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Pharmaceuticals, Volume 17, Issue 7 (July 2024) – 123 articles

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25 pages, 741 KiB  
Article
 Rubus urticifolius Compounds with Antioxidant Activity, and Inhibition Potential against Tyrosinase, Melanin, Hyaluronidase, Elastase, and Collagenase
by Luis Apaza Ticona, Javier Sánchez Sánchez-Corral, Carolina Díaz-Guerra Martín, Sara Calderón Jiménez, Alejandra López González and Cristina Thiebaut Estrada
Pharmaceuticals 2024, 17(7), 937; https://doi.org/10.3390/ph17070937 (registering DOI) - 13 Jul 2024
Abstract
In our study, using chromatographic techniques, we isolated three bioactive compounds, which were structurally elucidated as (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-N-methylbenzamide (1), 4-Hydroxyquinoline-2-carboxylic acid (2), and (E)-2-Cyano-3-(4-hydroxyphenyl)acrylic acid (3), using spectroscopic methods. The anti-melanogenic, anti-inflammatory, [...] Read more.
In our study, using chromatographic techniques, we isolated three bioactive compounds, which were structurally elucidated as (E)-2-(3-(3,4-dimethoxyphenyl)acrylamido)-N-methylbenzamide (1), 4-Hydroxyquinoline-2-carboxylic acid (2), and (E)-2-Cyano-3-(4-hydroxyphenyl)acrylic acid (3), using spectroscopic methods. The anti-melanogenic, anti-inflammatory, antioxidant, and anti-aging properties were evaluated in vitro by measuring the activity of pharmacological targets including tyrosinase, melanin, NF-κB, hyaluronidase, elastase, collagenase, and Nrf2. Our results show that compound 1 is the most active with IC50 values of 14.19 μM (tyrosinase inhibition), 22.24 μM (melanin inhibition), 9.82–12.72 μM (NF-κB inhibition), 79.71 μM (hyaluronidase inhibition), 80.13 μM (elastase inhibition), 76.59 μM (collagenase inhibition), and 116–385 nM (Nrf2 activation) in the THP-1, HEK001, WS1, and HMCB cells. These findings underscore the promising profiles of the aqueous extract of R. urticifolius at safe cytotoxic concentrations. Additionally, we report, for the first time, the isolation and characterisation of these nitrogenous compounds in the R. urticifolius species. Finally, compound 1, isolated from R. urticifolius, is a promising candidate for the development of more effective and safer compounds for diseases related to skin pigmentation, protection against inflammation, and oxidative stress. Full article
15 pages, 29647 KiB  
Article
The Effects of Seleno-Methionine in Cadmium-Challenged Human Primary Chondrocytes
by Valentina Urzì Brancati, Federica Aliquò, José Freni, Alice Pantano, Erika Galipò, Domenico Puzzolo, Letteria Minutoli, Herbert Ryan Marini, Giuseppe Maurizio Campo and Angela D’Ascola
Pharmaceuticals 2024, 17(7), 936; https://doi.org/10.3390/ph17070936 - 12 Jul 2024
Viewed by 76
Abstract
Cadmium (Cd) is a potentially toxic element able to interfere with cellular functions and lead to disease or even death. Cd accumulation has been demonstrated in cartilage, where it can induce damage in joints. The aim of this study was to evaluate the [...] Read more.
Cadmium (Cd) is a potentially toxic element able to interfere with cellular functions and lead to disease or even death. Cd accumulation has been demonstrated in cartilage, where it can induce damage in joints. The aim of this study was to evaluate the effect of CdCl2 on primary cultures of human chondrocytes and the possible protective effect of seleno-methionine (Se-Met). Human primary articular chondrocytes were cultured and treated as follows: control groups, cells challenged with 7.5 μM and 10 μM CdCl2 alone, and cells pretreated with 10 and 20 μM Se-Met and then challenged with 7.5 μM and 10 μM CdCl2. Twenty-four hours after incubation, cell viability, histological evaluation with hematoxylin–eosin stain, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were performed. Furthermore, reverse transcription-PCR was carried out to evaluate mRNA levels of BAX, BAK1, CASP-3, and CASP-9. After CdCl2 challenge at both doses, a reduced cell viability and an overexpression of BAX, BAK1, CASP-3, and CASP-9 genes, as well as a high number of TUNEL-positive cells, were demonstrated, all parameters becoming higher as the dose of CdCl2 was increased. The pretreatment with Se-Met lowered the expression of all considered genes, improved cell viability and morphological changes, and reduced the number of TUNEL-positive cells. It was concluded that Se-Met plays a protective role against CdCl2-induced structural and functional changes in chondrocytes in vitro, as it improved cell viability and showed a positive role in the context of the apoptotic pathways. It is therefore suggested that a translational, multifaceted approach, with plant-based diets, bioactive functional foods, nutraceuticals, micronutrients, and drugs, is possibly advisable in situations of environmental pollution caused by potentially toxic elements. Full article
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19 pages, 4637 KiB  
Article
Discovery of Novel Allosteric SHP2 Inhibitor Using Pharmacophore-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation, and Principal Component Analysis
by Pooja Singh, Vikas Kumar, Keun Woo Lee and Jong Chan Hong
Pharmaceuticals 2024, 17(7), 935; https://doi.org/10.3390/ph17070935 - 12 Jul 2024
Viewed by 110
Abstract
SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting [...] Read more.
SHP2 belongs to a cytoplasmic non-receptor protein tyrosine phosphatase class. It plays a critical role in the development of various cancers, such as gastric cancer, leukemia, and breast cancer. Thus, SHP2 has gained the interest of researchers as a potential target for inhibiting tumor cell proliferation in SHP2-dependent cancers. This study employed pharmacophore-based virtual screening, molecular docking, molecular dynamic (MD) simulations, MM/PBSA, and principal component analysis (PCA), followed by ADME prediction. We selected three potential hits from a collective database of more than one million chemical compounds. The stability of these selected hit–protein complexes was analyzed using 500 ns MD simulations and binding free energy calculations. The identified hits Lig_1, Lig_6, and Lig_14 demonstrated binding free energies of −161.49 kJ/mol, −151.28 kJ/mol, and −107.13 kJ/mol, respectively, compared to the reference molecule (SHP099) with a ΔG of −71.48 kJ/mol. Our results showed that the identified compounds could be used as promising candidates for selective SHP2 allosteric inhibition in cancer. Full article
(This article belongs to the Special Issue Computer-Aided Drug Design and Drug Discovery)
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20 pages, 8678 KiB  
Article
Exploring Vacuum Compression Molding as a Preparation Method for Flexible-Dose Pediatric Orodispersible Films
by Dana Hales, Cătălina Bogdan, Lucia Ruxandra Tefas, Andreea Cornilă, Maria-Andreea Chiver, Ioan Tomuță, Tibor Casian, Rareș Iovanov, Gábor Katona, Rita Ambrus and Sonia Iurian
Pharmaceuticals 2024, 17(7), 934; https://doi.org/10.3390/ph17070934 - 12 Jul 2024
Viewed by 146
Abstract
In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies [...] Read more.
