapid clearance. This study aims to [...] Read more.

Background: Albumin-bound paclitaxel (nab-PTX) nanoparticles have been proven effective in treating advanced pancreatic cancer. However, the clinical application of nab-PTX nanoparticles is often associated with suboptimal outcomes and severe side effects due to its non-specific distribution and rapid clearance. This study aims to develop a novel nanoplatform that integrates sonodynamic therapy (SDT) and chemotherapy to enhance treatment efficacy and reduce systemic side effects. Methods: Bovine serum albumin (BSA) was conjugated with chlorin e6 and paclitaxel (PTX) to form stable nanoparticles (NPs). These NPs were then incorporated into a biodegradable poly(lactic-co-glycolic acid)–b-polyethylene glycol–b–poly(lactic-co-glycolic acid) hydrogel for targeted drug delivery. The system’s stability and drug release profile were analyzed, followed by in vitro studies to evaluate cellular uptake and cancer cell killing efficacy. In vivo evaluation was performed using pancreatic cancer xenograft models, with intratumoral injection of the drug-loaded hydrogel. Results: The developed hydrogel system demonstrated enhanced stability and sustained release of PTX. In vitro analyses revealed significant cellular uptake and synergistic cancer cell killing effects through combined SDT and chemotherapy. In vivo studies showed prolonged intratumoral retention of the drug and remarkable inhibition of tumor growth. Conclusions: This novel nanoplatform offers a promising approach for improving pancreatic cancer treatment by enhancing intratumoral drug retention and minimizing systemic side effects. The synergistic effects of SDT and chemotherapy demonstrate the potential of this strategy in achieving better therapeutic outcomes. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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30 pages, 2372 KiB

Open AccessReview

Rhein: An Updated Review Concerning Its Biological Activity, Pharmacokinetics, Structure Optimization, and Future Pharmaceutical Applications

by Yuqi Fu, Le Yang, Lei Liu, Ling Kong, Hui Sun, Ye Sun, Fengting Yin, Guangli Yan and Xijun Wang

Pharmaceuticals 2024, 17(12), 1665; https://doi.org/10.3390/ph17121665 - 10 Dec 2024

Abstract

Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and [...] Read more.

Rhein is a natural active ingredient in traditional Chinese medicine that has attracted much attention due to its wide range of pharmacological activities. However, its clinical application is limited by low water solubility, poor oral absorption, and potential toxicity to the liver and kidneys. Recently, advanced extraction and synthesis techniques have made it possible to develop derivatives of rhein, which have better pharmacological properties and lower toxicity. This article comprehensively summarizes the biological activity and action mechanism of rhein. Notably, we found that TGF-β1 is the target of rhein improving tissue fibrosis, while NF-κB is the main target of its anti-inflammatory effect. Additionally, we reviewed the current research status of the pharmacokinetics, toxicology, structural optimization, and potential drug applications of rhein and found that the coupling and combination therapy of rhein and other active ingredients exhibit a synergistic effect, significantly enhancing therapeutic efficacy. Finally, we emphasize the necessity of further studying rhein’s pharmacological mechanisms, toxicology, and development of analogs, aiming to lay the foundation for its widespread clinical application as a natural product and elucidate its prospects in modern medicine. Full article

(This article belongs to the Section Natural Products)

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22 pages, 2761 KiB

Open AccessArticle

New Benzofuran–Pyrazole-Based Compounds as Promising Antimicrobial Agents: Design, Synthesis, DNA Gyrase B Inhibition, and In Silico Studies

by Somaia S. Abd El-Karim, Manal M. Anwar, Yasmin M. Syam, Hassan M. Awad, Asmaa Negm El-Dein, Mohamed K. El-Ashrey, Hamad M. Alkahtani and Sameh H. Abdelwahed

Pharmaceuticals 2024, 17(12), 1664; https://doi.org/10.3390/ph17121664 - 10 Dec 2024

Abstract

Background/Objectives: The alarming rise in antibiotic resistance necessitates the discovery of novel antimicrobial agents. This study aims to design, synthesize, and evaluate new benzofuran–pyrazole-based compounds for their antimicrobial, antioxidant, and anti-inflammatory properties. Methods: New benzofuran–pyrazole hybrid molecules were synthesized using the Vilsmeier–Haach reaction [...] Read more.

