Pharmaceuticals

22 pages, 7627 KiB

Open AccessArticle

Development and Characterization of Eudragit^® EPO-Based Solid Dispersion of Rosuvastatin Calcium to Foresee the Impact on Solubility, Dissolution and Antihyperlipidemic Activity

by Sana Inam, Muhammad Irfan, Noor ul ain Lali, Haroon Khalid Syed, Sajid Asghar, Ikram Ullah Khan, Salah-Ud-Din Khan, Muhammad Shahid Iqbal, Imran Zaheer, Ahmed Khames, Heba A. Abou-Taleb and Mohammad A. S. Abourehab

Pharmaceuticals 2022, 15(4), 492; https://doi.org/10.3390/ph15040492 - 18 Apr 2022

Cited by 12 | Viewed by 3051

Abstract

Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly [...] Read more.

Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 4640 KiB

Open AccessArticle

Augmentation of Antidiabetic Activity of Glibenclamide Microspheres Using S-Protected Okra Powered by QbD: Scintigraphy and In Vivo Studies

by Waleed Y. Rizg, N. Raghavendra Naveen, Mallesh Kurakula, Awaji Y. Safhi, Samar S. Murshid, Rayan Y. Mushtaq, Walaa A. Abualsunun, Majed Alharbi, Rana B. Bakhaidar, Alshaimaa M. Almehmady, Ahmad Salawi, Adel Al Fatease and Khaled M. Hosny

Pharmaceuticals 2022, 15(4), 491; https://doi.org/10.3390/ph15040491 - 18 Apr 2022

Cited by 5 | Viewed by 2079

Abstract

Successful drug delivery by mucoadhesive systems depends on the polymer type, which usually gets adherent on hydration. The intended polymers must sustain the association with biomembranes and preserve or accommodate the drug for an extended time. The majority of hydrophilic polymers tend to [...] Read more.

Successful drug delivery by mucoadhesive systems depends on the polymer type, which usually gets adherent on hydration. The intended polymers must sustain the association with biomembranes and preserve or accommodate the drug for an extended time. The majority of hydrophilic polymers tend to make weak interactions like noncovalent bonds, which hampers the positioning of dosage forms at the required target sites, leading to inefficient therapeutic outcomes. It is possible to overcome this by functionalizing the natural polymers with thiol moiety. Further, considering that S-protected thiomers can benefit by improving thiol stability at a broad range of pH and enhancing the residence period at the required target, 2-mercapto-nicotinic acid (MA) was utilized in this present study to shield the free thiol groups on thiolated okra (TO). S-protected TO (STO) was synthesized and characterized for various parameters. Glibenclamide-loaded microspheres were formulated using STO (G-STO-M), and the process was optimized. The optimized formulation has shown complete and controlled release of the loaded drug at the end of the dissolution study. Cell viability assay indicated that the thiolated S-protected polymers gelated very well, and the formulated microspheres were safe. Further, G-STO-M showed considerable in vivo mucoadhesion strength. The glucose tolerance test confirmed the efficacy of STO formulation in minimizing the plasma glucose level. These results favor S-protection as an encouraging tool for improving the absorption of poorly aqueous soluble drugs like glibenclamide. Full article

(This article belongs to the Section Pharmaceutical Technology)

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16 pages, 3025 KiB

Open AccessArticle

Development of Astaxanthin-Loaded Nanosized Liposomal Formulation to Improve Bone Health

by Hsin-I. Chang, Chu-Wen Shao, Evelyn Huang and Kuo-Yuan Huang

Pharmaceuticals 2022, 15(4), 490; https://doi.org/10.3390/ph15040490 - 18 Apr 2022

Cited by 7 | Viewed by 2142

Abstract

Astaxanthin is a xanthophyll carotenoid commonly found in marine organisms. Due to its super antioxidative ability, astaxanthin has been widely applied as a human nutraceutical supplement for health benefits. In order to enhance the bioavailability of astaxanthin, we used soybean phosphatidylcholine to encapsulate [...] Read more.