In recent years, solid dosage forms have gained interest in pediatric therapy because they can provide valuable benefits in terms of dose accuracy and stability. Particularly for orodispersible films (ODFs), the literature evidences increased acceptability and dose flexibility. Among the various available technologies for obtaining ODFs, such as solvent casting, hot-melt extrusion, and ink printing technologies, the solvent-free preparation methods exhibit significant advantages. This study investigated Vacuum Compression Molding (VCM) as a solvent-free manufacturing method for the preparation of flexible-dose pediatric orodispersible films. The experimental approach focused on selecting the appropriate plasticizer and ratios of the active pharmaceutical ingredient, diclofenac sodium, followed by the study of their impacts on the mechanical properties, disintegration time, and drug release profile of the ODFs. Additional investigations were performed to obtain insights regarding the solid-state properties. The ODFs obtained by VCM displayed adequate quality in terms of their critical characteristics. Therefore, this proof-of-concept study shows how VCM could be utilized as a standalone method for the production of small-scale ODFs, enabling the customization of doses to meet the individual needs of pediatric patients. Full article
(This article belongs to the Special Issue Advances in Pediatric Drug Formulations)
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12 pages, 3385 KiB  
Article
Adenosine Monophosphate as a Metabolic Adjuvant Enhances Antibiotic Efficacy against Drug-Resistant Bacterial Pathogens
by Wenxuan Zhang, Zhenyi Wu, Zulifukeer Maituersong, Ting Wang and Yubin Su
Pharmaceuticals 2024, 17(7), 933; https://doi.org/10.3390/ph17070933 - 11 Jul 2024
Viewed by 208
Abstract
Global bacterial infections are on the rise, and drug resistance to bacteria is gradually rendering existing antibiotics ineffective. Therefore, the discovery of new strategies is urgently needed. Cellular metabolism is a key factor in the regulation of bacterial drug resistance, which cannot be [...] Read more.
Global bacterial infections are on the rise, and drug resistance to bacteria is gradually rendering existing antibiotics ineffective. Therefore, the discovery of new strategies is urgently needed. Cellular metabolism is a key factor in the regulation of bacterial drug resistance, which cannot be separated from the utilization of energetic substances, suggesting that energetic substances may be associated with bacterial drug resistance. In this study, we found that adenosine monophosphate (AMP) can enhance the bactericidal effect of gentamicin against gentamicin-resistant Staphylococcus aureus. This synergistic effect can be generalized for use with different antibiotics and Gram-positive or Gram-negative bacteria. We also validated that the mechanism of AMP reversal of antibiotic resistance involves enhancing the proton motive force via the tricarboxylic acid cycle to increase antibiotic uptake. Simultaneously, AMP increases oxidative stress-induced cell death. This study presents a strategy for adopting low-dose antibiotics to control drug-resistant bacteria, which is important for future drug development and bacterial control. Full article
(This article belongs to the Section Biopharmaceuticals)
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25 pages, 3634 KiB  
Review
Photodynamic Therapy in the Treatment of Cancer—The Selection of Synthetic Photosensitizers
by David Aebisher, Iga Serafin, Katarzyna Batóg-Szczęch, Klaudia Dynarowicz, Ewa Chodurek, Aleksandra Kawczyk-Krupka and Dorota Bartusik-Aebisher
Pharmaceuticals 2024, 17(7), 932; https://doi.org/10.3390/ph17070932 - 11 Jul 2024
Viewed by 198
Abstract
Photodynamic therapy (PDT) is a promising cancer treatment method that uses photosensitizing (PS) compounds to selectively destroy tumor cells using laser light. This review discusses the main advantages of PDT, such as its low invasiveness, minimal systemic toxicity and low risk of complications. [...] Read more.
Photodynamic therapy (PDT) is a promising cancer treatment method that uses photosensitizing (PS) compounds to selectively destroy tumor cells using laser light. This review discusses the main advantages of PDT, such as its low invasiveness, minimal systemic toxicity and low risk of complications. Special attention is paid to photosensitizers obtained by chemical synthesis. Three generations of photosensitizers are presented, starting with the first, based on porphyrins, through the second generation, including modified porphyrins, chlorins, 5-aminolevulinic acid (ALA) and its derivative hexyl aminolevulinate (HAL), to the third generation, which is based on the use of nanotechnology to increase the selectivity of therapy. In addition, current research trends are highlighted, including the search for new photosensitizers that can overcome the limitations of existing therapies, such as heavy-atom-free nonporphyrinoid photosensitizers, antibody–drug conjugates (ADCs) or photosensitizers with a near-infrared (NIR) absorption peak. Finally, the prospects for the development of PDTs are presented, taking into account advances in nanotechnology and biomedical engineering. The references include both older and newer works. In many cases, when writing about a given group of first- or second-generation photosensitizers, older publications are used because the properties of the compounds described therein have not changed over the years. Moreover, older articles provide information that serves as an introduction to a given group of drugs. Full article
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16 pages, 4083 KiB  
Article
Small Structural Differences in Proline-Rich Decapeptides Have Specific Effects on Oxidative Stress-Induced Neurotoxicity and L-Arginine Generation by Arginosuccinate Synthase
by Carlos Alberto-Silva, Brenda Rufino da Silva, Julio Cezar Araujo da Silva, Felipe Assumpção da Cunha e Silva, Roberto Tadashi Kodama, Wilmar Dias da Silva, Maricilia Silva Costa and Fernanda Calheta Vieira Portaro
Pharmaceuticals 2024, 17(7), 931; https://doi.org/10.3390/ph17070931 - 11 Jul 2024
Viewed by 225
Abstract
Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated [...] Read more.
Introduction. The proline-rich decapeptide 10c (Bj-PRO-10c; ENWPHPQIPP) from the Bothrops jararaca snake modulates argininosuccinate synthetase (AsS) activity to stimulate L-arginine metabolite production and neuroprotection in the SH-SY5Y cell line. The relationships between structure, interactions with AsS, and neuroprotection are little known. We evaluated the neuroprotective effects of Bj-PRO-10c and three other PROs (Bn-PRO-10a, <ENWPRPKIPP; Bn-PRO-10a-MK, <ENWPRPKIPPMK; and, Bn-PRO-10c, <ENWPRPKVPP) identified from Bitis nasicornis snake venom, with a high degree of similarity to Bj-PRO-10c, on oxidative stress-induced toxicity in neuronal PC12 cells and L-arginine metabolite generation via AsS activity regulation. Methods. Cell integrity, metabolic activity, reactive oxygen species (ROS) production, and arginase activity were examined after 4 h of PRO pre-treatment and 20 h of H2O2-induced damage. Results. Only Bn-PRO-10a-MK and Bn-PRO-10c restored cell integrity and arginase function under oxidative stress settings, but they did not reduce ROS or cell metabolism. The MK dipeptide in Bn-PRO-10a-MK and valine (V8) in Bn-PRO-10c are important to these effects when compared to Bn-PRO-10a. Bj-PRO-10c is not neuroprotective in PC12 cells, perhaps because of their limited NMDA-type glutamate receptor activity. The PROs interaction analysis on AsS activation can be rated as follows: Bj-PRO-10c > Bn-PRO-10c > Bn-PRO-10a-MK > Bn-PRO-10a. The structure of PROs and their correlations with enzyme activity revealed that histidine (H5) and glutamine (Q7) in Bj-PRO-10c potentiated their affinity for AsS. Conclusions. Our investigation provides the first insights into the structure and molecular interactions of PROs with AsS, which could possibly further their neuropharmacological applications. Full article
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12 pages, 1411 KiB  
Article
Pirfenidone in Idiopathic Pulmonary Fibrosis: Real-World Observation on Efficacy and Safety, Focus on Patients Undergoing Antithrombotic and Anticoagulant
by Nicolò Reccardini, Maria Chernovsky, Francesco Salton, Paola Confalonieri, Lucrezia Mondini, Mariangela Barbieri, Antonio Romallo, Marta Maggisano, Chiara Torregiani, Pietro Geri, Michael Hughes, Corrado Campochiaro, Marco Confalonieri, Angelo Scarda, Umberto Zuccon and Barbara Ruaro
Pharmaceuticals 2024, 17(7), 930; https://doi.org/10.3390/ph17070930 - 11 Jul 2024
Viewed by 204
Abstract
Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 584 KiB  
Systematic Review
Examining the Impact of Ertugliflozin on Cardiovascular Outcomes in Patients with Diabetes and Metabolic Syndrome: A Systematic Review of Clinical Trials
by Silvius Alexandru Pescariu, Ahmed Elagez, Balaji Nallapati, Felix Bratosin, Adina Bucur, Alina Negru, Laura Gaita, Ioana Mihaela Citu, Zoran Laurentiu Popa and Paula Irina Barata
Pharmaceuticals 2024, 17(7), 929; https://doi.org/10.3390/ph17070929 - 11 Jul 2024
Viewed by 185
Abstract
Cardiovascular diseases (CVDs) constitute a significant cause of morbidity and mortality globally, particularly among individuals with type 2 diabetes mellitus (T2DM). Ertugliflozin, a Sodium-Glucose Co-transporter-2 (SGLT2) inhibitor, is hypothesized to confer cardiovascular protection; however, long-term follow-up studies are necessary to support the hypothesis. [...] Read more.