Background/Objectives: The alarming rise in antibiotic resistance necessitates the discovery of novel antimicrobial agents. This study aims to design, synthesize, and evaluate new benzofuran–pyrazole-based compounds for their antimicrobial, antioxidant, and anti-inflammatory properties. Methods: New benzofuran–pyrazole hybrid molecules were synthesized using the Vilsmeier–Haach reaction and other chemical processes. The structures of the synthesized compounds were confirmed through micro-analytical and spectral analyses. Their antimicrobial activities were assessed against various bacterial and fungal strains, while antioxidant and anti-inflammatory properties were evaluated using DPPH-free radical scavenging and HRBC membrane stabilization assays, respectively. The most promising compounds were further tested for DNA gyrase B inhibition. Results: Compounds 9, 10, and 11b–d exhibited significant broad-spectrum antimicrobial activity with MIC values ranging from 2.50 to 20 µg/mL. Compounds 4, 6, 9, 11b, and 11d demonstrated high antioxidant activity, with DPPH scavenging percentages between 84.16% and 90.52%. Most compounds showed substantial anti-inflammatory effects, with HRBC membrane stabilization percentages ranging from 86.70% to 99.25%. Compound 9 notably inhibited E. coli DNA gyrase B with an IC50 of 9.80 µM, comparable to ciprofloxacin. Conclusions: The benzofuran–pyrazole-based compounds, particularly compound 9, show great potential as new antimicrobial agents due to their broad-spectrum activity and potent DNA gyrase B inhibition. These findings support further development and optimization of these compounds for clinical applications. Full article

(This article belongs to the Special Issue Small Molecules as Antimicrobials 2024)

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22 pages, 2015 KiB

Open AccessReview

Visualizing the Tumor Microenvironment: Molecular Imaging Probes Target Extracellular Matrix, Vascular Networks, and Immunosuppressive Cells

by Hui-Wen Chan, Deng-Yu Kuo, Pei-Wei Shueng and Hui-Yen Chuang

Pharmaceuticals 2024, 17(12), 1663; https://doi.org/10.3390/ph17121663 - 10 Dec 2024

Abstract

The tumor microenvironment (TME) is a critical factor in cancer progression, driving tumor growth, immune evasion, therapeutic resistance, and metastasis. Understanding the dynamic interactions within the TME is essential for advancing cancer management. Molecular imaging provides a non-invasive, real-time, and longitudinal approach to [...] Read more.

The tumor microenvironment (TME) is a critical factor in cancer progression, driving tumor growth, immune evasion, therapeutic resistance, and metastasis. Understanding the dynamic interactions within the TME is essential for advancing cancer management. Molecular imaging provides a non-invasive, real-time, and longitudinal approach to studying the TME, with techniques such as positron emission tomography (PET), magnetic resonance imaging (MRI), and fluorescence imaging offering complementary strengths, including high sensitivity, spatial resolution, and intraoperative precision. Recent advances in imaging probe development have enhanced the ability to target and monitor specific components of the TME, facilitating early cancer diagnosis, therapeutic monitoring, and deeper insights into tumor biology. By integrating these innovations, molecular imaging offers transformative potential for precision oncology, improving diagnostic accuracy and treatment outcomes through a comprehensive assessment of TME dynamics. Full article

(This article belongs to the Special Issue Molecular Imaging of the Tumor Microenvironment)

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13 pages, 4472 KiB

Open AccessArticle

The Small GTPase Ran Increases Sensitivity of Ovarian Cancer Cells to Oncolytic Vesicular Stomatitis Virus

by Karen Geoffroy, Mélissa Viens, Emma Mary Kalin, Zied Boudhraa, Dominic Guy Roy, Jian Hui Wu, Diane Provencher, Anne-Marie Mes-Masson and Marie-Claude Bourgeois-Daigneault

Pharmaceuticals 2024, 17(12), 1662; https://doi.org/10.3390/ph17121662 - 10 Dec 2024

Abstract

Background/Objectives: Ovarian cancer is the deadliest gynecologic cancer, and with the majority of patients dying within the first five years of diagnosis, new therapeutic options are required. The small guanosine triphosphatase (GTPase) Ras-related nuclear protein (Ran) has been reported to be highly expressed [...] Read more.

