Pharmaceuticals

18 pages, 5002 KiB

Open AccessArticle

Apigenin Ameliorates Hyperuricemia and Renal Injury through Regulation of Uric Acid Metabolism and JAK2/STAT3 Signaling Pathway

by Tianyuan Liu, Huimin Gao, Yueyi Zhang, Shan Wang, Meixi Lu, Xuan Dai, Yage Liu, Hanfen Shi, Tianshu Xu, Jiyuan Yin, Sihua Gao, Lili Wang and Dongwei Zhang

Pharmaceuticals 2022, 15(11), 1442; https://doi.org/10.3390/ph15111442 - 21 Nov 2022

Cited by 8 | Viewed by 2744 | Correction

Abstract

Hyperuricemia (HUA) is a kind of metabolic disease with high incidence that still needs new countermeasures. Apigenin has uric-lowering and kidney-protective activities, but how apigenin attenuates HUA and renal injury remains largely unexploited. To this end, an acute HUA mouse model was established [...] Read more.

Hyperuricemia (HUA) is a kind of metabolic disease with high incidence that still needs new countermeasures. Apigenin has uric-lowering and kidney-protective activities, but how apigenin attenuates HUA and renal injury remains largely unexploited. To this end, an acute HUA mouse model was established by intraperitoneal injection of potassium oxazinate and oral administration with hypoxanthine for 7 consecutive days. Apigenin intervention decreased serum uric acid (UA), creatinine (CRE), blood urea nitrogen (BUN), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNF-α), interleukin-18 (IL-18), liver xanthine oxidase (XOD), and urine protein levels, and increased serum interleukin-10 (IL-10) and urine UA and CRE levels in HUA mice. Moreover, administration of apigenin to HUA mice prevented renal injury, decreased renal glucose transporter 9 (GLUT9) and urate anion transporter 1 (URAT1) levels, and increased renal organic anion transporter 1 (OAT1). These alterations were associated with an inhibition of IL-6, phospho-janus kinase 2 (P-JAK2), phospho-signal transducer, and activator of transcription 3 (P-STAT3), and suppression of cytokine signaling 3 (SOCS3) expression in the kidneys. Additionally, the molecular docking results showed that apigenin had strong binding capacity with UA transporters and JAK2 proteins. In summary, apigenin could improve UA metabolism and attenuate renal injury through inhibiting UA production, promoting excretion, and suppressing the JAK2/STAT3 signaling pathway in HUA mice. The results suggest that apigenin may be a suitable drug candidate for management of HUA and its associated renal injury. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)

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15 pages, 41347 KiB

Open AccessArticle

Schinus terebinthifolius Leaf Lectin (SteLL) Reduces the Bacterial and Inflammatory Burden of Wounds Infected by Staphylococcus aureus Promoting Skin Repair

by Marcio Anderson Sousa Nunes, Lucas dos Santos Silva, Deivid Martins Santos, Brenda da Silva Cutrim, Silvamara Leite Vieira, Izadora Souza Soeiro Silva, Simeone Júlio dos Santos Castelo Branco, Mayara de Santana do Nascimento, André Alvares Marques Vale, Ana Paula Silva dos Santos-Azevedo, Adrielle Zagmignan, Joicy Cortez de Sá Sousa, Thiago Henrique Napoleão, Patrícia Maria Guedes Paiva, Valério Monteiro-Neto and Luís Cláudio Nascimento da Silva

Pharmaceuticals 2022, 15(11), 1441; https://doi.org/10.3390/ph15111441 - 21 Nov 2022

Viewed by 3539

Abstract

Staphylococcus aureus is commonly found in wound infections where this pathogen impairs skin repair. The lectin isolated from leaves of Schinus terebinthifolius (named SteLL) has antimicrobial and antivirulence action against S. aureus. This study evaluated the effects of topical administration of SteLL on [...] Read more.

Staphylococcus aureus is commonly found in wound infections where this pathogen impairs skin repair. The lectin isolated from leaves of Schinus terebinthifolius (named SteLL) has antimicrobial and antivirulence action against S. aureus. This study evaluated the effects of topical administration of SteLL on mice wounds infected by S. aureus. Seventy-two C57/BL6 mice (6–8 weeks old) were allocated into four groups: (i) uninfected wounds; (ii) infected wounds, (iii) infected wounds treated with 32 µg/mL SteLL solution; (iv) infected wounds treated with 64 µg/mL SteLL solution. The excisional wounds (64 mm²) were induced on the dorsum and infected by S. aureus 432170 (4.0 × 10⁶ CFU/wound). The daily treatment started 1-day post-infection (dpi). The topical application of both SteLL concentrations significantly accelerated the healing of S. aureus-infected wounds until the 7th dpi, when compared to untreated infected lesions (reductions of 1.95–4.55-fold and 1.79–2.90-fold for SteLL at 32 µg/mL and 64 µg/mL, respectively). The SteLL-based treatment also amended the severity of wound infection and reduced the bacterial load (12-fold to 72-fold for 32 µg/mL, and 14-fold to 282-fold for 64 µg/mL). SteLL-treated wounds show higher collagen deposition and restoration of skin structure than other groups. The bacterial load and the levels of inflammatory markers (IL-6, MCP-1, TNF-α, and VEGF) were also reduced by both SteLL concentrations. These results corroborate the reported anti-infective properties of SteLL, making this lectin a lead candidate for developing alternative agents for the treatment of S. aureus-infected skin lesions. Full article

(This article belongs to the Special Issue Targeting Lectins as a Strategy for Developing New Drugs)

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23 pages, 8340 KiB

Open AccessArticle

Identification of Novel Arachidonic Acid 15-Lipoxygenase Inhibitors Based on the Bayesian Classifier Model and Computer-Aided High-Throughput Virtual Screening

by Yinglin Liao, Peng Cao and Lianxiang Luo

Pharmaceuticals 2022, 15(11), 1440; https://doi.org/10.3390/ph15111440 - 20 Nov 2022

Cited by 4 | Viewed by 2065

Abstract

Ferroptosis is an iron-dependent lipid peroxidative form of cell death that is distinct from apoptosis and necrosis. ALOX15, also known as arachidonic acid 15-lipoxygenase, promotes ferroptosis by converting intracellular unsaturated lipids into oxidized lipid intermediates and is an important ferroptosis target. In this [...] Read more.

Ferroptosis is an iron-dependent lipid peroxidative form of cell death that is distinct from apoptosis and necrosis. ALOX15, also known as arachidonic acid 15-lipoxygenase, promotes ferroptosis by converting intracellular unsaturated lipids into oxidized lipid intermediates and is an important ferroptosis target. In this study, a naive Bayesian machine learning classifier with a structure-based, high-throughput screening approach and a molecular docking program were combined to screen for three compounds with excellent target-binding potential. In the absorption, distribution, metabolism, excretion, and toxicity characterization, three candidate molecules were predicted to exhibit drug-like properties. The subsequent molecular dynamics simulations confirmed their stable binding to the targets. The findings indicated that the compounds exhibited excellent potential ALOX15 inhibitor capacity, thereby providing novel candidates for the treatment of inflammatory ischemia-related diseases caused by ferroptosis. Full article

(This article belongs to the Special Issue Machine Learning Methods for Medicinal Chemistry)

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29 pages, 4200 KiB

Open AccessReview

Changes in Tryptophan-Kynurenine Metabolism in Patients with Depression Undergoing ECT—A Systematic Review

by Tore Ivar Malmei Aarsland, Johanne Telnes Instanes, Maj-Britt Rocio Posserud, Arve Ulvik, Ute Kessler and Jan Haavik

Pharmaceuticals 2022, 15(11), 1439; https://doi.org/10.3390/ph15111439 - 19 Nov 2022

Cited by 3 | Viewed by 2546

Abstract

The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a [...] Read more.