Cardiovascular diseases (CVDs) constitute a significant cause of morbidity and mortality globally, particularly among individuals with type 2 diabetes mellitus (T2DM). Ertugliflozin, a Sodium-Glucose Co-transporter-2 (SGLT2) inhibitor, is hypothesized to confer cardiovascular protection; however, long-term follow-up studies are necessary to support the hypothesis. This systematic review was conducted to evaluate the cardiovascular effects of ertugliflozin in diabetic versus non-diabetic cohorts, focusing on major adverse cardiovascular events (MACEs), hospitalizations for heart failure, and cardiovascular mortality. Adhering to PRISMA guidelines, the review encompassed studies indexed in PubMed, Scopus, and Web of Science up to March 2024. Eligibility was restricted to studies involving T2DM patients undergoing ertugliflozin treatment with reported outcomes relevant to cardiovascular health. Out of 767 initially identified articles, 6 met the inclusion criteria. Data concerning hazard ratios (HR) and confidence intervals (CI) were extracted to compare the effects of ertugliflozin with those of a placebo or other standard therapies. The collective sample size across these studies was 8246 participants. Ertugliflozin was associated with a significant reduction in hospitalizations for heart failure relative to a placebo (HR 0.70, 95% CI 0.54–0.90, p < 0.05). Furthermore, when combined with metformin, ertugliflozin potentially reduced MACEs (HR 0.92, 95% CI 0.79–1.07), although this finding did not reach statistical significance. Importantly, for patients with pre-existing heart failure, ertugliflozin significantly decreased the exacerbations of heart failure (HR 0.53, 95% CI 0.33–0.84, p < 0.01). Overall, ertugliflozin markedly reduces hospitalizations due to heart failure in T2DM patients and may improve additional cardiovascular outcomes. These results endorse the integration of ertugliflozin into therapeutic protocols for T2DM patients at elevated cardiovascular risk and substantiate its efficacy among SGLT2 inhibitors. Continued investigations are recommended to delineate its long-term cardiovascular benefits in diverse patient populations, including the potential impact on arrhythmias. Full article
(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy)
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14 pages, 2115 KiB  
Article
Phytochemical Profile, Antioxidant, Anti-Atopic, and Anti-Inflammatory Activities of Filipendula glaberrima Nakai at Different Growth Stages
by Hak-Dong Lee, Genevieve Tonog, Neil Patrick Uy, Yunji Lee, Ki-Young Kim, Hangeun Kim and Sanghyun Lee
Pharmaceuticals 2024, 17(7), 928; https://doi.org/10.3390/ph17070928 - 11 Jul 2024
Viewed by 326
Abstract
Since atopic dermatitis is an inflammatory skin disease, natural remedies, such as Filipendula glaberrima Nakai (FG), with anti-inflammatory properties are possible promising therapeutic options. This study aimed to investigate the therapeutic potential of FG extracts at different growth stages. Seven compounds were isolated [...] Read more.
Since atopic dermatitis is an inflammatory skin disease, natural remedies, such as Filipendula glaberrima Nakai (FG), with anti-inflammatory properties are possible promising therapeutic options. This study aimed to investigate the therapeutic potential of FG extracts at different growth stages. Seven compounds were isolated from the FG leaf extracts using open-column chromatography, and they were analyzed using HPLC. The extracts were further evaluated for their total polyphenol and flavonoid content (TPC and TFC). The in vitro antioxidant properties of the FG extracts were evaluated using radical scavenging assays, whereas their anti-inflammatory activities were assessed by evaluating their ability to inhibit the production of inflammation-associated biomarkers using the Griess assay and ELISA, respectively. The MTT assay was used to evaluate the viability and cytotoxicity of the FG extracts in keratinocyte cell lines. The results showed that the full-flowering stage exhibited the highest TPC, TFC, and antioxidant activities, thus suggesting a positive correlation between these properties. All FG extracts showed significant anti-inflammatory activity by inhibiting the production of pro-inflammatory biomarkers in lipopolysaccharide-stimulated macrophages. Additionally, the FG extracts suppressed the production of cytokines and chemokines in keratinocytes, indicating their anti-atopic potential. HPLC analysis revealed that the full-flowering stage had the highest content of all the analyzed phytochemicals (gallic acid, (+)-catechin, hyperin, miquelianin, astragalin, afzelin, and quercetin). These results suggest that the full-flowering stage of FG is the most promising source for therapeutic applications owing to its superior phytochemical profile and biological activities. This study highlights the potential of FG extracts, particularly in its full-flowering stage, as a natural therapeutic agent for the management of inflammation-related diseases, and it can also serve as a reference for further research on FG. Full article
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14 pages, 708 KiB  
Article
Locoregional Radiotherapy in Patients with Advanced Breast Cancer Treated with Cyclin-Dependent Kinase 4/6 Inhibitors Based on Real-World Data
by Marcin Kubeczko, Dorota Gabryś, Anna Polakiewicz-Gilowska, Barbara Bobek-Billewicz and Michał Jarząb
Pharmaceuticals 2024, 17(7), 927; https://doi.org/10.3390/ph17070927 - 11 Jul 2024
Viewed by 255
Abstract
Background. The use of locoregional radiotherapy (RT) in patients with advanced ER-positive, HER2-negative breast cancer remains a topic of ongoing debate. In this study, we aimed to evaluate the efficacy of locoregional RT in advanced breast cancer patients treated with cyclin-dependent kinase 4/6 [...] Read more.