Background/Objectives: Ovarian cancer is the deadliest gynecologic cancer, and with the majority of patients dying within the first five years of diagnosis, new therapeutic options are required. The small guanosine triphosphatase (GTPase) Ras-related nuclear protein (Ran) has been reported to be highly expressed in high-grade serous ovarian cancers (HGSOCs) and associated with poor outcomes. Blocking Ran function or preventing its expression were shown to be promising treatment strategies, however, there are currently no small molecule inhibitors available to specifically inhibit Ran function. Interestingly, a previous study suggested that the Vesicular stomatitis virus (VSV) could inhibit Ran activity. Given that VSV is an oncolytic virus (OV) and, therefore, has anti-cancer activity, we reasoned that oncolytic VSV (oVSV) might be particularly effective against ovarian cancer via Ran inhibition. Methods: We evaluated the sensitivity of patient-derived ovarian cancer cell lines to oVSV, as well as the impact of oVSV on Ran and vice versa, using overexpression systems, small interfering RNAs (siRNAs), and drug inhibition. Results: In this study, we evaluated the interplay between oVSV and Ran and found that, although oVSV does not consistently block Ran, increased Ran activation allows for better oVSV replication and tumor cell killing. Conclusions: Our study reveals a positive impact of Ran on oVSV sensitivity. Given the high expression of Ran in HGSOCs, which are particularly aggressive ovarian cancers, our data suggest that oVSV could be effective against the deadliest form of the disease. Full article

(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)

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30 pages, 6814 KiB

Open AccessArticle

Effects of Alnus japonica Hot Water Extract and Oregonin on Muscle Loss and Muscle Atrophy in C2C12 Murine Skeletal Muscle Cells

by Da Hyeon An, Chan Ho Lee, Yeeun Kwon, Tae Hee Kim, Eun Ji Kim, Jae In Jung, Sangil Min, Eun Ju Cheong, Sohyun Kim, Hee Kyu Kim and Sun Eun Choi

Pharmaceuticals 2024, 17(12), 1661; https://doi.org/10.3390/ph17121661 - 10 Dec 2024

Abstract

Background/Objectives: Sarcopenia is characterized by the loss of muscle mass and function, increases in mortality rate, and risk of comorbidities in the elderly. This study evaluated the effects of Alnus japonica hot water extract (AJHW) and its active compound, oregonin, on muscle atrophy [...] Read more.

Background/Objectives: Sarcopenia is characterized by the loss of muscle mass and function, increases in mortality rate, and risk of comorbidities in the elderly. This study evaluated the effects of Alnus japonica hot water extract (AJHW) and its active compound, oregonin, on muscle atrophy and apoptosis in vitro. Methods: AJHW underwent phytochemical analysis. C2C12 cells were subjected to H₂O₂ and dexamethasone to induce oxidative stress and muscle loss, after which AJHW and oregonin were administered to assess their impacts on cell viability, apoptosis, muscle protein synthesis stimulation, and muscle protein degradation inhibition. Cell viability was assessed via an MTT assay, and apoptosis was analyzed by measuring Bcl-2, Bax, cleaved caspase-3, and cleaved PARP through Western blotting. Western blotting and RT-PCR were utilized to analyze MyoD, Myogenin, Atrogin-1, and MuRF1 protein and gene expression in a muscle atrophy model, as well as the Akt/mTOR and FoxO3α pathways. Results: AJHW was confirmed to contain oregonin, an active compound. AJHW and oregonin significantly increased cell viability and reduced apoptosis by upregulating Bcl-2 and downregulating Bax, cleaved caspase-3, and cleaved PARP. They significantly enhanced muscle protein synthesis through the upregulation of MyoD and Myogenin, while diminishing muscle degradation by downregulating Atrogin-1 and MuRF1. The activation of the Akt/mTOR pathway and inhibition of the FoxO3α pathway were also observed. Conclusions: AJHW and oregonin effectively prevented muscle cell apoptosis, promoted muscle protein synthesis, and inhibited muscle protein degradation in vitro. These results suggest that AJHW and oregonin could serve as therapeutic agents to prevent and treat sarcopenia. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 2593 KiB

Open AccessArticle

Boronic Acid-Containing 3H- pyrazolo[4,3-f]quinoline Compounds as Dual CLK/ROCK Inhibitors with Anticancer Properties

by Neetu Dayal, Riddhi Chaudhuri, Kofi Simpa Yeboah, Nickolas R. Brauer and Herman O. Sintim

Pharmaceuticals 2024, 17(12), 1660; https://doi.org/10.3390/ph17121660 - 10 Dec 2024

Abstract

Background: The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as [...] Read more.