Astaxanthin is a xanthophyll carotenoid commonly found in marine organisms. Due to its super antioxidative ability, astaxanthin has been widely applied as a human nutraceutical supplement for health benefits. In order to enhance the bioavailability of astaxanthin, we used soybean phosphatidylcholine to encapsulate astaxanthin for liposomal formation. The physical properties of astaxanthin (asta)-loaded liposomes were determined by particle size, encapsulation efficiency and polydispersity index. The results revealed that the particle sizes of asta-loaded liposomes with various concentrations exhibited mean diameters in the range of 109 to 134 nm and had a narrow PDI value. As expected, the entrapment efficiency of liposomes loaded with a low concentration of astaxanthin (0.05 μg/mL) was 89%, and that was reduced to 29% for 1.02 μg/mL asta loading. Alizarin red staining and calcium content measurement showed that there was a significant reduction in calcium deposition for 7F2 osteoblasts treated with asta-loaded liposomes (0.25–1.02 μg/mL) in comparison with the cells treated with drug-free liposomes and mineralization medium (MM). Although liposomal formulation can reduce the cytotoxicity of astaxanthin and possess antioxidant, anti-inflammatory and anti-osteoclastogenic activities in RAW264.7 macrophages, asta-loaded liposomes with high concentrations may suppress ALP activity and mineralization level in 7F2 osteoblasts. Therefore, astaxanthin extract may be able to protect bones against oxidative stress and inflammation through liposomal formulation. Full article

(This article belongs to the Special Issue Development of Bone Targeted Drug Delivery Technologies)

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9 pages, 1539 KiB

Open AccessArticle

Effectiveness and Cost-Effectiveness Profile of Second-Line Treatments with Nivolumab, Pembrolizumab and Atezolizumab in Patients with Advanced Non-Small Cell Lung Cancer

by Matteo Franchi, Giacomo Pellegrini and Giovanni Corrao

Pharmaceuticals 2022, 15(4), 489; https://doi.org/10.3390/ph15040489 - 18 Apr 2022

Cited by 6 | Viewed by 2450

Abstract

No evidence is available on the head-to-head comparison of clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell lung cancer (NSCLC) in a real-world setting. We aimed to compare the effectiveness and cost-effectiveness profile of nivolumab, pembrolizumab and [...] Read more.

No evidence is available on the head-to-head comparison of clinical outcomes of patients treated with immune checkpoint inhibitors (ICIs) for advanced non-small cell lung cancer (NSCLC) in a real-world setting. We aimed to compare the effectiveness and cost-effectiveness profile of nivolumab, pembrolizumab and atezolizumab. We used a population-based retrospective cohort study based on the healthcare utilization databases of the Lombardy Region, Italy. The study cohort included all patients with a diagnosis of lung cancer, who started a second-line treatment for advanced NSCLC with nivolumab, pembrolizumab or atezolizumab from 2015 to 30 June 2020. Overall survival and average cumulative healthcare costs were measured from the start of second-line treatment until 31 December 2020. The study cohort included 1607 patients who started a second-line treatment with ICIs, of which there were 1193 with nivolumab, 138 with pembrolizumab and 276 with atezolizumab. No differences were observed between treatment arms in terms of sex, age or comorbidities. Median OS was very similar between groups, being 8.9, 9.4 and 8.7 months, respectively, in patients treated with nivolumab, pembrolizumab and atezolizumab (p = 0.898). The adjusted hazard ratio of death of patients treated with pembrolizumab and atezolizumab, as compared to nivolumab, were 1.01 (95% CI: 0.81 to 1.25) and 1.03 (0.88 to 1.21), respectively. Healthcare cumulative costs measured in the first two years of follow-up were EUR 43,764, 46,233 and 34,116, on average, associated with nivolumab, pembrolizumab and atezolizumab, respectively. In our real-world study, atezolizumab was the ICI associated with the most favorable cost-effectiveness profile. Full article

(This article belongs to the Special Issue Advances in Non-small Cell Lung Cancer Treatment - Current and Future)

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14 pages, 2037 KiB

Open AccessArticle

Synergistic Effect of Combination of a Temoporfin-Based Photodynamic Therapy with Potassium Iodide or Antibacterial Agents on Oral Disease Pathogens In Vitro

by Yin-Hwa Shih, Cheng-Chia Yu, Kai-Chi Chang, Yu-Hsin Tseng, Po-Jung Li, Shih-Min Hsia, Kuo-Chou Chiu and Tzong-Ming Shieh

Pharmaceuticals 2022, 15(4), 488; https://doi.org/10.3390/ph15040488 - 18 Apr 2022

Cited by 4 | Viewed by 2135

Abstract

5, 10, 15, 20-Tetrakis(3-hydroxyphenyl)chlorin (temoporfin) is a photosensitizer used in photodynamic therapy for oral cancer and periodontal disease treatment. This study determined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of temoporfin. Additionally, the combination of potassium iodide (KI) or antimicrobial [...] Read more.