The kynurenine pathway of tryptophan (Trp) metabolism generates multiple biologically active metabolites (kynurenines) that have been implicated in neuropsychiatric disorders. It has been suggested that modulation of kynurenine metabolism could be involved in the therapeutic effect of electroconvulsive therapy (ECT). We performed a systematic review with aims of summarizing changes in Trp and/or kynurenines after ECT and assessing methodological issues. The inclusion criterium was measures of Trp and/or kynurenines before and after ECT. Animal studies and studies using Trp administration or Trp depletion were excluded. Embase, MEDLINE, PsycInfo and PubMed were searched, most recently in July 2022. Outcomes were levels of Trp, kynurenines and ratios before and after ECT. Data on factors affecting Trp metabolism and ECT were collected for interpretation and discussion of the reported changes. We included 17 studies with repeated measures for a total of 386 patients and 27 controls. Synthesis using vote counting based on the direction of effect found no evidence of effect of ECT on any outcome variable. There were considerable variations in design, patient characteristics and reported items. We suggest that future studies should include larger samples, assess important covariates and determine between- and within-subject variability. PROSPERO (CRD42020187003). Full article

(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)

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19 pages, 10820 KiB

Open AccessArticle

Identification of Novel Diarylpyrimidines as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors by Exploring the Primer Grip Region

by Tao Zhang, Zhongxia Zhou, Fabao Zhao, Zihao Sang, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan and Xinyong Liu

Pharmaceuticals 2022, 15(11), 1438; https://doi.org/10.3390/ph15111438 - 19 Nov 2022

Viewed by 1890

Abstract

HIV-1 reverse transcriptase (RT) plays a crucial role in the viral replication cycle, and RT inhibitors can represent a promising pathway in treating AIDS. To explore the primer grip region of HIV-1 RT, using -CH₂O- as a linker, substituted benzene or [...] Read more.

HIV-1 reverse transcriptase (RT) plays a crucial role in the viral replication cycle, and RT inhibitors can represent a promising pathway in treating AIDS. To explore the primer grip region of HIV-1 RT, using -CH₂O- as a linker, substituted benzene or pyridine rings were introduced into the left wing of diarylpyrimidines (DAPYs). A total of 17 compounds with new structures were synthesized. It showed that all compounds exhibited anti-HIV-1 (wild-type) activity values ranging from 7.6–199.0 nM. Among them, TF2 (EC₅₀ = 7.6 nM) showed the most potent activity, which was better than that of NVP (EC₅₀ = 122.6 nM). Notably, compared with RPV (CC₅₀ = 3.98 μM), TF2 (CC₅₀ > 279,329.6 nM) showed low cytotoxicity. For HIV-1 mutant strains K103N and E138K, most compounds showed effective activities. Especially for K103N, TF2 (EC₅₀ = 28.1 nM), TF12 (EC₅₀ = 34.7 nM) and TF13 (EC₅₀ = 28.0 nM) exhibited outstanding activity, being superior to that of NVP (EC₅₀ = 7495.1 nM) and EFV (EC₅₀ = 95.1 nM). Additionally, TF2 also showed the most potent activity against E138K (EC₅₀ = 44.0 nM) and Y181C mutant strains (EC₅₀ = 139.3 nM). In addition, all the compounds showed strong enzyme inhibition (IC₅₀ = 0.036–0.483 μM), which demonstrated that their target was HIV-1 RT. Moreover, molecular dynamics simulation studies were implemented to predict the binding mode of TF2 in the binding pocket of wild-type and K103N HIV-1 RT. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of HIV/AIDS)

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12 pages, 2162 KiB

Open AccessArticle

Pharmacokinetics of Phenprocoumon in Emergency Situations–Results of the Prospective Observational RADOA-Registry (Reversal Agent Use in Patients Treated with Direct Oral Anticoagulants or Vitamin K Antagonists Registry)

by Edelgard Lindhoff-Last, Ingvild Birschmann, Antonia J. Bidenharn, Joachim Kuhn, Simone Lindau, Stavros Konstantinides, Oliver Grottke, Ulrike Nowak-Göttl, Jessica Lucks, Barbara Zydek, Christian von Heymann, Ariane Sümnig, Jan Beyer-Westendorf, Sebastian Schellong, Patrick Meybohm, Andreas Greinacher and Eva Herrmann

Pharmaceuticals 2022, 15(11), 1437; https://doi.org/10.3390/ph15111437 - 19 Nov 2022

Cited by 2 | Viewed by 1755

Abstract

Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a [...] Read more.

Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days. Full article

(This article belongs to the Special Issue Anticoagulants and Antiplatelet Drugs)

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15 pages, 4543 KiB

Open AccessArticle

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals

by Esam M. Aboubakr, Ahmed R. N. Ibrahim, Fares E. M. Ali, Ahmed A. E. Mourad, Adel M. Ahmad and Amal Hofni

Pharmaceuticals 2022, 15(11), 1436; https://doi.org/10.3390/ph15111436 - 19 Nov 2022

Cited by 3 | Viewed by 1573

Abstract

Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate [...] Read more.

Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1β. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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20 pages, 4878 KiB

Open AccessArticle

Integrated Chemical Characterization, Network Pharmacology and Transcriptomics to Explore the Mechanism of Sesquiterpenoids Isolated from Gynura divaricata (L.) DC. against Chronic Myelogenous Leukemia

by Xinyuan Ye, Long Wang, Xin Yang, Jie Yang, Jie Zhou, Cai Lan, Fahsai Kantawong, Warunee Kumsaiyai, Jianming Wu and Jing Zeng

Pharmaceuticals 2022, 15(11), 1435; https://doi.org/10.3390/ph15111435 - 19 Nov 2022

Cited by 1 | Viewed by 1594

Abstract

Chronic myelogenous leukemia (CML) is a serious threat to human health, while drugs for CML are limited. Herbal medicines with structural diversity, low toxicity and low drug resistance are always the most important source for drug discoveries. Gynura divaricata (L.) DC. is a [...] Read more.

Chronic myelogenous leukemia (CML) is a serious threat to human health, while drugs for CML are limited. Herbal medicines with structural diversity, low toxicity and low drug resistance are always the most important source for drug discoveries. Gynura divaricata (L.) DC. is a well-known herbal medicine whose non-alkaline ingredients (GD-NAIs) were isolated. The GD-NAIs demonstrated potential anti-CML activity in our preliminary screening tests. However, the chemical components and underlying mechanism are still unknown. In this study, GD-NAIs were tentatively characterized using UHPLC-HRMS combined with molecular networking, which were composed of 75 sesquiterpenoids. Then, the anti-CML activities of GD-NAIs were evaluated and demonstrated significant suppression of proliferation and promotion of apoptosis in K562 cells. Furthermore, the mechanism of GD-NAIs against CML were elucidated using network pharmacology combined with RNA sequencing. Four sesquiterpenoids would be the main active ingredients of GD-NAIs against CML, which could regulate PD-L1 expression and the PD-1 checkpoint pathway in cancer, PI3K/AKT, JAK/STAT, TGF-β, estrogen, Notch and Wnt signaling pathways. In conclusion, our study reveals the composition of GD-NAIs, confirms its anti-CML activity and elucidates their underlying mechanism, which is a potential countermeasure for the treatment of CML. Full article

(This article belongs to the Section Pharmacology)

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11 pages, 2601 KiB

Open AccessArticle

Acute and Reproductive Toxicity Evaluation of Ormona^® SI and Ormona^® RC—Two New Nutraceuticals with Geranylgeraniol, Tocotrienols, Anthocyanins, and Isoflavones—In Adult Zebrafish

by Clarice Flexa da Rocha, Camila de Nazaré Nunes Flexa, Gisele Custodio de Souza, Arlindo César Matias Pereira, Helison de Oliveira Carvalho, Aline Lopes do Nascimento, Natasha Juliana Perdigão de Jesus Vasconcelos, Heitor Ribeiro da Silva and José Carlos Tavares Carvalho

Pharmaceuticals 2022, 15(11), 1434; https://doi.org/10.3390/ph15111434 - 19 Nov 2022

Cited by 1 | Viewed by 1421

Abstract

The zebrafish is a popular organism to test the toxicity of compounds. Here, we evaluate the acute and reproductive toxicity of Ormona SI^® (OSI) and RC^® (ORC), two herbal products developed for menopausal women with tocotrienols, geranylgeraniol, isoflavones, and anthocyanins. The [...] Read more.