Background: The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as anticancer agents. Compounds with polypharmacology are desired, especially in oncology, due to the potential for high efficacy as well as addressing resistance issues. In this report, we have identified and characterized novel, boron-containing dual CLK/ROCK inhibitors with promising anticancer properties. Methods: A library of boronic acid-based CLK/ROCKi was synthesized via Povarov/Doebner-type multicomponent reactions. Kinase inhibition screening and cancer cell viability assays were performed to identify the hit compounds. To gain insights into the probable binding modes of the compounds to the kinases, docking studies were performed. Cell cycle analysis, qPCR and immunoblotting were carried out to further characterize the mode(s) of action of the lead candidates. Results: At 25 nM, the top compounds HSD1400 and HSD1791 inhibited CLK1 and 2 and ROCK2 at greater than 70%. While HSD1400 also inhibited CLK4, the C1 methylated analog HSD1791 did not inhibit CLK4. Antitumor effects of the top compounds were evaluated and dose–response analysis indicated potent inhibition of renal cancer and leukemia cell growth. Immunoblotting results indicated that the top compounds induce DNA damage via upregulation of p-H2AX. Moreover, flow cytometry results demonstrated that the top compounds promote cell cycle arrest in the renal cancer cell line, Caki-1. qPCR and immunoblotting analysis upon HSD1791 dosing indicated suppression of cyclin D/Rb oncogenic pathway upon compound treatment. Conclusions: Novel boronic acid-containing pyrazolo[4,3-f]quinoline-based dual CLK/ROCK inhibitors were identified. The so-called “magic methylation” design approach was used to tune CLK selectivity. Additionally, the findings demonstrate potent in vitro anticancer activity of the lead candidates against renal cancer and leukemia. This adds to the growing list of boron-containing compounds that display biological activities. Full article

(This article belongs to the Special Issue Boron in Medicinal Chemistry: From Synthesis to Therapeutic Applications)

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18 pages, 1123 KiB

Open AccessArticle

A Quantitative Chemometric Study of Pharmaceutical Tablet Formulations Using Multi-Spectroscopic Fibre Optic Probes

by Peter J. G. Remoto, Keith C. Gordon and Sara J. Fraser-Miller

Pharmaceuticals 2024, 17(12), 1659; https://doi.org/10.3390/ph17121659 - 9 Dec 2024

Abstract

Background/Objectives: Two fibre optic probes were custom designed to perform Raman and near-infrared spectroscopic measurements. Our long-term objective is to develop a non-destructive tool able to collect data in hard-to-access locations for real-time analysis or diagnostic purposes. This study evaluated the quantitative performances [...] Read more.

Background/Objectives: Two fibre optic probes were custom designed to perform Raman and near-infrared spectroscopic measurements. Our long-term objective is to develop a non-destructive tool able to collect data in hard-to-access locations for real-time analysis or diagnostic purposes. This study evaluated the quantitative performances of Probe A and Probe B using model pharmaceutical tablets. Methods: Measurements were performed using pharmaceutical tablets containing hydroxyl propylcellulose, titanium dioxide (anatase), lactose monohydrate, and indomethacin (γ form). Material content and thickness of bilayer samples (samples consisting of a top layer and a bottom layer of differing materials) were also assessed using Probe A to evaluate its capabilities to collect sub-surface information. Principal component analysis and partial least squares regression models were using individual and fused data to evaluate the performances of the different probe configurations. Results: Hydroxymethyl cellulose (

R_{P}^{2} = 0.98

, RMSEP = 2.27% w/w) and lactose monohydrate (

R_{P}^{2} = 0.97

, RMSEP = 2.96% w/w) content were most effectively estimated by near-infrared spectroscopy data collected using Probe A. Titanium dioxide (

R_{P}^{2} = 0.99

, RMSEP = 0.21% w/w) content was most effectively estimated using a combination of 785 nm Raman spectroscopy and near-infrared spectroscopy using Probe B. Indomethacin (

R_{P}^{2} = 0.97

, RMSEP = 1.01% w/w) was best estimated using a low-level fused dataset collected using 0 mm, 2.5 mm, and 5.0 mm lateral offsets of 785 nm spatially offset Raman spectroscopy using Probe A. Conclusions: The different probe configurations were able to reliably collect data and demonstrated robust quantitative performances. These results highlight the advantage of using multiple techniques for analysing different structures. Full article