5, 10, 15, 20-Tetrakis(3-hydroxyphenyl)chlorin (temoporfin) is a photosensitizer used in photodynamic therapy for oral cancer and periodontal disease treatment. This study determined the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) of temoporfin. Additionally, the combination of potassium iodide (KI) or antimicrobial agents in oral pathogens under hypoxic or normoxic conditions were determined. We also evaluated the biofilm removal effect and detected the expressions of the antibiotic resistance-related genes and biofilm formation-related genes of methicillin-resistant staphylococcus aureus (MRSA). The results provided reveal that the combination of the temoporfin and KI had a synergistic effect of reducing the MICs and MBCs of Lactobacillus acidophilus and Lactobacillus paracasei under normoxic and hypoxic conditions due to increasing H₂O₂ production. Temoporfin increased the biofilm removal of Aggregatibacter actinomycetemcomitans, Enterococcus faecalis, and Staphylococcus aureus under normoxic condition, and it reduced the antibiotic resistance-related genes expression of MRSA. The combination of temoporfin with ampicillin or chlorhexidine significantly enhanced the bactericidal effect on MRSA. This study provides a potential application of temoporfin on the clinical side against oral pathogens and the prevention of oral diseases. Full article

(This article belongs to the Special Issue Photodynamic Therapy 2022)

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21 pages, 3124 KiB

Open AccessReview

Photodynamic Anti-Bacteria by Carbon Dots and Their Nano-Composites

by Xiaoyan Wu, Khurram Abbas, Yuxiang Yang, Zijian Li, Antonio Claudio Tedesco and Hong Bi

Pharmaceuticals 2022, 15(4), 487; https://doi.org/10.3390/ph15040487 - 18 Apr 2022

Cited by 25 | Viewed by 3921

Abstract

The misuse of many types of broad-spectrum antibiotics leads to increased antimicrobial resistance. As a result, the development of a novel antibacterial agent is essential. Photodynamic antimicrobial chemotherapy (PACT) is becoming more popular due to its advantages in eliminating drug-resistant strains and providing [...] Read more.

The misuse of many types of broad-spectrum antibiotics leads to increased antimicrobial resistance. As a result, the development of a novel antibacterial agent is essential. Photodynamic antimicrobial chemotherapy (PACT) is becoming more popular due to its advantages in eliminating drug-resistant strains and providing broad-spectrum antibacterial resistance. Carbon dots (CDs), zero-dimensional nanomaterials with diameters smaller than 10 nm, offer a green and cost-effective alternative to PACT photosensitizers. This article reviewed the synthesis methods of antibacterial CDs as well as the recent progress of CDs and their nanocomposites in photodynamic sterilization, focusing on maximizing the bactericidal impact of CDs photosensitizers. This review establishes the base for future CDs development in the PACT field. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Nanodrugs)

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14 pages, 3851 KiB

Open AccessArticle

Anti-Diabetic Effects of Allium hookeri Extracts Prepared by Different Methods in Type 2 C57BL/J-db/db Mice

by Ji-Hye Choi, Si-Hyun Kim, Eun-Byeol Lee, Ji-Su Kim, Ji-Eeun Jung, Un-Yul Jeong, Ju-Hui Kim, Hwan-Hee Jang, Shin-Young Park, Gi-Chang Kim, Jung-Hyun Lim and Sung-Hyen Lee

Pharmaceuticals 2022, 15(4), 486; https://doi.org/10.3390/ph15040486 - 17 Apr 2022

Cited by 8 | Viewed by 2328

Abstract

This study was conducted to evaluate whether Allium hookeri can control diabetic symptoms. Aqueous extract (AE1: 100 mg/kg BW, AE2: 200 mg/kg BW) and ethanol extract (EE1: 100 mg/kg BW, EE2: 200 mg/kg BW) of A. hookeri were orally administrated to diabetic mice [...] Read more.

This study was conducted to evaluate whether Allium hookeri can control diabetic symptoms. Aqueous extract (AE1: 100 mg/kg BW, AE2: 200 mg/kg BW) and ethanol extract (EE1: 100 mg/kg BW, EE2: 200 mg/kg BW) of A. hookeri were orally administrated to diabetic mice (C57BL/J-db/db) for 8 weeks. The negative (NC) and the positive (PC) control groups were treated with 0.9% saline and metformin (150 mg/kg BW), respectively. Glucose and lipid profile (triglyceride, total cholesterol (TC), LDL-C, and HDL-C) as biochemical parameters, toxicological factors such as liver/kidney functional parameters (ALT, AST, BUN, and Cr), and NK cell activity in blood were measured. Oral glucose tolerance test (OGTT) and histopathological examination were also conducted. Compared with the NC group, AE and EE decreased blood glucose, HbA1c, area under the curve (AUC) during OGTT, and leptin levels while increasing adiponectin levels. Serum lipid profiles and toxicological factors levels were reduced by the A. hookeri extract. Interestingly, HDL-C, glomerular mesangial expansion score in the kidney, and NK cell activity were effectively controlled in EE groups. Based on the results, EE is considered to be more effective in reducing high blood glucose, lipid profile, and related factor levels than AE, and is comparable to metformin in some biomarkers. It can be presumed that EE can more effectively control the major anomalies in the diabetic model than AE, and it may be used to prevent diabetic symptoms without toxicity in the Type 2 diabetic model. Full article