The zebrafish is a popular organism to test the toxicity of compounds. Here, we evaluate the acute and reproductive toxicity of Ormona SI^® (OSI) and RC^® (ORC), two herbal products developed for menopausal women with tocotrienols, geranylgeraniol, isoflavones, and anthocyanins. The acute toxicity was evaluated by behavioral alterations, lethality, and tissue changes (intestine, liver, kidney) after oral treatment with high product doses (500, 1000, and 2000 mg/kg). The reproductive toxicity was evaluated after 21 days of oral treatment with OSI and ORC at 200 mg/kg. Our results show that the LD₅₀ could not be assessed due to the low mortality rate even with the highest dose; the behavioral alterations were not different from those of the group treated only with the vehicle (2% DMSO). The tissue changes were minor in OSI and more severe in ORC at the highest (2000 mg/kg) dose, while no tissue abnormality was observed at 500 mg/kg. In the reproductive assessment, continuous treatment could decrease the maturation of the reproductive cells, which also significantly decreases the egg spawning. This effect was attributed to the estrogenic activity of the isoflavones. In conclusion, the acute toxicity analysis shows that the products did not elicit lethal or sublethal effects observed in the model when used up to 500 mg/kg. Regarding the reproductive toxicity, decreased fertility was observed, which was expected due to the presence of isoflavones (phytoestrogens). Considering that the product is intended for menopausal and postmenopausal women, the presence of isoflavones is beneficial. Further studies should be performed to corroborate these results in mammals. Full article

(This article belongs to the Special Issue Herbal Products: Development and Innovation)

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17 pages, 4029 KiB

Open AccessArticle

Optimization of Formulation Parameters in Preparation of Fructus ligustri lucidi Dropping Pills by Solid Dispersion Using 2³ Full Experimental Design

by Kai-Rong Wu, Wen-Ho Chuo and Yuh-Tyng Huang

Pharmaceuticals 2022, 15(11), 1433; https://doi.org/10.3390/ph15111433 - 19 Nov 2022

Cited by 2 | Viewed by 1416

Abstract

Oleanolic acid (OA) is an active ingredient of the traditional Chinese medicine (TCM) Fructus ligustri lucidi (FLL). Its clinical use is restricted because it is water-insoluble and has limited dosage forms of administration at present. Hence, the FFL dropping pills were prepared by [...] Read more.

Oleanolic acid (OA) is an active ingredient of the traditional Chinese medicine (TCM) Fructus ligustri lucidi (FLL). Its clinical use is restricted because it is water-insoluble and has limited dosage forms of administration at present. Hence, the FFL dropping pills were prepared by the hot-melt method of solid dispersion technology. A 2³ factorial design was used to examine the effects of the materials used to prepare the dropping pills (e.g., different ratios of PEG4000 and PEG6000, FLL extract loading, and percentage of Tween 80) on parameters such as dropping pill roundness, weight variation, and disintegration time. Moreover, 2³ full factorial design was utilized to search for the optimal formulation for dissolution experiments. The results showed that the percentage of Tween 80 demonstrated significant effects on dropping pill roundness, weight variation, and disintegration time; FLL extract loading affected roundness and weight variation; and different ratios of PEG4000 and PEG6000 only affected disintegration time. The optimal formulation of the dropping pills released 70% of the drug after 30 min of dissolution release, which was faster than commercially available FLL Chinese medicines. Furthermore, the amount released was higher than that of commercially available formulations. In this study, a solid dispersion technique was used to successfully produce FLL dropping pills. In addition to improving the water insolubility of FLL and increasing the dissolution release percentage of the drug, we increased the application value of FLL and reduced the issues of traditional administration dosage forms. Full article

(This article belongs to the Section Pharmaceutical Technology)

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9 pages, 1390 KiB

Open AccessCommunication

Naringin’s Prooxidant Effect on Tumor Cells: Copper’s Role and Therapeutic Implications

by Mohd Farhan

Pharmaceuticals 2022, 15(11), 1431; https://doi.org/10.3390/ph15111431 - 19 Nov 2022

Cited by 5 | Viewed by 1528

Abstract

Plant-derived polyphenolic chemicals are important components of human nutrition and have been found to have chemotherapeutic effects against a variety of cancers. Several studies in animal models have proven polyphenols’ potential to promote apoptosis and tumor regression. However, the method by which polyphenols [...] Read more.

Plant-derived polyphenolic chemicals are important components of human nutrition and have been found to have chemotherapeutic effects against a variety of cancers. Several studies in animal models have proven polyphenols’ potential to promote apoptosis and tumor regression. However, the method by which polyphenols show their anticancer effects on malignant cells is not well understood. It is generally known that cellular copper rises within malignant cells and in the serum of cancer patients. In this communication, investigations reveal that naringin (a polyphenol found in citrus fruits) can strongly suppress cell proliferation and trigger apoptosis in various cancer cell lines in the presence of copper ions. The cuprous chelator neocuproine, which confirms copper-mediated DNA damage, prevents such cell death to a large extent. The studies further show that the cellular copper transporters CTR1 and ATP7A have a role in the survival dynamics of malignant cells after naringin exposure. The findings emphasize the crucial function of copper dynamics and mobilization in cancer cells and pave the path for a better understanding of polyphenols as nutraceutical supplements for cancer prevention and treatment. Full article

(This article belongs to the Special Issue Design of Small Molecules to Target Metastatic Cancer Cells)

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24 pages, 1426 KiB

Open AccessReview

Mechanism and Prospect of Gastrodin in Osteoporosis, Bone Regeneration, and Osseointegration

by Yi Li and Fenglan Li

Pharmaceuticals 2022, 15(11), 1432; https://doi.org/10.3390/ph15111432 - 18 Nov 2022

Cited by 5 | Viewed by 2262

Abstract

Gastrodin, a traditional Chinese medicine ingredient, is widely used to treat vascular and neurological diseases. However, recently, an increasing number of studies have shown that gastrodin has anti-osteoporosis effects, and its mechanisms of action include its antioxidant effect, anti-inflammatory effect, and anti-apoptotic effect. [...] Read more.