(This article belongs to the Special Issue Polymorphs, Salts, Cocrystals and Cationic Lipid Nanoparticle Complexes in Drug Delivery)

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14 pages, 785 KiB

Open AccessReview

Dietary Supplements for Weight Loss and Drug Interactions

by Francisco Rivas García, José Antonio García Sierra, Maria-Isabel Valverde-Merino and Maria Jose Zarzuelo Romero

Pharmaceuticals 2024, 17(12), 1658; https://doi.org/10.3390/ph17121658 - 9 Dec 2024

Abstract

Food supplements are used for a variety of purposes, one of which is weight reduction. As excess weight is a long-term condition, some supplements are expected to be used for long periods of time. The long-term use of these dietary supplements makes it [...] Read more.

Food supplements are used for a variety of purposes, one of which is weight reduction. As excess weight is a long-term condition, some supplements are expected to be used for long periods of time. The long-term use of these dietary supplements makes it highly likely that they will be combined with medications, increasing the risk of food supplement–drug interactions, which are not always known or disclosed, and can lead to serious health problems, as has been observed. This article discusses some of the compounds used as food supplements for weight reduction (green tea extract, Garcinia cambogia, chitosan, quercetin and resveratrol) and the interactions they may cause with some drugs such as: dextromethorphan, buspirone, diclofenac, irinotecan, 5-fluorouracil, cytochrome P450 inducers and inhibitors, statins, orlistat, warfarina, acenocoumarol, fluoxetine, valproate, quetiapine, carbamazepine. This information is expected to be useful for healthcare professionals to detect and intervene on food supplement–drug interactions to ensure the optimization of therapy and patient safety. Full article

(This article belongs to the Special Issue Medications: Interactions with Diet, Herbs, Dietary Supplements and Probiotics)

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18 pages, 10280 KiB

Open AccessArticle

The Potential of TRPA1 as a Therapeutic Target in Cancer—A Study Using Bioinformatic Tools

by Dana Cucu

Pharmaceuticals 2024, 17(12), 1657; https://doi.org/10.3390/ph17121657 - 9 Dec 2024

Abstract

Background: The expression of the transient receptor potential 1 (TRPA1) gene is increased in many solid tumours, and its function relates to inflammation, oxidative stress or the presence of toxic substances. However, little is known about the correlation of clinical parameters with patients’ [...] Read more.

Background: The expression of the transient receptor potential 1 (TRPA1) gene is increased in many solid tumours, and its function relates to inflammation, oxidative stress or the presence of toxic substances. However, little is known about the correlation of clinical parameters with patients’ cancer stages, metastases and the degree of tumour infiltration by immune cells. Methods: We performed a bioinformatic analysis, using databases and public resources to investigate TRPA1 for many available samples. We used samples from the TCGA project and quantified the mRNA expression and survival analysis using TIMER, TIMER.2 and GEPIA. To analyse hypermethylation, a more extensive database was available from the UALCAN website. Results: We show that the TRPA1 gene is hypermethylated in many cancers. The high expression of TRPA1 is correlated with a better prognosis for several cancer types and correlates with cancer stage and metastasis, while in others the TRPA1 is pro-oncogenic. We also report the effect of TRPA1 expression in immune infiltrating cells. Moreover, the expression is linked to genes essential for inflammation, oxidative stress and cellular motility processes. Conclusions: Our study brings new insights into the regulation of TRPA1 expression in different tumours based on analysis provided by public databases, opening the possibility to further investigate the protein as a putative target for cancer. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels as Novel Therapeutic Targets)

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15 pages, 7500 KiB

Open AccessArticle

The Comparative Effect of Morphine on Proliferation of Cancer Cell Lines Originating from Different Organs: An In Vitro Study

by Lydia Whitham, Mahdi Sheikh, Markus W. Hollmann and Marie-Odile Parat

Pharmaceuticals 2024, 17(12), 1656; https://doi.org/10.3390/ph17121656 - 9 Dec 2024

Abstract

Background/Objectives: Opium consumption was recently classified by the International Agency for Research on Cancer (IARC) monograph as carcinogenic to humans based on strong evidence for cancers of the larynx, lung, and urinary bladder, and limited evidence for cancers of the oesophagus, stomach, [...] Read more.