Background. The use of locoregional radiotherapy (RT) in patients with advanced ER-positive, HER2-negative breast cancer remains a topic of ongoing debate. In this study, we aimed to evaluate the efficacy of locoregional RT in advanced breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in a first-line setting. Methods. We conducted a retrospective analysis of patients diagnosed with advanced breast cancer between 2018 and 2023 who received treatment with CDK4/6i and underwent locoregional radiotherapy. Results. Among the 371 patients treated with CDK4/6i as part of their first-line therapy, 23 received locoregional RT either concurrently or sequentially with CDK4/6 inhibitors. Disease progression within the breast occurred in 19 patients (5.1%). Among these cases, five patients had previously undergone breast RT (5/23, 21.7%), while 14 did not (14/348, 4.0%, p = 0.004). All cases of local progression after RT followed palliative doses and were accompanied by early systemic progression. The 2-year PFS in the entire cohort of patients treated with locoregional RT was 65.7% (95% CI: 40.5–82.3%). Notably, patients who received higher RT doses had longer 2-year PFS (83.3%, 95% CI: 27.3–97.5%) than those with palliative RT doses (59.3%, 95% CI: 30.7–79.3%); however, the results were not statistically significant (p = 0.58). Furthermore, the 2-year local control in the entire cohort with locoregional RT was 73.0% (95% CI: 46.5–87.9%). Importantly, no local progression was observed after RT when using high doses. Conclusions. The addition of locoregional radiotherapy to first-line CDK4/6 inhibitors warrants further investigation across various clinical scenarios in advanced breast cancer. Palliative radiation regimens delivered early in breast oligoprogression may not always suffice, emphasizing the need for comprehensive studies in this context. Full article
(This article belongs to the Section Medicinal Chemistry)
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16 pages, 4748 KiB  
Article
Prunus yedoensis Bark Downregulates the Expression of Cell Adhesion Molecules in Human Endothelial Cell Lines and Relaxes Blood Vessels in Rat Aortic Rings
by Ye Eun Choi, Jung Mo Yang, Chae Won Jeong, Sujin Shin, Junkyu Park, Kyungjin Lee and Ju Hyun Cho
Pharmaceuticals 2024, 17(7), 926; https://doi.org/10.3390/ph17070926 - 10 Jul 2024
Viewed by 262
Abstract
The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and [...] Read more.
The incidence of cardiovascular diseases, such as high blood pressure, is increasing worldwide, owing to population aging and irregular lifestyle habits. Previous studies have reported the vasorelaxant effects of Prunus yedoensis bark methanol extract. However, various solvent extracts of P. yedoensis bark and their vascular relaxation mechanisms have not been sufficiently studied. We prepared extracts of P. yedoensis bark using various solvents (water, 30% ethanol, and 70% ethanol). P. yedoensis bark 30% ethanol extract (PYB-30E) decreased the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in human umbilical vein endothelial cells (HUVECs) activated with 200 ng/mL TNF-α. Additionally, PYB-30E showed vasodilatory effects on isolated rat aortic rings. This was confirmed to be the result of the activation of the NO/cGMP pathway, regulation of non-selective calcium-activated K+ channels, and calcium channel blockade. Additionally, PYB-30E significantly reduced systolic and diastolic blood pressure in spontaneously hypertensive rats (SHR). Taken together, our results indicated that PYB-30E is a candidate functional material with preventive and therapeutic effects against hypertension. Full article
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39 pages, 627 KiB  
Review
Biosimilars in the Era of Artificial Intelligence—International Regulations and the Use in Oncological Treatments
by Tomas Gabriel Bas and Vannessa Duarte
Pharmaceuticals 2024, 17(7), 925; https://doi.org/10.3390/ph17070925 - 10 Jul 2024
Viewed by 237
Abstract
This research is based on three fundamental aspects of successful biosimilar development in the challenging biopharmaceutical market. First, biosimilar regulations in eight selected countries: Japan, South Korea, the United States, Canada, Brazil, Argentina, Australia, and South Africa, represent the four continents. The regulatory [...] Read more.
This research is based on three fundamental aspects of successful biosimilar development in the challenging biopharmaceutical market. First, biosimilar regulations in eight selected countries: Japan, South Korea, the United States, Canada, Brazil, Argentina, Australia, and South Africa, represent the four continents. The regulatory aspects of the countries studied are analyzed, highlighting the challenges facing biosimilars, including their complex approval processes and the need for standardized regulatory guidelines. There is an inconsistency depending on whether the biosimilar is used in a developed or developing country. In the countries observed, biosimilars are considered excellent alternatives to patent-protected biological products for the treatment of chronic diseases. In the second aspect addressed, various analytical AI modeling methods (such as machine learning tools, reinforcement learning, supervised, unsupervised, and deep learning tools) were analyzed to observe patterns that lead to the prevalence of biosimilars used in cancer to model the behaviors of the most prominent active compounds with spectroscopy. Finally, an analysis of the use of active compounds of biosimilars used in cancer and approved by the FDA and EMA was proposed. Full article
(This article belongs to the Special Issue Analytical Techniques in the Pharmaceutical Sciences 2023)
15 pages, 1685 KiB  
Article
A Comprehensive Physiologically Based Pharmacokinetic Model for Predicting Vildagliptin Pharmacokinetics: Insights into Dosing in Renal Impairment
by Mahnoor Pasha, Ammara Zamir, Muhammad Fawad Rasool, Hamid Saeed, Tanveer Ahmad, Nawaf Shalih Alqahtani, Lamya Saif Alqahtani and Faleh Alqahtani
Pharmaceuticals 2024, 17(7), 924; https://doi.org/10.3390/ph17070924 - 10 Jul 2024
Viewed by 432
Abstract
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly [...] Read more.
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration–time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients. Full article
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17 pages, 3079 KiB  
Review
Hydrogel Loaded with Extracellular Vesicles: An Emerging Strategy for Wound Healing
by Yucan Yang, Huizhi Chen, Yunjie Li, Junting Liang, Feng Huang, Liyan Wang, Huilai Miao, Himansu Sekhar Nanda, Jin Wu, Xinsheng Peng and Yubin Zhou
Pharmaceuticals 2024, 17(7), 923; https://doi.org/10.3390/ph17070923 - 10 Jul 2024
Viewed by 379
Abstract
An increasing number of novel biomaterials have been applied in wound healing therapy. Creating beneficial environments and containing various bioactive molecules, hydrogel- and extracellular vesicle (EV)-based therapies have respectively emerged as effective approaches for wound healing. Moreover, the synergistic combination of these two [...] Read more.