(This article belongs to the Special Issue Searching for New Therapeutic Targets with Anti-obesity Potential)

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21 pages, 1557 KiB

Open AccessReview

The Potential Use of Ebselen in Treatment-Resistant Depression

by Fitri Fareez Ramli, Philip J. Cowen and Beata R. Godlewska

Pharmaceuticals 2022, 15(4), 485; https://doi.org/10.3390/ph15040485 - 16 Apr 2022

Cited by 6 | Viewed by 3921

Abstract

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere’s Disease and severe [...] Read more.

Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere’s Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium’s anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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17 pages, 2191 KiB

Open AccessArticle

Growth Differentiation Factor-15 Correlates Inversely with Protease-Activated Receptor-1-Mediated Platelet Reactivity in Patients with Left Ventricular Assist Devices

by Maximilian Tscharre, Franziska Wittmann, Daniela Kitzmantl, Silvia Lee, Beate Eichelberger, Patricia P. Wadowski, Günther Laufer, Dominik Wiedemann, Simon Panzer, Thomas Perkmann, Daniel Zimpfer and Thomas Gremmel

Pharmaceuticals 2022, 15(4), 484; https://doi.org/10.3390/ph15040484 - 15 Apr 2022

Cited by 4 | Viewed by 1649

Abstract

Growth differentiation factor (GDF)-15 inhibits platelet activation, prevents thrombus formation, and has been linked to bleeding events. This was a prospective study including 51 left-ventricular assist device (LVAD) patients on aspirin and phenprocoumon. Platelet surface expression of activated glycoprotein (GP) IIb/IIIa was assessed [...] Read more.

Growth differentiation factor (GDF)-15 inhibits platelet activation, prevents thrombus formation, and has been linked to bleeding events. This was a prospective study including 51 left-ventricular assist device (LVAD) patients on aspirin and phenprocoumon. Platelet surface expression of activated glycoprotein (GP) IIb/IIIa was assessed by flow cytometry, and platelet aggregation was measured by multiple electrode aggregometry (MEA) in response to arachidonic acid (AA), adenosine diphosphate (ADP), and thrombin receptor-activating peptide (TRAP), a protease-activated-receptor-1 (PAR-1) agonist. GDF-15 was determined with a commercially-available assay. There was a trend towards an inverse correlation of GDF-15 with activated GPIIb/IIIa in response to TRAP (r = −0.275, p = 0.0532) but not in response to AA and ADP. Moreover, GDF-15 correlated with MEA TRAP (r = −0.326, p = 0.0194), whereas it did not correlate with MEA ADP and MEA AA. In a second step, GDF-15 levels in the fourth quartile were defined as high GDF-15. Patients with high GDF-15 showed significantly lower TRAP-inducible platelet aggregation by MEA compared to patients in the first quartile (63 AU vs. 113 AU, p = 0.0065). In conclusion, in LVAD patients receiving state-of-the-art antithrombotic therapy, GDF-15 correlates inversely with residual platelet reactivity via PAR-1. Full article

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

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10 pages, 1697 KiB

Open AccessArticle

One-Year Outcome of Combination Therapy with Full or Reduced Photodynamic Therapy and One Anti-Vascular Endothelial Growth Factor in Pachychoroid Neovasculopathy

by Miki Sato-Akushichi, Shinji Ono, Tatsuro Taneda, Gerd Klose, Asuka Sasamori and Youngseok Song

Pharmaceuticals 2022, 15(4), 483; https://doi.org/10.3390/ph15040483 - 15 Apr 2022

Cited by 1 | Viewed by 1435

Abstract

This paper evaluates a one-year treatment outcome after full or reduced photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) combination therapy for pachychoroid neovasculopathy (PNV). After the initial combination therapy, a total of 29 eyes from 29 patients (16 for full treatment [...] Read more.