Gastrodin, a traditional Chinese medicine ingredient, is widely used to treat vascular and neurological diseases. However, recently, an increasing number of studies have shown that gastrodin has anti-osteoporosis effects, and its mechanisms of action include its antioxidant effect, anti-inflammatory effect, and anti-apoptotic effect. In addition, gastrodin has many unique advantages in promoting bone healing in tissue engineering, such as inducing high hydrophilicity in the material surface, its anti-inflammatory effect, and pro-vascular regeneration. Therefore, this paper summarized the effects and mechanisms of gastrodin on osteoporosis and bone regeneration in the current research. Here we propose an assumption that the use of gastrodin in the surface loading of oral implants may greatly promote the osseointegration of implants and increase the success rate of implants. In addition, we speculated on the potential mechanisms of gastrodin against osteoporosis, by affecting actin filament polymerization, renin–angiotensin system (RAS) and ferroptosis, and proposed that the potential combination of gastrodin with Mg²⁺, angiotensin type 2 receptor blockers or artemisinin may greatly inhibit osteoporosis. The purpose of this review is to provide a reference for more in-depth research and application of gastrodin in the treatment of osteoporosis and implant osseointegration in the future. Full article

(This article belongs to the Special Issue Pharmacotherapy of Bone Diseases)

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16 pages, 3417 KiB

Open AccessReview

Osmotic Pump Drug Delivery Systems—A Comprehensive Review

by Yosif Almoshari

Pharmaceuticals 2022, 15(11), 1430; https://doi.org/10.3390/ph15111430 - 18 Nov 2022

Cited by 14 | Viewed by 7916

Abstract

In the last couple of years, novel drug delivery systems (NDDS) have attracted much attention in the food and pharmaceutical industries. NDDS is a broad term that encompasses many dosage forms, one of which is osmotic pumps. Osmotic pumps are considered to be [...] Read more.

In the last couple of years, novel drug delivery systems (NDDS) have attracted much attention in the food and pharmaceutical industries. NDDS is a broad term that encompasses many dosage forms, one of which is osmotic pumps. Osmotic pumps are considered to be the most reliable source of controlled drug delivery, both in humans and in animals. These pumps are osmotically controlled and release active agents through osmotic pressure. To a large extent, drug release from such a system is independent of gastric fluids. Based on such unique properties and advantages, osmotic pumps have made their mark on the pharmaceutical industry. This review summarizes the available osmotic devices for implantation and osmotic tablets for oral administration. Full article

(This article belongs to the Section Pharmaceutical Technology)

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9 pages, 1716 KiB

Open AccessArticle

Protection against Lipopolysaccharide-Induced Endotoxemia by Terrein Is Mediated by Blocking Interleukin-1β and Interleukin-6 Production

by Yeo Dae Yoon, Myeong Youl Lee, Byeong Jo Choi, Chang Woo Lee, Hyunju Lee, Joo-Hee Kwon, Jeong-Wook Yang and Jong Soon Kang

Pharmaceuticals 2022, 15(11), 1429; https://doi.org/10.3390/ph15111429 - 18 Nov 2022

Cited by 3 | Viewed by 1298

Abstract

Terrein is a fungal metabolite and has been known to exert anti-melanogenesis, anti-cancer, and anti-bacterial activities. However, its role in endotoxemia has never been investigated until now. In the present study, we examined the effect of terrein on lipopolysaccharide (LPS)-induced endotoxemia in mice [...] Read more.

Terrein is a fungal metabolite and has been known to exert anti-melanogenesis, anti-cancer, and anti-bacterial activities. However, its role in endotoxemia has never been investigated until now. In the present study, we examined the effect of terrein on lipopolysaccharide (LPS)-induced endotoxemia in mice and characterized the potential mechanisms of action. Treatment with terrein increased the survival of mice and decreased the production of inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-6 (IL-6) in an LPS-induced endotoxemia model. In addition, terrein suppressed the LPS-induced production of IL-1β and IL-6 in RAW 264.7 cells, a murine macrophage-like cell line, and the mRNA expression of IL-1β and IL-6 was also inhibited by terrein in LPS-stimulated RAW 264.7 cells. Further study demonstrated that terrein blocked LPS-induced phosphorylation of p65 subunit of nuclear factor (NF)/κB and the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) was also suppressed by terrein treatment. Collectively, these results suggest that terrein exerts a protective effect again LPS-induced endotoxemia in mice by blocking the production of inflammatory cytokines. Our results also suggest that the anti-inflammatory effect of terrein might be mediated, at least in part, by blocking the activation of NF-κB, JNK, and p38 MAPK signaling pathways. Full article

(This article belongs to the Special Issue Fungal-Derived Natural Product: Synthesis, Function, and Applications)

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16 pages, 1711 KiB

Open AccessReview

Integrating Mechanisms in Thrombotic Peripheral Arterial Disease

by Magdolna Nagy, Paola E. J. van der Meijden, Julia Glunz, Leon Schurgers, Esther Lutgens, Hugo ten Cate, Stefan Heitmeier and Henri M. H. Spronk

Pharmaceuticals 2022, 15(11), 1428; https://doi.org/10.3390/ph15111428 - 18 Nov 2022

Cited by 2 | Viewed by 2344

Abstract

Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis, is underdiagnosed in the general population. Despite the extensive research performed to unravel its pathophysiology, inadequate knowledge exists, thus preventing the development of new treatments. This review aims to highlight the essential elements of [...] Read more.

Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis, is underdiagnosed in the general population. Despite the extensive research performed to unravel its pathophysiology, inadequate knowledge exists, thus preventing the development of new treatments. This review aims to highlight the essential elements of atherosclerosis contributing to the pathophysiology of PAD. Furthermore, emphasis will be placed on the role of thrombo-inflammation, with particular focus on platelet and coagulation activation as well as cell–cell interactions. Additional insight will be then discussed to reveal the contribution of hypercoagulability to the development of vascular diseases such as PAD. Lastly, the current antithrombotic treatments will be discussed, and light will be shed on promising new targets aiming to aid the development of new treatments. Full article

(This article belongs to the Special Issue Anticoagulants and Antiplatelet Drugs)

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43 pages, 14709 KiB

Open AccessReview

New Antifungal Agents with Azole Moieties

by Melissa Martins Teixeira, Diogo Teixeira Carvalho, Emília Sousa and Eugénia Pinto

Pharmaceuticals 2022, 15(11), 1427; https://doi.org/10.3390/ph15111427 - 17 Nov 2022

Cited by 16 | Viewed by 7662

Abstract

Fungal conditions affect a multitude of people worldwide, leading to increased hospitalization and mortality rates, and the need for novel antifungals is emerging with the rise of resistance and immunocompromised patients. Continuous use of azole drugs, which act by inhibiting the fungal CYP51, [...] Read more.

Fungal conditions affect a multitude of people worldwide, leading to increased hospitalization and mortality rates, and the need for novel antifungals is emerging with the rise of resistance and immunocompromised patients. Continuous use of azole drugs, which act by inhibiting the fungal CYP51, involved in the synthesis of ergosterol, essential to the fungal cell membrane, has enhanced the resistance and tolerance of some fungal strains to treatment, thereby limiting the arsenal of available drugs. The goal of this review is to gather literature information on new promising azole developments in clinical trials, with in vitro and in vivo results against fungal strains, and complementary assays, such as toxicity, susceptibility assays, docking studies, among others. Several molecules are reviewed as novel azole structures in clinical trials and with recent/imminent approvals, as well as other innovative molecules with promising antifungal activity. Structure–activity relationship (SAR) studies are displayed whenever possible. The azole moiety is brought over as a privileged structure, with multiple different compounds emerging with distinct pharmacophores and SAR. Particularly, 1,2,3-triazole natural product conjugates emerged in the last years, presenting promising antifungal activity and a broad spectrum against various fungi. Full article

(This article belongs to the Special Issue Feature Reviews in Medicinal Chemistry)

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10 pages, 837 KiB

Open AccessArticle

Heavy Metal (Arsenic) Induced Antibiotic Resistance among Extended-Spectrum β-Lactamase (ESBL) Producing Bacteria of Nosocomial Origin

by Naveed Ahmed, Kinza Tahir, Sara Aslam, Sara Masood Cheema, Ali A. Rabaan, Safaa A. Turkistani, Mohammed Garout, Muhammad A. Halwani, Mohammed Aljeldah, Basim R. Al Shammari, Amal A. Sabour, Maha A. Alshiekheid, Saleh A. Alshamrani, Reyouf Al Azmi, Ghadeer H. Al-Absi, Shah Zeb and Chan Yean Yean

Pharmaceuticals 2022, 15(11), 1426; https://doi.org/10.3390/ph15111426 - 17 Nov 2022

Cited by 5 | Viewed by 2809

Abstract

Antimicrobial resistance (AMR) is a leading cause of treatment failure for many infectious diseases worldwide. Improper overdosing and the misuse of antibiotics contributes significantly to the emergence of drug-resistant bacteria. The co-contamination of heavy metals and antibiotic compounds existing in the environment might [...] Read more.