An increasing number of novel biomaterials have been applied in wound healing therapy. Creating beneficial environments and containing various bioactive molecules, hydrogel- and extracellular vesicle (EV)-based therapies have respectively emerged as effective approaches for wound healing. Moreover, the synergistic combination of these two components demonstrates more favorable outcomes in both chronic and acute wound healing. This review provides a comprehensive discussion and summary of the combined application of EVs and hydrogels to address the intricate scenario of wounds. The wound healing process and related biological mechanisms are outlined in the first section. Subsequently, the utilization of EV-loaded hydrogels during the wound healing process is evaluated and discussed. The moist environment created by hydrogels is conducive to wound tissue regeneration. Additionally, the continuous and controlled release of EVs from various origins could be achieved by hydrogel encapsulation. Finally, recent in vitro and in vivo studies reported on hydrogel dressings loaded with EVs are summarized and challenges and opportunities for the future clinical application of this therapeutic approach are outlined. Full article
(This article belongs to the Special Issue Hydrogels for Pharmaceutical and Biomedical Applications 2024)
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53 pages, 15493 KiB  
Review
Indole Compounds in Oncology: Therapeutic Potential and Mechanistic Insights
by Sara M. Hassan, Alyaa Farid, Siva S. Panda, Mohamed S. Bekheit, Holden Dinkins, Walid Fayad and Adel S. Girgis
Pharmaceuticals 2024, 17(7), 922; https://doi.org/10.3390/ph17070922 - 10 Jul 2024
Viewed by 448
Abstract
Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the [...] Read more.
Cancer remains a formidable global health challenge, with current treatment modalities such as chemotherapy, radiotherapy, surgery, and targeted therapy often hindered by low efficacy and adverse side effects. The indole scaffold, a prominent heterocyclic structure, has emerged as a promising candidate in the fight against cancer. This review consolidates recent advancements in developing natural and synthetic indolyl analogs, highlighting their antiproliferative activities against various cancer types over the past five years. These analogs are categorized based on their efficacy against common cancer types, supported by biochemical assays demonstrating their antiproliferative properties. In this review, emphasis is placed on elucidating the mechanisms of action of these compounds. Given the limitations of conventional cancer therapies, developing targeted therapeutics with enhanced selectivity and reduced side effects remains a critical focus in oncological research. Full article
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19 pages, 5390 KiB  
Article
Unveiling the Mechanisms Underlying the Immunotherapeutic Potential of Gene–miRNA and Drugs in Head and Neck Cancer
by Danishuddin, Md Azizul Haque, Md. Zubbair Malik, Rakesh Arya, Pooja Singh, Jeong-Sang Lee, Jong-Joo Kim, Keun-Woo Lee and Tae-Sung Jung
Pharmaceuticals 2024, 17(7), 921; https://doi.org/10.3390/ph17070921 - 10 Jul 2024
Viewed by 236
Abstract
Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify [...] Read more.
Head and neck cancer ranks as the sixth-most common malignancy worldwide, characterized by high mortality and recurrence rates. Research studies indicate that molecular diagnostics play a crucial role in the early detection and prognostic evaluation of these diseases. This study aimed to identify potential biomarkers for head and neck cancer and elucidate their interactions with miRNAs and possible therapeutic drugs. Four drivers, namely, FN1, IL1A, COL1A1, and MMP9, were identified using network biology and machine learning approaches. Gene set variation analysis (GSVA) showed that these genes were significantly involved in different biological processes and pathways, including coagulation, UV-response-down, apoptosis, NOTCH signaling, Wnt-beta catenin, and other signal pathways. The diagnostic value of these hub genes was validated using receiver operating characteristic (ROC) curves. The top interactive miRNAs, including miR-128-3p, miR-218-5p, miR-214-3p, miR-124-3p, miR-129-2-3p, and miR-1-3p, targeted the key genes. Furthermore, the interaction between the key genes and drugs was also identified. In summary, the key genes and miRNAs or drugs reported in this study might provide valuable information for potential biomarkers to increase the prognosis and diagnosis of head and neck cancer. Full article
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8 pages, 528 KiB  
Study Protocol
Role of Dapagliflozin in Ischemic Preconditioning in Patients with Symptomatic Coronary Artery Disease—DAPA-IP Study Protocol
by Marco Alexander Valverde Akamine, Beatriz Moreira Ayub Ferreira Soares, João Paulo Mota Telles, Arthur Cicupira Rodrigues de Assis, Gabriela Nicole Valverde Rodriguez, Paulo Rogério Soares, William Azem Chalela and Thiago Luis Scudeler
Pharmaceuticals 2024, 17(7), 920; https://doi.org/10.3390/ph17070920 - 10 Jul 2024
Viewed by 216
Abstract
Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation [...] Read more.
Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5′-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia–reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD. Full article
(This article belongs to the Special Issue Advancements in Cardiovascular and Antidiabetic Drug Therapy)
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26 pages, 1375 KiB  
Review
Oral Nanoformulations in Cardiovascular Medicine: Advances in Atherosclerosis Treatment
by Xu Sun, Xushuang Jia, Zhaolin Tan, Dongmei Fan, Meiqi Chen, Ning Cui, Aidong Liu and Da Liu
Pharmaceuticals 2024, 17(7), 919; https://doi.org/10.3390/ph17070919 - 10 Jul 2024
Viewed by 319
Abstract
Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels [...] Read more.
Atherosclerosis (AS) is the formation of atherosclerotic plaques on the walls of the arteries, causing them to narrow. If this occurs in the coronary arteries, the blood vessels may be completely blocked, resulting in myocardial infarction; if it occurs in the blood vessels of the brain, the blood vessels may be blocked, resulting in cerebral infarction, i.e., stroke. Studies have shown that the pathogenesis of atherosclerosis involves the processes of inflammation, lipid infiltration, oxidative stress, and endothelial damage, etc. SIRT, as a key factor regulating the molecular mechanisms of oxidative stress, inflammation, and aging, has an important impact on the pathogenesis of plaque formation, progression, and vulnerability. Statistics show that AS accounts for about 50 per cent of deaths in Western countries. Currently, oral medication is the mainstay of AS treatment, but its development is limited by side effects, low bioavailability and other unfavourable factors. In recent years, with the rapid development of nano-preparations, researchers have combined statins and natural product drugs within nanopreparations to improve their bioavailability. Based on this, this paper summarises the main pathogenesis of AS and also proposes new oral nanoformulations such as liposomes, nanoparticles, nanoemulsions, and nanocapsules to improve their application in the treatment of AS. Full article
(This article belongs to the Section Pharmaceutical Technology)
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14 pages, 2318 KiB  
Article
Impact of Microbiota and Metabolites on Intestinal Integrity and Inflammation in Severe Obesity
by Emma Custers, Debby Vreeken, Frank Schuren, Tim J. van den Broek, Lieke van Dongen, Bram Geenen, Ivo de Blaauw, Maximilian Wiesmann, Eric J. Hazebroek, Robert Kleemann and Amanda J. Kiliaan
Pharmaceuticals 2024, 17(7), 918; https://doi.org/10.3390/ph17070918 - 10 Jul 2024
Viewed by 230
Abstract
Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the [...] Read more.
Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the relation between gut pathology, microbiota, its metabolites and cytokines in adults with severe obesity. Individuals eligible for bariatric surgery were included. Fecal and plasma samples were collected at surgery timepoint, to assess microbiota and metabolite composition. Jejunal biopsies were collected during surgery and stained for cytotoxic T cells, macrophages, mast cells and tight junction component zonula occludens-1. Based on these stainings, the cohort was divided into four groups: high versus low intestinal inflammation and high versus low intestinal integrity. We found no significant differences in microbiota diversity between groups, nor for individual bacterial species. No significant differences in metabolites were observed between the intestinal inflammatory groups. However, some metabolites and cytokines differed between the intestinal integrity groups. Higher plasma levels of interleukin-8 and tauro-chenodeoxycholic acid were found, whereas isovaleric acid and acetic acid were lower in the high intestinal integrity group. As the results were very subtle, we suggest that our cohort shows very early and minor intestinal pathology. Full article
(This article belongs to the Special Issue Gut Microbiota Metabolites in Intestinal Inflammation and Fibrosis)
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16 pages, 4520 KiB  
Article
Anti-Human Immunodeficiency Virus-1 Property of Thai Herbal Extract Kerra™
by Siriwan Saehlee, Supaphorn Seetaha, Wiwat Klankaew, Pussadee Srathong, Kiattawee Choowongkomon and Khuanjarat Choengpanya
Pharmaceuticals 2024, 17(7), 917; https://doi.org/10.3390/ph17070917 - 9 Jul 2024
Viewed by 266
Abstract
Kerra™, a Thai traditional herbal medicine derived from the “Tak-Ka-Si-La Scripture” and composed of nine medicinal plants, has demonstrated potential antiviral properties against HIV. This study investigated the inhibitory effects of Kerra™ on HIV-1 reverse transcriptase (RT) and its ability to prevent pseudo-HIV [...] Read more.
Kerra™, a Thai traditional herbal medicine derived from the “Tak-Ka-Si-La Scripture” and composed of nine medicinal plants, has demonstrated potential antiviral properties against HIV. This study investigated the inhibitory effects of Kerra™ on HIV-1 reverse transcriptase (RT) and its ability to prevent pseudo-HIV viral infection in HEK293 cells. The results showed that Kerra™ extract achieved a 95.73 ± 4.24% relative inhibition of HIV-1 RT, with an IC50 value of 42.66 ± 8.74 µg/mL. Docking studies revealed that key phytochemicals in Kerra™, such as oleamide, formononetin, and biochanin A, interact with several residues in the RT non-nucleoside binding pocket, contributing to their inhibitory effects. Furthermore, Kerra™ was able to reduce pseudo-HIV infection in HEK293 cells at a concentration of 10 µg/mL, suggesting its potential as a supplementary treatment for HIV. Full article
(This article belongs to the Section Natural Products)
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18 pages, 680 KiB  
Review
Where Are We Now with Oncolytic Viruses in Melanoma and Nonmelanoma Skin Malignancies?
by George Nassief, Angela Anaeme, Karen Moussa, David Chen and George Ansstas
Pharmaceuticals 2024, 17(7), 916; https://doi.org/10.3390/ph17070916 - 9 Jul 2024
Viewed by 262
Abstract
Skin cancer prognosis has greatly improved recently due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients with advanced skin cancer still experience immunotherapy resistance and disease progression during ICI treatment, thus calling for novel therapeutics which address this treatment gap. [...] Read more.
Skin cancer prognosis has greatly improved recently due to the introduction of immune checkpoint inhibitors (ICIs). However, many patients with advanced skin cancer still experience immunotherapy resistance and disease progression during ICI treatment, thus calling for novel therapeutics which address this treatment gap. Talimogene laherparepvec (T-VEC) has gained popularity in recent years as a viable treatment option for patients with skin cancer. In preclinical studies, T-VEC demonstrated both a direct anti-tumor effect in injected lesions as well as a systemic immune-mediated effect in non-injected lesions, which could pose additional benefits when combined with ICI therapy. Following promising results from the OPTiM trial, the Food and Drug Administration (FDA) approved the usage of T-VEC as a single agent in advanced melanoma. However, the MASTERKEY-265 trial demonstrated that adding T-VEC to pembrolizumab did not offer additional clinical benefit in patients with melanoma. Nevertheless, the promising efficacy of T-VEC and its approval by the FDA helped oncolytic viruses (OVs) gain wide attention in cancer therapy, and extensive research has been undertaken to evaluate the usage of OVs in other tumors such as sarcomas and breast cancers. Here, we provide a review of clinical results from 2022 to 2024 that investigate the efficacy and safety of OVs as a monotherapy or in combination with other therapies in skin malignancies. Furthermore, we delineate the current limitations in OV utilization and outline future directions to enhance clinical outcomes for patients with skin malignancies receiving OV-based therapies. Full article
(This article belongs to the Special Issue Oncolytic Viruses: New Cancer Immunotherapy Drugs)
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24 pages, 3455 KiB  
Article
Biomedical Promise of Aspergillus Flavus-Biosynthesized Selenium Nanoparticles: A Green Synthesis Approach to Antiviral, Anticancer, Anti-Biofilm, and Antibacterial Applications
by Eman Jassim Mohammed, Ahmed E. M. Abdelaziz, Alsayed E. Mekky, Nashaat N. Mahmoud, Mohamed Sharaf, Mahmoud M. Al-Habibi, Nehal M. Khairy, Abdulaziz A. Al-Askar, Fady Sayed Youssef, Mahmoud Ali Gaber, Ebrahim Saied, Gehad AbdElgayed, Shimaa A Metwally and Aly A. Shoun
Pharmaceuticals 2024, 17(7), 915; https://doi.org/10.3390/ph17070915 - 9 Jul 2024
Viewed by 407
Abstract
This study utilized Aspergillus flavus to produce selenium nanoparticles (Se-NPs) in an environmentally friendly and ecologically sustainable manner, targeting several medicinal applications. These biosynthesized Se-NPs were meticulously characterized using X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscope (TEM), and UV–visible spectroscopy [...] Read more.
This study utilized Aspergillus flavus to produce selenium nanoparticles (Se-NPs) in an environmentally friendly and ecologically sustainable manner, targeting several medicinal applications. These biosynthesized Se-NPs were meticulously characterized using X-ray diffraction (XRD), Fourier-transform infrared (FT-IR) spectroscopy, transmission electron microscope (TEM), and UV–visible spectroscopy (UV), revealing their spherical shape and size ranging between 28 and 78 nm. We conducted further testing of Se-NPs to evaluate their potential for biological applications, including antiviral, anticancer, antibacterial, antioxidant, and antibiofilm activities. The results indicate that biosynthesized Se-NPs could be effective against various pathogens, including Salmonella typhimurium (ATCC 14028), Bacillus pumilus (ATCC 14884), Staphylococcus aureus (ATCC 6538), Clostridium sporogenes (ATCC 19404), Escherichia coli (ATCC 8739), and Bacillus subtilis (ATCC 6633). Additionally, the biosynthesized Se-NPs exhibited anticancer activity against three cell lines: pancreatic carcinoma (PANC1), cervical cancer (Hela), and colorectal adenocarcinoma (Caco-2), with IC50 values of 177, 208, and 216 μg/mL, respectively. The nanoparticles demonstrated antiviral activity against HSV-1 and HAV, achieving inhibition rates of 66.4% and 15.1%, respectively, at the maximum non-toxic concentration, while also displaying antibiofilm and antioxidant properties. In conclusion, the biosynthesized Se-NPs by A. flavus present a promising avenue for various biomedical applications with safe usage. Full article
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21 pages, 12205 KiB  
Article
Exploring the Mechanism of Topical Application of Clematis Florida in the Treatment of Rheumatoid Arthritis through Network Pharmacology and Experimental Validation
by Ting Lei, Chang Jiang, Li Zhao, Jizhou Zhang, Qing Xiao, Yanhong Chen, Jie Zhang, Chunquan Zhou, Gong Wang and Jing Han
Pharmaceuticals 2024, 17(7), 914; https://doi.org/10.3390/ph17070914 (registering DOI) - 9 Jul 2024
Viewed by 173
Abstract
Clematis Florida (CF) is a folk medicinal herb in the southeast of China, which is traditionally used for treating osteoarticular diseases. However, the mechanism of its action remains unclear. The present study used network pharmacology and experimental validation to explore the mechanism of [...] Read more.