Background/Objectives: Opium consumption was recently classified by the International Agency for Research on Cancer (IARC) monograph as carcinogenic to humans based on strong evidence for cancers of the larynx, lung, and urinary bladder, and limited evidence for cancers of the oesophagus, stomach, pancreas, and pharynx. This poses the question of a potential pro-cancer effect of pharmaceutical opioid analgesics. In vitro studies employing a variety of experimental conditions suggest that opioid alkaloids have proliferative or antiproliferative effects. We set out to reconcile this discrepancy and explore the hypothesis that opioids promote cancer cell proliferation in an organ-dependent fashion. Methods: Using strictly controlled conditions, we tested the effect of morphine on the proliferation of a series of human cancer cell lines isolated from organs where cancer risk was linked causally to opium consumption in human studies (i.e., lung, bladder, and larynx), or control organs where no link between cancer risk and opium consumption has been reported in human studies (i.e., breast, colon, prostate). Results: Our results showed a minimal effect on proliferation on any cell line and no trend supporting an organ-specific effect of morphine. Conclusions: This argues against a direct effect of opioids on tumour cell proliferation to support their organ-specific effect. Full article

(This article belongs to the Special Issue Pharmacology and Toxicology of Opioids)

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12 pages, 3049 KiB

Open AccessArticle

Effects of Semaglutide and Tirzepatide on Bone Metabolism in Type 2 Diabetic Mice

by Fang Lv, Xiaoling Cai, Chu Lin, Wenjia Yang and Linong Ji

Pharmaceuticals 2024, 17(12), 1655; https://doi.org/10.3390/ph17121655 - 9 Dec 2024

Abstract

Background/Objectives: Type 2 diabetes and weight loss are associated with detrimental skeletal health. Incretin-based therapies (GLP-1 receptor agonists, and dual GIP/GLP-1 receptor agonists) are used clinically to treat diabetes and obesity. The potential effects of semaglutide and tirzepatide on bone metabolism in type [...] Read more.

Background/Objectives: Type 2 diabetes and weight loss are associated with detrimental skeletal health. Incretin-based therapies (GLP-1 receptor agonists, and dual GIP/GLP-1 receptor agonists) are used clinically to treat diabetes and obesity. The potential effects of semaglutide and tirzepatide on bone metabolism in type 2 diabetic mice remain uncertain. Methods: Combined streptozotocin and high fat feeding were employed in female C57BL/6J mice to promote hyperglycemia. Mice were administered for 4 weeks with a saline vehicle (sc., once-daily), semaglutide (40 μg/kg/d, sc., every three days), or tirzepatide (10 nmol/kg, sc., once-daily). Bone strength was assessed by three-point bending. Femur microarchitecture was determined by micro-CT, and bone formation and resorption parameters were measured by histomorphometric analysis. Serum was collected to measure bone resorption (C-telopeptide fragments of type I collagen, CTX) and formation (procollagen type 1 N-terminal propeptide, P1NP) biomarkers, respectively. The expression of bone metabolism-related genes was evaluated in the bone using RT-PCR. Results: Glucose levels significantly reduced after 4 weeks of semaglutide and tirzepatide treatment (both p < 0.05) compared with vehicle treatment. Tirzepatide led to more weight loss than semaglutide. Compared to saline-treated diabetic mice, the mean femur length was shorter in the tirzepatide group. After treatment with tirzepatide or semaglutide, cortical bone and trabecular bone parameters did not change significantly compared to saline-treated diabetic mice, except that cortical thickness was lower in the semaglutide group compared to the saline group (p = 0.032). Though CTX and P1NP levels decreased, however, the change in CTX and P1NP levels did not differ among the four groups during the 4 weeks of treatment (all p > 0.05). Semaglutide affected RANKL and OPG mRNA expression and increased the ratio of OPG/RANKL. No significant difference was found in the quantity of Col1a1, RANKL, OPG, and RUNX2 between tirzepatide- and saline-treated diabetic mice. Conclusions: The 4-week treatment with semaglutide and tirzepatide had a neutral effect on bone mass compared with the controls, and most of the bone microarchitecture parameters were also comparable between groups in diabetic mice. A better understanding of incretin-based therapies on bone metabolism in patients with diabetes requires further evaluation in large clinical trials. Full article

(This article belongs to the Section Biopharmaceuticals)

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