Antimicrobial resistance (AMR) is a leading cause of treatment failure for many infectious diseases worldwide. Improper overdosing and the misuse of antibiotics contributes significantly to the emergence of drug-resistant bacteria. The co-contamination of heavy metals and antibiotic compounds existing in the environment might also be involved in the spread of AMR. The current study was designed to test the efficacy of heavy metals (arsenic) induced AMR patterns in clinically isolated extended-spectrum β-lactamase (ESBL) producing bacteria. A total of 300 clinically isolated ESBL-producing bacteria were collected from a tertiary care hospital in Lahore, Pakistan, with the demographic characteristics of patients. After the collection of bacterial isolates, these were reinoculated on agar media for reidentification purposes. Direct antimicrobial sensitivity testing (AST) for bacterial isolates by disk diffusion methods was used to determine the AST patterns with and without heavy metal. The heavy metal was concentrated in dilutions of 1.25 g/mL. The collected bacterial isolates were isolated from wounds (n = 63, 21%), urine (n = 112, 37.3%), blood (n = 43, 14.3%), pus (n = 49, 16.3%), and aspirate (n = 33, 11%) samples. From the total 300 bacterial isolates, n = 172 were Escherichia coli (57.3%), 57 were Klebsiella spp. (19%), 32 were Pseudomonas aeruginosa (10.6%), 21 were Proteus mirabilis (7%) and 18 were Enterobacter spp. (6%). Most of the antibiotic drugs were found resistant to tested bacteria. Colistin and Polymyxin-B showed the highest sensitivity against all tested bacteria, but when tested with heavy metals, these antibiotics were also found to be significantly resistant. We found that heavy metals induced the resistance capability in bacterial isolates, which leads to higher AMR patterns as compared to without heavy metal tested isolates. The results of the current study explored the heavy metal as an inducer of AMR and may contribute to the formation and spread of AMR in settings that are contaminated with heavy metals. Full article

(This article belongs to the Special Issue Antibiotic Resistance in Gram-Negative Bacteria: The Threat from the Pink Corner)

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24 pages, 4604 KiB

Open AccessReview

Recent Synthesis, Characterization, and Pharmacological Evaluation of Multifunctional Hemorphins Containing Non-Natural Amino Acids with Potential Biological Importance

by Petar Todorov, Stela Georgieva and Jana Tchekalarova

Pharmaceuticals 2022, 15(11), 1425; https://doi.org/10.3390/ph15111425 - 17 Nov 2022

Cited by 3 | Viewed by 1490

Abstract

The endogenous hemorphins are bioactive peptides with activity on opioid receptors. They are extensively studied and summarized in numerous reviews. During the last decade, several research teams have synthesized, characterized, and pharmacologically evaluated synthetic hemorphin analogs containing unusual amino acids, D-amino acids, α-aminophosphonic [...] Read more.

The endogenous hemorphins are bioactive peptides with activity on opioid receptors. They are extensively studied and summarized in numerous reviews. During the last decade, several research teams have synthesized, characterized, and pharmacologically evaluated synthetic hemorphin analogs containing unusual amino acids, D-amino acids, α-aminophosphonic acids, and their derivatives. The present review summarizes the current studies on short-chain synthetic hemorphin peptide derivates containing non-natural amino acids. This review focuses on the structure–activity relationship analysis, details on specific methods for their characterization, and the advantage of synthetic hemorphin analogs compared to endogenous peptides as potent biologically active compounds with a complex mechanism of action. Full article

(This article belongs to the Special Issue Non-Natural Amino Acids in Drug Design)

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14 pages, 7182 KiB

Open AccessReview

Adjuvant Chinese Medicine for the Treatment of Type 2 Diabetes Mellitus Combined with Mild Cognitive Impairment: A Systematic Review and Meta-Analysis of a Randomised Controlled Trial

by Changxing Liu and Xinyi Guo

Pharmaceuticals 2022, 15(11), 1424; https://doi.org/10.3390/ph15111424 - 17 Nov 2022

Cited by 1 | Viewed by 1791

Abstract

Mild cognitive impairment has a high prevalence in the type 2 diabetic population. Adjuvant therapy with Chinese herbal medicine can effectively improve the clinical symptoms of patients with T2DM combined with MCI. The aim of this study was to systematically evaluate the efficacy [...] Read more.

Mild cognitive impairment has a high prevalence in the type 2 diabetic population. Adjuvant therapy with Chinese herbal medicine can effectively improve the clinical symptoms of patients with T2DM combined with MCI. The aim of this study was to systematically evaluate the efficacy and safety of Chinese herbal adjunctive therapy in the treatment of diabetes mellitus combined with cognitive impairment. Information was analysed using the China Knowledge Network, Vip Database, Wanfang Database, China Biomedical Literature Database, PubMed, EMbase, Web of Science, and MedLine Database. The total clinical efficiency, blood glucose, blood lipids, Simple Mental-State Examination Scale (MMSE), Montreal Cognitive Assessment Scale (MoCA), Traditional Chinese Medicine Symptom Score (TCMSS), and incidence of adverse reactions were recorded. The methodological quality of the included studies was evaluated using the application of the Cochrane Collaboration Network Risk Bias Assessment Tool, and meta-analysis was performed using RevMan 5.4 software. Adjuvant treatment with Chinese herbal medicine was effective in improving the clinical outcomes (OR = 5.33, 95% CI (3.62, 7.84), p < 0.00001) and cognitive function by comparing with the control group: MMSE (MD = 1.56, 95% CI (1.29, 1.84), p < 0.00001) and MoCA (MD = 2.77, 95% CI (1.81, 3.73), p < 0.0001); lowered blood glucose: fasting blood glucose (FBG) (MD = −0.27, 95% CI (−0.42, −0.12), p = 0.0006), 2 hPG (MD = −0.28, 95% CI (−0.45, −0.10), p = 0.002), and glycated haemoglobin (HbA1c) (MD = −0.26, 95% CI (−0.39, −0.14), p < 0.001); and improved lipids: total cholesterol (TC) (MD = −0.51, 95% CI (−0.82, −0.21), p = 0.001), triglycerides (TGs) (MD = −0.46, 95% CI −0.46, 95% CI (−0.80, −0.11), p = 0.009), low-density lipoprotein (LDL-C) (MD = −0.28, 95% CI (−0.55, −0.02), p = 0.04), high-density lipoprotein (HDL-C) (MD = 0.17, 95% CI (0.07, 0.28), p = 0.001), reduced TCMSS (MD = −1.84, 95% CI (−2.58, −1.10), p < 0.0001), and incidence of adverse events (OR = 0.46, 95% CI (0.24, 0.88), p = 0.02). In conclusion, through the available evidence, herbal adjuvant therapy for T2DM combined with MCI was observed to be effective and did not significantly increase the adverse effects. Due to the limitation of the number and quality of the included studies, the abovementioned results need to be validated by further high-quality studies. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)

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10 pages, 259 KiB

Open AccessArticle

Antithymocyte Globulin Plus Post-Transplant Cyclophosphamide Combination as an Effective Strategy for Graft-versus-Host Disease Prevention in Haploidentical Peripheral Blood Stem Cell Transplantation for Children with High-Risk Malignancies

by Kang-Hsi Wu, Te-Fu Weng, Ju-Pi Li and Yu-Hua Chao

Pharmaceuticals 2022, 15(11), 1423; https://doi.org/10.3390/ph15111423 - 17 Nov 2022

Cited by 1 | Viewed by 1594

Abstract

Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this [...] Read more.

Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis has emerged as a valid alternative transplant strategy for patients lacking a suitable HLA-matched related donor. The high risk of severe GVHD remains the major clinical challenge in this setting. The addition of antithymocyte globulin (ATG) in PTCy-based regimens for GVHD reduction in haploidentical hematopoietic stem cell transplantation is rational and was reported in adult series. However, its feasibility is unknown in pediatric patients. Here, we firstly describe our experience of 15 consecutive children with high-risk malignancies receiving haploidentical peripheral blood stem cell transplantation using ATG plus PTCy for GVHD prophylaxis. Only three patients developed grade 1–2 acute GVHD, limited to skin. No grade 3–4 acute GVHD and chronic GVHD were observed. Viral reactivations were frequently seen but manageable. Six patients relapsed, as the main cause of death in our series. None died from events related to GVHD. Our data suggest that ATG plus PTCy is an effective strategy for GVHD prevention in haploidentical peripheral blood stem cell transplantation and is feasible in children with high-risk malignancies. Full article

(This article belongs to the Special Issue Development of Medicines for Rare Pediatric Diseases)

21 pages, 8609 KiB

Open AccessArticle

A Shape-Adaptive Gallic Acid Driven Multifunctional Adhesive Hydrogel Loaded with Scolopin2 for Wound Repair

by Huan Chen, Tingting Zheng, Chenyang Wu, Jinrui Wang, Fan Ye, Mengyao Cui, Shuhui Sun, Yun Zhang, Ying Li and Zhengqi Dong

Pharmaceuticals 2022, 15(11), 1422; https://doi.org/10.3390/ph15111422 - 17 Nov 2022

Cited by 6 | Viewed by 1751

Abstract

Wound healing is one of the major challenges in the biomedical fields. The conventional single drug treatment has unsatisfactory efficacy, and the drug delivery effectiveness is restricted by the short retention on the wound. Herein, we develop a multifunctional adhesive hydrogel that can [...] Read more.

Wound healing is one of the major challenges in the biomedical fields. The conventional single drug treatment has unsatisfactory efficacy, and the drug delivery effectiveness is restricted by the short retention on the wound. Herein, we develop a multifunctional adhesive hydrogel that can realize robust adhesion, transdermal delivery, and combination therapy for wound healing. Multifunctional hydrogels (CS-GA-S) are mixed with chitosan-gallic acid (CS-GA), sodium periodate, and centipede peptide-scolopin2, which slowly releases scolopin2 in the layer of the dermis. The released scolopin2 induces the pro-angiogenesis of skin wounds and enables excellent antibacterial effects. Separately, GA as a natural reactive-oxygen-species-scavenger promotes antioxidation, and further enables excellent antibacterial effects and wet tissue adhesion due to a Schiff base and Michael addition reaction for accelerating wound healing. Once adhered to the wound, the precursor solution becomes both a physically and covalently cross-linked network hydrogel, which has potential advantages for wound healing with ease of use, external environment-isolating, and minimal tissue damage. The therapeutic effects of CS-GA-S on wound healing are demonstrated with the full thickness cutaneous wounds of a mouse model. The significant improvement of wound healing is achieved for mice treated with CS-GA-S. This preparation reduces wound system exposure, prolongs local drug residence time, and improves efficacy. Accordingly, with the incorporation of scolopin2 into the shape-adaptive CS-GA hydrogel, the composite hydrogel possesses multi-functions of mechanical adhesion, drug therapy, and skin wound healing. Overall, such an injectable or sprayable hydrogel plays an effective role in emergency wound treatment with the advantage of convenience and portability. Full article

(This article belongs to the Special Issue Hydrogels in Biomedical Applications)

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10 pages, 1842 KiB

Open AccessArticle

Trypanosoma cruzi Antigenic Proteins Shared with Acute Lymphoblastic Leukemia and Neuroblastoma

by Leticia Eligio García, María del Pilar Crisóstomo Vázquez, Víctor Alberto Maravelez Acosta, Mariana Soria Guerrero, Adrián Cortés Campos and Enedina Jiménez Cardoso

Pharmaceuticals 2022, 15(11), 1421; https://doi.org/10.3390/ph15111421 - 17 Nov 2022

Cited by 1 | Viewed by 1309

Abstract

Background. Research studies indicate that immunization with protein extracts of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, prevents the appearance of tumors in 60% of mice injected with the murine lung carcinoma tumor line. The molecular basis of this process [...] Read more.

Background. Research studies indicate that immunization with protein extracts of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, prevents the appearance of tumors in 60% of mice injected with the murine lung carcinoma tumor line. The molecular basis of this process is unknown, although the presence of specific antigens in tumor cells and on the surface of T. cruzi suggests an antiparasitic immune response, with an effective cross-reaction against cancer cells, hence the importance to identify the antigens involved and determine their potential as target cells in anticancer therapy. Aim. This study aimed to determine the presence of antigenic proteins of T. cruzi shared with acute lymphoblastic leukemia and neuroblastoma cells. Material and methods. To achieve this, polyclonal antibodies against T. cruzi were developed in rabbits, and reactivity was determined with protein extracts of acute lymphoblastic leukemia cells and neuroblastoma. The immunodetection of five different strains of T. cruzi against anti-T. cruzi polyclonal antibodies was also performed. Conclusion. The study allows the knowledge of the immunological interactions between cancer and parasites to be expanded and, therefore, contributes to the design of more and better projects that improve the therapeutic strategies applied in oncology. Full article

(This article belongs to the Section Biopharmaceuticals)

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17 pages, 2555 KiB

Open AccessArticle

Lycopene Modulates Oxidative Stress and Inflammation in Hypercholesterolemic Rats

by Tarfa Albrahim

Pharmaceuticals 2022, 15(11), 1420; https://doi.org/10.3390/ph15111420 - 17 Nov 2022

Cited by 7 | Viewed by 1845

Abstract

The complicated disorder of hypercholesterolemia has several underlying factors, including genetic and lifestyle factors. Low LDL cholesterol and elevated serum total cholesterol are its defining features. A carotenoid with antioxidant quality is lycopene. Examining lycopene activity in an animal model of hypercholesterolemia induced [...] Read more.

The complicated disorder of hypercholesterolemia has several underlying factors, including genetic and lifestyle factors. Low LDL cholesterol and elevated serum total cholesterol are its defining features. A carotenoid with antioxidant quality is lycopene. Examining lycopene activity in an animal model of hypercholesterolemia induced using food was the aim of this investigation. Triglycerides, LDL cholesterol, HDL cholesterol, and plasma total cholesterol were all measured. Biomarkers of renal and cardiac function were also examined. Apoptotic indicators, pro-inflammatory markers, and oxidative stress were also assessed. Additionally, the mRNA expression of paraoxonase 1 (PON-1), peroxisome proliferator-activated receptor gamma (PPAR-γ), and PPAR-γ coactivator 1 alpha (PGC-1α) in cardiac and renal tissues was examined. Rats showed elevated serum lipid levels, renal and cardiac dysfunction, significant oxidative stress, and pro-inflammatory and apoptotic markers at the end of the study. Treatment with lycopene significantly corrected and restored these changes. Additionally, lycopene markedly increased the mRNA expression of PGC-1α and PON-1, and decreased PPAR-γ expression. It was determined that lycopene has the capacity to modulate the PPAR-γ and PON-1 signaling pathway in order to preserve the cellular energy metabolism of the heart and kidney, which in turn reduces tissue inflammatory response and apoptosis. According to these findings, lycopene may be utilized as a medication to treat hypercholesterolemia. However, further studies should be conducted first to determine the appropriate dose and any adverse effects that may appear after lycopene usage in humans. Full article

(This article belongs to the Special Issue Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease)

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26 pages, 1402 KiB

Open AccessReview

Therapeutic Potential of Honey and Propolis on Ocular Disease

by Norhashima Abd Rashid, Siti Nur Farhana Mohammed, Syarifah Aisyah Syed Abd Halim, Norzana Abd Ghafar and Nahdia Afiifah Abdul Jalil

Pharmaceuticals 2022, 15(11), 1419; https://doi.org/10.3390/ph15111419 - 17 Nov 2022

Cited by 10 | Viewed by 3990

Abstract

Honey and propolis have recently become the key target of attention for treating certain diseases and promoting overall health and well-being. A high content of flavonoids and phenolic acids found in both honey and propolis contributes to the antioxidant properties to scavenge free [...] Read more.