This paper evaluates a one-year treatment outcome after full or reduced photodynamic therapy (PDT) and anti-vascular endothelial growth factor (VEGF) combination therapy for pachychoroid neovasculopathy (PNV). After the initial combination therapy, a total of 29 eyes from 29 patients (16 for full treatment and 13 for reduced treatment), exhibited reduced, central retinal thickness and central choroidal thickness, and the improvements were maintained for 1 year after the initial combination therapy. Twenty-two eyes (75.9%) required no additional treatments for 1 year. The recurrence rate was 31.3% in the full treatment and 15.4% in the reduced treatment, with no significant differences between them. One shot of anti-VEGF and full or reduced PDT combination therapy had similar efficacy in treating PNV. Further prospective, large-scale, and long-term studies are required to determine a better treatment for PNV. Full article

(This article belongs to the Section Pharmacology)

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34 pages, 2325 KiB

Open AccessReview

Augmenting Azoles with Drug Synergy to Expand the Antifungal Toolbox

by Aidan Kane and Dee A. Carter

Pharmaceuticals 2022, 15(4), 482; https://doi.org/10.3390/ph15040482 - 14 Apr 2022

Cited by 15 | Viewed by 5838

Abstract

Fungal infections impact the lives of at least 12 million people every year, killing over 1.5 million. Wide-spread use of fungicides and prophylactic antifungal therapy have driven resistance in many serious fungal pathogens, and there is an urgent need to expand the current [...] Read more.

Fungal infections impact the lives of at least 12 million people every year, killing over 1.5 million. Wide-spread use of fungicides and prophylactic antifungal therapy have driven resistance in many serious fungal pathogens, and there is an urgent need to expand the current antifungal arsenal. Recent research has focused on improving azoles, our most successful class of antifungals, by looking for synergistic interactions with secondary compounds. Synergists can co-operate with azoles by targeting steps in related pathways, or they may act on mechanisms related to resistance such as active efflux or on totally disparate pathways or processes. A variety of sources of potential synergists have been explored, including pre-existing antimicrobials, pharmaceuticals approved for other uses, bioactive natural compounds and phytochemicals, and novel synthetic compounds. Synergy can successfully widen the antifungal spectrum, decrease inhibitory dosages, reduce toxicity, and prevent the development of resistance. This review highlights the diversity of mechanisms that have been exploited for the purposes of azole synergy and demonstrates that synergy remains a promising approach for meeting the urgent need for novel antifungal strategies. Full article

(This article belongs to the Special Issue Advances in Antifungal Development: Discovery of New Drugs and Drug Repurposing)

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28 pages, 5893 KiB

Open AccessArticle

New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer

by Haytham O. Tawfik, Anwar A. El-Hamaky, Eman A. El-Bastawissy, Kirill A. Shcherbakov, Alexander V. Veselovsky, Yulia A. Gladilina, Dmitry D. Zhdanov and Mervat H. El-Hamamsy

Pharmaceuticals 2022, 15(4), 481; https://doi.org/10.3390/ph15040481 - 14 Apr 2022

Cited by 10 | Viewed by 3063

Abstract

Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, [...] Read more.

Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening. The telomerase enzyme is a universal anticancer target that is expressed in 85–95% of cancers. BIBR1532 is a selective non-nucleoside potent telomerase inhibitor that acts by direct noncompetitive inhibition. Relying on its structural features, three different series were designed, and 30 novel compounds were synthesized and biologically evaluated as telomerase inhibitors using a telomeric repeat amplification protocol (TRAP) assay. Target compounds 29a, 36b, and 39b reported the greatest inhibitory effect on telomerase enzyme with IC₅₀ values of 1.7, 0.3, and 2.0 μM, respectively, while BIBR1532 displayed IC₅₀ = 0.2 μM. Compounds 29a, 36b, and 39b were subsequently tested using a living-cell TRAP assay and were able to penetrate the cell membrane and inhibit telomerase inside living cancer cells. Compound 36b was tested for cytotoxicity against 60 cancer cell lines using the NCI (USA) procedure, and the % growth was minimally impacted, indicating telomerase enzyme selectivity. To investigate the interaction of compound 36b with the telomerase allosteric binding site, molecular docking and molecular dynamics simulations were used. Full article

(This article belongs to the Special Issue Novel Anti-proliferative Agents)

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18 pages, 4195 KiB

Open AccessArticle

A Theranostic Nanocomplex Combining with Magnetic Hyperthermia for Enhanced Accumulation and Efficacy of pH-Triggering Polymeric Cisplatin(IV) Prodrugs

by Yang Qu, Zhiqi Wang, Miao Sun, Tian Zhao, Xuanlei Zhu, Xiaoli Deng, Man Zhang, Ying Xu and Hongfei Liu

Pharmaceuticals 2022, 15(4), 480; https://doi.org/10.3390/ph15040480 - 14 Apr 2022

Cited by 7 | Viewed by 1787

Abstract

Although polymeric platinum(IV) (Pt(IV)) prodrugs can reduce the side effects of cisplatin, the efficacy of the prodrug is still limited by its non-targeted distribution, poor penetration in deep tumor tissue, and low cytotoxicity in tumor cells. To improve the clinical potential of polymeric [...] Read more.