Clematis Florida (CF) is a folk medicinal herb in the southeast of China, which is traditionally used for treating osteoarticular diseases. However, the mechanism of its action remains unclear. The present study used network pharmacology and experimental validation to explore the mechanism of CF in the treatment of rheumatoid arthritis (RA). Liquid chromatography–mass spectrometry (LC-MS/MS) identified 50 main compounds of CF; then, their targets were obtained from TCMSP, ETCM, ITCM, and SwissTargetPrediction databases. RA disease-related targets were obtained from DisGeNET, OMIM, and GeneCards databases, and 99 overlapped targets were obtained using a Venn diagram. The protein–protein interaction network (PPI), the compound–target network (CT), and the compound–potential target genes–signaling pathways network (CPS) were constructed and analyzed. The results showed that the core compounds were screened as oleanolic acid, oleic acid, ferulic acid, caffeic acid, and syringic acid. The core therapeutic targets were predicted via network pharmacology analysis as PTGS2 (COX-2), MAPK1, NF-κB1, TNF, and RELA, which belong to the MAPK signaling pathway and NF-κB signaling pathway. The animal experiments indicated that topical application of CF showed significant anti-inflammatory activity in a mouse model of xylene-induced ear edema and had strong analgesic effect on acetic acid-induced writhing. Furthermore, in the rat model of adjuvant arthritis (AA), topical administration of CF was able to alleviate toe swelling and ameliorate joint damage. The elevated serum content levels of IL-6, COX-2, TNF-α, IL-1β, and RF caused by adjuvant arthritis were reduced by CF treatment. Western blotting tests showed that CF may regulate the ERK and NF-κB pathway. The results provide a new perspective for the topical application of CF for treatment of RA. Full article
(This article belongs to the Section Pharmacology)
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23 pages, 2320 KiB  
Review
Lipoprotein Metabolism, Dyslipidemia, and Lipid-Lowering Therapy in Women: A Comprehensive Review
by Jakub Michal Zimodro, Magda Mucha, Heiner K. Berthold and Ioanna Gouni-Berthold
Pharmaceuticals 2024, 17(7), 913; https://doi.org/10.3390/ph17070913 (registering DOI) - 9 Jul 2024
Viewed by 292
Abstract
Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use [...] Read more.
Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk. Full article
(This article belongs to the Special Issue Pharmacological Modulation of Lipoproteins)
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16 pages, 4214 KiB  
Article
Carbazole Derivatives Binding to Bcl-2 Promoter Sequence G-quadruplex
by Agata Głuszyńska, Joanna Kosman, Shang Shiuan Chuah, Marcin Hoffmann and Shozeb Haider
Pharmaceuticals 2024, 17(7), 912; https://doi.org/10.3390/ph17070912 (registering DOI) - 9 Jul 2024
Viewed by 202
Abstract
In this study, we used ultraviolet-visible (UV-Vis), fluorescence, and circular dichroism (CD) techniques, as well as molecular modeling, to probe the interactions between carbazole derivatives and the G-quadruplex structure formed in the promoter region of gene Bcl-2. This gene is a rational [...] Read more.
In this study, we used ultraviolet-visible (UV-Vis), fluorescence, and circular dichroism (CD) techniques, as well as molecular modeling, to probe the interactions between carbazole derivatives and the G-quadruplex structure formed in the promoter region of gene Bcl-2. This gene is a rational target for anticancer therapy due to its high expression in a variety of tumors as well as resistance to chemotherapy-induced apoptosis. We employed a sequence with a specific dual G-to-T mutation that may form a mixed-type hybrid G-quadruplex structure in the Bcl-2 P1 promoter region. The three tested carbazole compounds differing in substitution on the nitrogen atom of carbazole interact with the Bcl-2 G-quadruplex by the same binding mode with the very comparable binding affinities in the order of 105 M−1. During absorption and fluorescence measurements, large changes in the ligand spectra were observed at higher G4 concentrations. The spectrophotometric titration results showed a two-step complex formation between the ligands and the G-quadruplex in the form of initial hypochromicity followed by hyperchromicity with a bathochromic shift. The strong fluorescence enhancement of ligands was observed after binding to the DNA. All of the used analytical techniques, as well as molecular modeling, suggested the π–π interaction between carbazole ligands and a guanine tetrad of the Bcl-2 G-quadruplex. Molecular modeling has shown differences in the interaction between each of the ligands and the tested G-quadruplex, which potentially had an impact on the binding strength. Full article
(This article belongs to the Special Issue G‐quadruplex Ligands: Recent Advances)
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17 pages, 3702 KiB  
Article
Aronia Berry Extract Modulates MYD88/NF-kB/P-Glycoprotein Axis to Overcome Gemcitabine Resistance in Pancreatic Cancer
by Yuan Li, Caiming Xu, Haiyong Han, Silvia Pascual-Sabater, Cristina Fillat and Ajay Goel
Pharmaceuticals 2024, 17(7), 911; https://doi.org/10.3390/ph17070911 (registering DOI) - 9 Jul 2024
Viewed by 520
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor survival rates, primarily due to the limited effectiveness of gemcitabine (Gem)-based chemotherapy, as well as the acquisition of chemotherapeutic resistance. Aronia berry extracts (ABEs), abundant in phenolic constituents, have been recently recognized for their anticancer properties as well as their encouraging potential to help overcome chemoresistance in various cancers. In the present study, we explored ABE’s potential to overcome Gem resistance in PDAC and identify specific growth regulatory pathways responsible for its anticancer activity. Through a series of in vitro experiments in gemcitabine-resistant (Gem-R) cells, we elucidated the synergistic interactions between Gem and ABE treatments. Using advanced transcriptomic analysis and network pharmacology, we revealed key molecular pathways linked to chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. Subsequently, the findings from cell culture studies were validated in patient-derived 3D tumor organoids (PDOs). The combination treatment of ABE and Gem demonstrated significant synergism and anticancer effects on cell viability, proliferation, migration, and invasion in Gem-R cells. Transcriptomic analysis revealed a correlation between the NF-Κb signaling pathway and Gem-R (p < 0.05), exhibiting a marked upregulation of MYD88. Additionally, MYD88 exhibited a significant correlation with the overall survival rates in patients with PDAC patients in the TCGA cohort (HR = 1.58, p < 0.05). The MYD88/NF-Κb pathway contributes to chemoresistance by potentially upregulating efflux transporters like P-glycoprotein (P-gp). Our findings revealed that the combined treatment with ABE suppressed the NF-Κb pathway by targeting MYD88 and reducing P-gp expression to overcome Gem resistance. Lastly, the combination therapy proved highly effective in PDOs in reducing both their number and size (p < 0.05). Our study offers previously unrecognized insights into the ability of ABE to overcome Gem resistance in PDAC cells through its targeting of the MYD88/NF-κb/P-gp axis, hence providing a safe and cost-effective adjunctive therapeutic strategy to improve treatment outcomes in PDAC. Full article
(This article belongs to the Special Issue Network Pharmacology of Natural Products)
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26 pages, 4996 KiB  
Review
The Recent Trends of Systemic Treatments and Locoregional Therapies for Cholangiocarcinoma
by Abdullah Esmail, Mohamed Badheeb, Batool Wael Alnahar, Bushray Almiqlash, Yara Sakr, Ebtesam Al-Najjar, Ali Awas, Mohammad Alsayed, Bayan Khasawneh, Mohammed Alkhulaifawi, Amneh Alsaleh, Ala Abudayyeh, Yaser Rayyan and Maen Abdelrahim
Pharmaceuticals 2024, 17(7), 910; https://doi.org/10.3390/ph17070910 - 8 Jul 2024
Viewed by 363
Abstract
Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA [...] Read more.