Honey and propolis have recently become the key target of attention for treating certain diseases and promoting overall health and well-being. A high content of flavonoids and phenolic acids found in both honey and propolis contributes to the antioxidant properties to scavenge free radicals. Honey and propolis also exhibited antibacterial effects where they act in two ways, namely the production of hydrogen peroxide (H₂O₂) and gluconic acids following the enzymatic activities of glucose oxidase, which exerts oxidative damage on the bacteria. Additionally, the anti-inflammatory effects of honey and propolis are mainly by reducing proinflammatory factors such as interleukins and tumor necrosis factor alpha (TNF-α). Their effects on pain were discovered through modulation at a peripheral nociceptive neuron or binding to an opioid receptor in the higher center. The aforementioned properties of honey have been reported to possess potential therapeutic topical application on the exterior parts of the eyes, particularly in treating conjunctivitis, keratitis, blepharitis, and corneal injury. In contrast, most of the medicinal values of propolis are beneficial in the internal ocular area, such as the retina, optic nerve, and uvea. This review aims to update the current discoveries of honey and propolis in treating various ocular diseases, including their antioxidant, anti-inflammatory, antibacterial, and anti-nociceptive properties. In conclusion, research has shown that propolis and honey have considerable therapeutic promise for treating various eye illnesses, although the present study designs are primarily animal and in vitro studies. Therefore, there is an urgent need to translate this finding into a clinical setting. Full article

(This article belongs to the Special Issue Discovery, Metabolism and Potential Bio-Activities of Natural Products in Traditional Medicine)

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24 pages, 2830 KiB

Open AccessReview

Gut Microbiota-Assisted Synthesis, Cellular Interactions and Synergistic Perspectives of Equol as a Potent Anticancer Isoflavone

by Hardeep Singh Tuli, Ajay Kumar, Katrin Sak, Diwakar Aggarwal, Dhruv Sanjay Gupta, Ginpreet Kaur, Kanupriya Vashishth, Kuldeep Dhama, Jagjit Kaur, Adesh K. Saini, Mehmet Varol, Esra Capanoglu and Shafiul Haque

Pharmaceuticals 2022, 15(11), 1418; https://doi.org/10.3390/ph15111418 - 16 Nov 2022

Cited by 6 | Viewed by 2769

Abstract

It is well known that, historically, plants have been an important resource of anticancer agents, providing several clinically approved drugs. Numerous preclinical studies have shown a strong anticancer potential of structurally different phytochemicals, including polyphenolic constituents of plants, flavonoids. In this review article, [...] Read more.

It is well known that, historically, plants have been an important resource of anticancer agents, providing several clinically approved drugs. Numerous preclinical studies have shown a strong anticancer potential of structurally different phytochemicals, including polyphenolic constituents of plants, flavonoids. In this review article, suppressing effects of equol in different carcinogenesis models are unraveled, highlighting the mechanisms involved in these anticancer activities. Among flavonoids, daidzein is a well-known isoflavone occurring in soybeans and soy products. In a certain part of population, this soy isoflavone is decomposed to equol under the action of gut microflora. Somewhat surprisingly, this degradation product has been shown to be more bioactive than its precursor daidzein, revealing a strong and multifaceted anticancer potential. In this way, it is important to bear in mind that the metabolic conversion of plant flavonoids might lead to products that are even more efficient than the parent compounds themselves, definitely deserving further studies. Full article

(This article belongs to the Special Issue Health Effects of Colonic Microbiota-Derived Catabolites of Flavonoids)

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8 pages, 1276 KiB

Open AccessCommunication

The Effects of Positive Allosteric Modulators of α7–nAChR on Social Play Behavior in Adolescent Rats Prenatally Exposed to Valproic Acid

by Kinga Gzielo and Agnieszka Nikiforuk

Pharmaceuticals 2022, 15(11), 1417; https://doi.org/10.3390/ph15111417 - 16 Nov 2022

Cited by 2 | Viewed by 1489

Abstract

There is still no effective treatment that addresses the core symptoms of autism spectrum disorders (ASD), including social and communication deficits. A comprehensive body of evidence points to the cholinergic system, including alpha7–nicotinic acetylcholine receptors (α7–nAChRs), as a potential target of pharmacotherapy. A [...] Read more.

There is still no effective treatment that addresses the core symptoms of autism spectrum disorders (ASD), including social and communication deficits. A comprehensive body of evidence points to the cholinergic system, including alpha7–nicotinic acetylcholine receptors (α7–nAChRs), as a potential target of pharmacotherapy. A promising approach is based on positive allosteric modulators (PAMs) of these receptors due to their advantages over direct agonists. Nevertheless, α7 n–AChR ligands have not been widely studied in the context of autism. Therefore, using one of the most widely used rodent models of ASD, that is, prenatal exposure to valproic acid (VPA), we examined the impact of α7–nAChR PAMs (PNU–120596 and CCMI) on socio-communicative behavior during social play in adolescent male and female rats. The current study demonstrated that PAM treatment affected certain aspects of socio-communicative behavior in adolescent rats. Accordingly, PNU–120596 ameliorated deficient play abilities in VPA-exposed males, as revealed by increased play time during a social encounter. In addition, this compound enhanced the emission of ultrasonic vocalizations that accompanied playful interactions. Moreover, we observed the overall effect of PNU–120596 on non-playful forms of social behavior (i.e., social exploration) and acoustic parameters (i.e., the duration) of emitted calls. The present results suggest the ability of α7–nAChR PAMs to facilitate socio-communicative behavior in adolescent rats. Full article

(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)

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25 pages, 6178 KiB

Open AccessArticle

Design, Synthesis, Molecular Modeling, and Anticancer Evaluation of New VEGFR-2 Inhibitors Based on the Indolin-2-One Scaffold

by Mohamed A. Abdelgawad, Alaa M. Hayallah, Syed Nasir Abbas Bukhari, Arafa Musa, Mohammed Elmowafy, Hamdy M. Abdel-Rahman and Mohammed K. Abd El-Gaber

Pharmaceuticals 2022, 15(11), 1416; https://doi.org/10.3390/ph15111416 - 15 Nov 2022

Cited by 10 | Viewed by 1992

Abstract

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most [...] Read more.