Although polymeric platinum(IV) (Pt(IV)) prodrugs can reduce the side effects of cisplatin, the efficacy of the prodrug is still limited by its non-targeted distribution, poor penetration in deep tumor tissue, and low cytotoxicity in tumor cells. To improve the clinical potential of polymeric prodrug micelle, we synthesized amphiphilic polymeric Pt(IV) with high Pt content (22.5%), then developed a theranostic nanocomplex by integrating polymeric Pt(IV) with superparamagnetic Mn_0.6Zn_0.4Fe₂O₄ via simple self-assembly. Due to the high content of Mn_0.6Zn_0.4Fe₂O₄ (41.7% w/w), the theranostic nanocomplex showed high saturation magnetization (103.1 emu g⁻¹) and excellent magnetocaloric effect (404 W g⁻¹), both of them indicating its advantages in efficient magnetic targeting (MT), magnetic hyperthermia (MH), and magnetic resonance imaging (MRI). In vitro, in combination with MH, the theranostic nanocomplex showed as high cytotoxicity as cisplatin because of a significant increase in platinum of cellular uptake. In vivo, the accumulation of theranostic nanocomplex in tumors was increased by MT and confirmed by MRI. Furthermore, MH improved penetration of theranostic nanocomplex in tumors as expanding blackened area in tumors was observed by MRI. Based on these properties, the theranostic nanocomplex, under the assistance of MT and MH, showed the highest tumor growth inhibition rate (88.38%) after different treatments, while the body weight of mice increased slightly, indicating low side effects compared to those of cisplatin. The study provided an advanced theranostic nanocomplex with low toxicity and high efficacy, indicating a great clinical potential of polymeric Pt(IV). Full article

(This article belongs to the Special Issue Recent Progress of Nanomedicine and Targeted Drug Delivery for Cancer Treatment)

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5 pages, 196 KiB

Open AccessEditorial

Special Issue “Anticancer Drugs 2021”

by Mary J. Meegan and Niamh M. O’Boyle

Pharmaceuticals 2022, 15(4), 479; https://doi.org/10.3390/ph15040479 - 14 Apr 2022

Cited by 2 | Viewed by 2117

Abstract

This Special Issue of Pharmaceuticals is devoted to significant advances achieved in the field of Anticancer Drugs in 2021 [...] Full article

(This article belongs to the Special Issue Anticancer Drugs 2021)

29 pages, 9941 KiB

Open AccessArticle

4-Heteroaryl Substituted Amino-3,5-Dicyanopyridines as New Adenosine Receptor Ligands: Novel Insights on Structure-Activity Relationships and Perspectives

by Daniela Catarzi, Flavia Varano, Erica Vigiani, Sara Calenda, Fabrizio Melani, Katia Varani, Fabrizio Vincenzi, Silvia Pasquini, Natascia Mennini, Giulia Nerli, Diego Dal Ben, Rosaria Volpini and Vittoria Colotta

Pharmaceuticals 2022, 15(4), 478; https://doi.org/10.3390/ph15040478 - 14 Apr 2022

Cited by 5 | Viewed by 1976

Abstract

A new set of amino-3,5-dicyanopyridines was synthesized and biologically evaluated at the adenosine receptors (ARs). This chemical class is particularly versatile, as small structural modifications can influence not only affinity and selectivity, but also the pharmacological profile. Thus, in order to deepen the [...] Read more.

A new set of amino-3,5-dicyanopyridines was synthesized and biologically evaluated at the adenosine receptors (ARs). This chemical class is particularly versatile, as small structural modifications can influence not only affinity and selectivity, but also the pharmacological profile. Thus, in order to deepen the structure–activity relationships (SARs) of this series, different substituents were evaluated at the diverse positions on the dicyanopyridine scaffold. In general, the herein reported compounds show nanomolar binding affinity and interact better with both the human (h) A₁ and A_2A ARs than with the other subtypes. Docking studies at hAR structure were performed to rationalize the observed affinity data. Of interest are compounds 1 and 5, which can be considered as pan ligands as binding all the ARs with comparable nanomolar binding affinity (A₁AR: 1, K_i = 9.63 nM; 5, K_i = 2.50 nM; A_2AAR: 1, K_i = 21 nM; 5, Ki = 24 nM; A₃AR: 1, Ki = 52 nM; 5, Ki = 25 nM; A_2BAR: 1, EC₅₀ = 1.4 nM; 5, EC₅₀ = 1.12 nM). Moreover, these compounds showed a partial agonist profile at all the ARs. This combined AR partial agonist activity could lead us to hypothesize a potential effect in the repair process of damaged tissue that would be beneficial in both wound healing and remodeling. Full article