Cholangiocarcinoma (CCA) is a hepatic malignancy that has a rapidly increasing incidence. CCA is anatomically classified into intrahepatic (iCCA) and extrahepatic (eCCA), which is further divided into perihilar (pCCA) and distal (dCCA) subtypes, with higher incidence rates in Asia. Despite its rarity, CCA has a low 5-year survival rate and remains the leading cause of primary liver tumor-related death over the past 10–20 years. The systemic therapy section discusses gemcitabine-based regimens as primary treatments, along with oxaliplatin-based options. Second-line therapy is limited but may include short-term infusional fluorouracil (FU) plus leucovorin (LV) and oxaliplatin. The adjuvant therapy section discusses approaches to improve overall survival (OS) post-surgery. However, only a minority of CCA patients qualify for surgical resection. In comparison to adjuvant therapies, neoadjuvant therapy for unresectable cases shows promise. Gemcitabine and cisplatin indicate potential benefits for patients awaiting liver transplantation. The addition of immunotherapies to chemotherapy in combination is discussed. Nivolumab and innovative approaches like CAR-T cells, TRBAs, and oncolytic viruses are explored. We aim in this review to provide a comprehensive report on the systemic and locoregional therapies for CCA. Full article
(This article belongs to the Special Issue Drug Treatment of Cholangiocarcinoma)
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26 pages, 11706 KiB  
Article
Targeting JAK2/STAT3, NLRP3/Caspase-1, and PK2/PKR2 Pathways with Arbutin Ameliorates Lead Acetate-Induced Testicular Injury in Rats
by Hany H. Arab, Shuruq E. Alsufyani, Ahmed M. Ashour, Amany M. Gad, Alzahraa A. Elhemiely, Mohamed H. A. Gadelmawla, Marwa Ahmed Mahmoud and Ali Khames
Pharmaceuticals 2024, 17(7), 909; https://doi.org/10.3390/ph17070909 - 8 Jul 2024
Viewed by 383
Abstract
The reproductive system of males is adversely impacted by lead (Pb), a toxic heavy metal. The present study examined arbutin, a promising hydroquinone glycoside, for its potential ameliorative impact against Pb-induced testicular impairment in rats. The testicular injury was induced by the intraperitoneal [...] Read more.
The reproductive system of males is adversely impacted by lead (Pb), a toxic heavy metal. The present study examined arbutin, a promising hydroquinone glycoside, for its potential ameliorative impact against Pb-induced testicular impairment in rats. The testicular injury was induced by the intraperitoneal administration of Pb acetate (20 mg/kg/day) for 10 consecutive days. Thirty-six rats were divided into six experimental groups (n = 6 per group): control, control treated with oral arbutin (250 mg/kg), control treated with intraperitoneal arbutin (75 mg/kg), untreated Pb, Pb treated with oral arbutin, and Pb treated with intraperitoneal arbutin. The treatments were administered daily for 10 days. Arbutin was administered by the oral and intraperitoneal routes to compare the efficacy of both routes in mitigating Pb acetate-induced testicular dysfunction. The current data revealed that both oral and intraperitoneal administration of arbutin significantly enhanced serum testosterone and sperm count/motility, indicating the amelioration of testicular dysfunction. In tandem, both routes lowered testicular histopathological aberrations and Johnsen’s damage scores. These favorable outcomes were driven by dampening testicular oxidative stress, evidenced by lowered lipid peroxidation and increased glutathione and catalase antioxidants. Moreover, arbutin lowered testicular p-JAK2 and p-STAT3 levels, confirming the inhibition of the JAK2/STAT3 pro-inflammatory pathway. In tandem, arbutin suppressed the testicular NLRP3/caspase-1/NF-B axis and augmented the cytoprotective PK2/PKR2 pathway. Notably, intraperitoneal arbutin at a lower dose prompted a more pronounced mitigation of Pb-induced testicular dysfunction compared to oral administration. In conclusion, arbutin ameliorates Pb-evoked testicular damage by stimulating testicular antioxidants and the PK2/PKR2 pathway and inhibiting the JAK2/STAT3 and NLRP3/caspase-1 pro-inflammatory pathways. Hence, arbutin may be used as an adjunct agent for mitigating Pb-induced testicular impairment. Full article
(This article belongs to the Section Pharmacology)
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13 pages, 3231 KiB  
Article
Synthesis and Characterization of Chemically and Green-Synthesized Silver Oxide Particles for Evaluation of Antiviral and Anticancer Activity
by Muhammad Asif, Wajeeha Iqbal, Muhammad Fakhar-e-Alam, Zahid Hussain, Malik Saadullah, Mudassir Hassan, Javed Rehman, Kholood A. Dahlous and Noora H. Al-Qahtani
Pharmaceuticals 2024, 17(7), 908; https://doi.org/10.3390/ph17070908 - 8 Jul 2024
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Abstract
Silver oxide (Ag2O) particles are wonderful candidates due to their unique properties, and their use in a wide range of research, industrial and biomedical applications is rapidly increasing. This makes it fundamental to develop simple, environmentally friendly methods with possible scaling. [...] Read more.
Silver oxide (Ag2O) particles are wonderful candidates due to their unique properties, and their use in a wide range of research, industrial and biomedical applications is rapidly increasing. This makes it fundamental to develop simple, environmentally friendly methods with possible scaling. Herein, sodium borohydride and Datura innoxia leaf extract were applied as chemical and biological stabilizing and reducing agents to develop Ag2O particles. The primary aim was to evaluate the anticancer and antiviral activity of Ag2O particles prepared via two methods. XRD, UV-visible and SEM analyses were used to examine the crystallite structure, optical properties and morphology, respectively. The resulting green-synthesized Ag2O particles exhibited small size, spherically agglomerated shape, and high anticancer and antiviral activities compared to chemically synthesized Ag2O particles. The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium-bromide) assay of green-synthesized Ag2O particles showed high anticancer activity against MCF-7 cells with IC50 = 17.908 µg/mL compared to chemically synthesized Ag2O particles with IC50 = 23.856 µg/mL. The antiviral activity of green-synthesized Ag2O particles and chemically synthesized Ag2O particles was also evaluated by a plaque-forming assay, and green-synthesized Ag2O particles showed higher antiviral ability with IC50 = 0.618 µg/mL as compared to chemically synthesized Ag2O particles with IC50 = 6.129 µg/mL. We propose the use of green-synthesized Ag2O particles in cancer treatment and drug delivery. Full article
(This article belongs to the Special Issue Therapeutic Potential of Silver Nanoparticles (AgNPs))
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