A new series of indoline-2-one derivatives was designed and synthesized based on the essential pharmacophoric features of VEGFR-2 inhibitors. Anti-proliferative activities were assessed for all derivatives against breast (MCF-7) and liver (HepG2) cancer cell lines, using sunitinib as a reference agent. The most potent anti-proliferative derivatives were evaluated for their VEGFR-2 inhibition activity. The effects of the most potent inhibitor, 17a, on cell cycle, apoptosis, and expression of apoptotic markers (caspase-3&-9, BAX, and Bcl-2) were studied. Molecular modeling studies, such as docking simulations, physicochemical properties prediction, and pharmacokinetic profiling were performed. The results revealed that derivatives 5b, 10e, 10g, 15a, and 17a exhibited potent anticancer activities with IC₅₀ values from 0.74–4.62 µM against MCF-7 cell line (sunitinib IC₅₀ = 4.77 µM) and from 1.13–8.81 µM against HepG2 cell line (sunitinib IC₅₀ = 2.23 µM). Furthermore, these compounds displayed potent VEGFR-2 inhibitory activities with IC₅₀ values of 0.160, 0.358, 0.087, 0.180, and 0.078 µM, respectively (sunitinib IC₅₀ = 0.139 µM). Cell cycle analysis demonstrated the ability of 17a to induce a cell cycle arrest of the HepG2 cells at the S phase and increase the total apoptosis by 3.5-fold. Moreover, 17a upregulated the expression levels of apoptotic markers caspase-3 and -9 by 6.9-fold and 3.7-fold, respectively. In addition, 17a increased the expression level of BAX by 2.7-fold while decreasing the expression level of Bcl-2 by 1.9-fold. The molecular docking simulations displayed enhanced binding interactions and similar placement as sunitinib inside the active pocket of VEGFR-2. The molecular modeling calculations showed that all the test compounds were in accordance with Lipinski and Veber rules for oral bioavailability and had promising drug-likeness behavior. Full article

(This article belongs to the Section Medicinal Chemistry)

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24 pages, 15973 KiB

Open AccessReview

Implications of Fragment-Based Drug Discovery in Tuberculosis and HIV

by Mohan Krishna Mallakuntla, Namdev S. Togre, Destiny B. Santos and Sangeeta Tiwari

Pharmaceuticals 2022, 15(11), 1415; https://doi.org/10.3390/ph15111415 - 15 Nov 2022

Cited by 4 | Viewed by 1930

Abstract

Tuberculosis (TB) remains a global health problem and the emergence of HIV has further worsened it. Long chemotherapy and the emergence of drug-resistance strains of Mycobacterium tuberculosis as well as HIV has aggravated the problem. This demands urgent the need to develop new [...] Read more.

Tuberculosis (TB) remains a global health problem and the emergence of HIV has further worsened it. Long chemotherapy and the emergence of drug-resistance strains of Mycobacterium tuberculosis as well as HIV has aggravated the problem. This demands urgent the need to develop new anti-tuberculosis and antiretrovirals to treat TB and HIV. The lack of diversity in drugs designed using traditional approaches is a major disadvantage and limits the treatment options. Therefore, new technologies and approaches are required to solve the current issues and enhance the production of drugs. Interestingly, fragment-based drug discovery (FBDD) has gained an advantage over high-throughput screenings as FBDD has enabled rapid and efficient progress to develop potent small molecule compounds that specifically bind to the target. Several potent inhibitor compounds of various targets have been developed using FBDD approach and some of them are under progression to clinical trials. In this review, we emphasize some of the important targets of mycobacteria and HIV. We also discussed about the target-based druggable molecules that are identified using the FBDD approach, use of these druggable molecules to identify novel binding sites on the target and assays used to evaluate inhibitory activities of these identified druggable molecules on the biological activity of the targets. Full article

(This article belongs to the Special Issue Recent Advances in Fragment-Based Lead Discovery and Design)

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19 pages, 3865 KiB

Open AccessArticle

Copaiba Oil Resin Exerts an Additive Effect to Babassu Oil on Behavioral Changes in Human Endometriotic Cell Cultures

by Julianna Henriques da Silva, Leticia Coli Louvisse de Abreu, Renato Ferrari, Celia Yelimar Palmero Quintana, Eliane Gouvêa de Oliveira Barros, Natália de Moraes Cordeiro, Bruno Pontes, Valeria Pereira de Sousa, Lucio Mendes Cabral, Patricia Dias Fernandes and Luiz Eurico Nasciutti

Pharmaceuticals 2022, 15(11), 1414; https://doi.org/10.3390/ph15111414 - 15 Nov 2022

Cited by 1 | Viewed by 1529

Abstract

Background: Current drugs for the treatment of endometriosis are not able to completely cure the condition, and significant side effects hinder the continuation of treatment. Therefore, it is necessary to search for new drug candidates. In the present paper, the use of plant [...] Read more.

Background: Current drugs for the treatment of endometriosis are not able to completely cure the condition, and significant side effects hinder the continuation of treatment. Therefore, it is necessary to search for new drug candidates. In the present paper, the use of plant extracts is highlighted. Babassu oil and Copaiba oil resin have several therapeutic properties. We investigated the in vitro effects of two nanoemulsions containing oil extracted from Babassu (Orbignya speciosa) nuts (called SNEDDS-18) and/or oil resin extracted from Copaiba trunk (Copaifera langsdorffii) (called SNEDDS-18/COPA) on cultured human eutopic endometrium stromal cells from endometrial biopsies of patients without (CESC) and with (EuESC) endometriosis as well as human stromal cells from biopsies of endometriotic lesions (EctESC). Methods: CESC, EuESC, and EctESC were taken and treated with SNEDDS-18 and SNEDDS-18/COPA to evaluate their effects on cytotoxicity, cell morphology, proliferation, and signaling pathways. Results: After 48 h of incubation with SNEDDS-18 and SNEDDS-18/COPA, cell viability and proliferation were inhibited, especially in EctESC. The lowest concentration of both nanoemulsions reduced cell viability and proliferation and broke down the cytoskeleton in EctESCs. After 24 h of treatment a decrease in IL-1, TNF-α, and MCP-1 was observed, as well as an increase in IL-10 production. Conclusions: Both nanoemulsions can affect endometriotic stromal cell behaviors, thus revealing two potential candidates for new phytotherapeutic agents for the management of endometriosis. Full article

(This article belongs to the Special Issue Ethnopharmacology in Latin America)

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21 pages, 1642 KiB

Open AccessReview

A Review of Pickering Emulsions: Perspectives and Applications

by Fernanda Brito de Carvalho-Guimarães, Kamila Leal Correa, Tatiane Pereira de Souza, Jesus Rafael Rodríguez Amado, Roseane Maria Ribeiro-Costa and José Otávio Carréra Silva-Júnior

Pharmaceuticals 2022, 15(11), 1413; https://doi.org/10.3390/ph15111413 - 15 Nov 2022

Cited by 25 | Viewed by 12957

Abstract

Pickering emulsions are systems composed of two immiscible fluids stabilized by organic or inorganic solid particles. These solid particles of certain dimensions (micro- or nano-particles), and desired wettability, have been shown to be an alternative to conventional emulsifiers. The use of biodegradable and [...] Read more.

Pickering emulsions are systems composed of two immiscible fluids stabilized by organic or inorganic solid particles. These solid particles of certain dimensions (micro- or nano-particles), and desired wettability, have been shown to be an alternative to conventional emulsifiers. The use of biodegradable and biocompatible stabilizers of natural origin, such as clay minerals, presents a promising future for the development of Pickering emulsions and, with this, they deliver some advantages, especially in the area of biomedicine. In this review, the effects and characteristics of microparticles in the preparation and properties of Pickering emulsions are presented. The objective of this review is to provide a theoretical basis for a broader type of emulsion, in addition to reviewing the main aspects related to the mechanisms and applications to promote its stability. Through this review, we highlight the use of this type of emulsion and its excellent properties as permeability promoters of solid particles, providing ideal results for local drug delivery and use in Pickering emulsions. Full article

(This article belongs to the Section Pharmaceutical Technology)

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Pharmaceuticals, Volume 15, Issue 11 (November 2022) – 139 articles

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