(This article belongs to the Section Medicinal Chemistry)

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31 pages, 4188 KiB

Open AccessArticle

Beta and Gamma Amino Acid-Substituted Benzenesulfonamides as Inhibitors of Human Carbonic Anhydrases

by Benas Balandis, Tomas Šimkūnas, Vaida Paketurytė-Latvė, Vilma Michailovienė, Aurelija Mickevičiūtė, Elena Manakova, Saulius Gražulis, Sergey Belyakov, Visvaldas Kairys, Vytautas Mickevičius, Asta Zubrienė and Daumantas Matulis

Pharmaceuticals 2022, 15(4), 477; https://doi.org/10.3390/ph15040477 - 13 Apr 2022

Cited by 5 | Viewed by 2273

Abstract

A series of novel benzenesulfonamide derivatives were synthesized bearing para-N β,γ-amino acid or para-N β-amino acid and thiazole moieties and their binding to the human carbonic anhydrase (CA) isozymes determined. These enzymes are involved in various illnesses, such as [...] Read more.

A series of novel benzenesulfonamide derivatives were synthesized bearing para-N β,γ-amino acid or para-N β-amino acid and thiazole moieties and their binding to the human carbonic anhydrase (CA) isozymes determined. These enzymes are involved in various illnesses, such as glaucoma, altitude sickness, epilepsy, obesity, and even cancer. There are numerous compounds that are inhibitors of CA and used as pharmaceuticals. However, most of them bind to most CA isozymes with little selectivity. The design of high affinity and selectivity towards one CA isozyme remains a significant challenge. The beta and gamma amino acid-substituted compound affinities were determined by the fluorescent thermal shift assay and isothermal titration calorimetry for all 12 catalytically active human carbonic anhydrase isozymes, showing the full affinity and selectivity profile. The structures of several compounds were determined by X-ray crystallography, and the binding mode in the active site of CA enzyme was shown. Full article

(This article belongs to the Special Issue New Developments in High-Throughput Screening)

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55 pages, 12417 KiB

Open AccessReview

β-Lactam Antibiotics and β-Lactamase Enzymes Inhibitors, Part 2: Our Limited Resources

by Silvana Alfei and Anna Maria Schito

Pharmaceuticals 2022, 15(4), 476; https://doi.org/10.3390/ph15040476 - 13 Apr 2022

Cited by 26 | Viewed by 7445

Abstract

β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel [...] Read more.

β-lactam antibiotics (BLAs) are crucial molecules among antibacterial drugs, but the increasing emergence of resistance to them, developed by bacteria producing β-lactamase enzymes (BLEs), is becoming one of the major warnings to the global public health. Since only a small number of novel antibiotics are in development, a current clinical approach to limit this phenomenon consists of administering proper combinations of β-lactam antibiotics (BLAs) and β-lactamase inhibitors (BLEsIs). Unfortunately, while few clinically approved BLEsIs are capable of inhibiting most class-A and -C serine β-lactamases (SBLEs) and some carbapenemases of class D, they are unable to inhibit most part of the carbapenem hydrolyzing enzymes of class D and the worrying metallo-β-lactamases (MBLEs) of class B. Particularly, MBLEs are a set of enzymes that catalyzes the hydrolysis of a broad range of BLAs by a zinc-mediated mechanism, and currently no clinically available molecule capable of inhibiting MBLEs exists. Additionally, new types of alarming “superbugs”, were found to produce the New Delhi metallo-β-lactamases (NDMs) encoded by increasing variants of a plasmid-mediated gene capable of rapidly spreading among bacteria of the same species and even among different species. Particularly, NDM-1 possesses a flexible hydrolysis mechanism that inactivates all BLAs, except for aztreonam. The present review provides first an overview of existing BLAs and the most clinically relevant BLEs detected so far. Then, the BLEsIs and their most common associations with BLAs already clinically applied and those still in development are reviewed. Full article

(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2022)

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42 pages, 2177 KiB

Open AccessReview

Levetiracetam Mechanisms of Action: From Molecules to Systems

by Itzel Jatziri Contreras-García, Noemí Cárdenas-Rodríguez, Antonio Romo-Mancillas, Cindy Bandala, Sergio R. Zamudio, Saúl Gómez-Manzo, Beatriz Hernández-Ochoa, Julieta Griselda Mendoza-Torreblanca and Luz Adriana Pichardo-Macías

Pharmaceuticals 2022, 15(4), 475; https://doi.org/10.3390/ph15040475 - 13 Apr 2022

Cited by 23 | Viewed by 10699

Abstract

Epilepsy is a chronic disease that affects millions of people worldwide. Antiepileptic drugs (AEDs) are used to control seizures. Even though parts of their mechanisms of action are known, there are still components that need to be studied. Therefore, the search for novel [...] Read more.

Epilepsy is a chronic disease that affects millions of people worldwide. Antiepileptic drugs (AEDs) are used to control seizures. Even though parts of their mechanisms of action are known, there are still components that need to be studied. Therefore, the search for novel drugs, new molecular targets, and a better understanding of the mechanisms of action of existing drugs is still crucial. Levetiracetam (LEV) is an AED that has been shown to be effective in seizure control and is well-tolerable, with a novel mechanism of action through an interaction with the synaptic vesicle protein 2A (SV2A). Moreover, LEV has other molecular targets that involve calcium homeostasis, the GABAergic system, and AMPA receptors among others, that might be integrated into a single mechanism of action that could explain the antiepileptogenic, anti-inflammatory, neuroprotective, and antioxidant properties of LEV. This puts it as a possible multitarget drug with clinical applications other than for epilepsy. According to the above, the objective of this work was to carry out a comprehensive and integrative review of LEV in relation to its clinical uses, structural properties, therapeutical targets, and different molecular, genetic, and systemic action mechanisms in order to consider LEV as a candidate for drug repurposing. Full article

(This article belongs to the Section Pharmacology)

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9 pages, 3413 KiB

Open AccessArticle

A New Pyrroloquinoline-Derivative-Based Fluorescent Probe for the Selective Detection and Cell Imaging of Lysine

by Bing Yang, Jiahua Zhou, Xu Huang, Zhongping Chen, Shu Tian and Yujun Shi

Pharmaceuticals 2022, 15(4), 474; https://doi.org/10.3390/ph15040474 - 13 Apr 2022

Cited by 6 | Viewed by 1710

Abstract

In this paper, a new pyrroloquinoline-derivative-based fluorescent probe, PQP-1, was prepared for the selective detection of Lys in living cells and natural mineral water for drinking. PQP-1 exhibited high selectivity, low limit of detection, and a wide pH range. PQP-1 could be [...] Read more.

In this paper, a new pyrroloquinoline-derivative-based fluorescent probe, PQP-1, was prepared for the selective detection of Lys in living cells and natural mineral water for drinking. PQP-1 exhibited high selectivity, low limit of detection, and a wide pH range. PQP-1 could be successfully applied for imaging Lys in living cells and in natural mineral water for drinking. We expect that PQP-1 will expand the detection reaction mechanism and the practical biological applications of Lys. Full article

(This article belongs to the Special Issue Novel Fluorescent Probes for Drug Discovery and Development)

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19 pages, 2682 KiB

Open AccessArticle

Cannabinoid CB1 Receptor Involvement in the Actions of CBD on Anxiety and Coping Behaviors in Mice

by Amaya Austrich-Olivares, María Salud García-Gutiérrez, Lucía Illescas, Ani Gasparyan and Jorge Manzanares

Pharmaceuticals 2022, 15(4), 473; https://doi.org/10.3390/ph15040473 - 13 Apr 2022

Cited by 18 | Viewed by 4970

Abstract

The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was [...] Read more.

The anxiolytic and antidepressant properties of cannabidiol (CBD) have been evaluated in several studies. However, the molecular mechanisms involved in these actions remain unclear. A total of 130 male mice were used. CBD’s ability to modulate emotional disturbances (anxiety and depressive-like behaviors) was evaluated at different doses in wild-type (CD1; 10, 20 and 30 mg/kg; i.p.) and knockout (CB1KO, CB2KO; GPR55KO; 20 mg/kg) mice. Moreover, CBD effects (20 mg/kg; i.p.) were evaluated in mice previously treated with the CB1r-antagonist SR141716A (2mg/kg; i.p.). Relative gene expression analyses of Cnr1 and Cnr2, Gpr55 and GABA(A)α2 and γ2 receptor subunits were performed in the amygdala (AMY) and hippocampus (HIPP) of CD1 mice. CBD (10 and 20 mg/kg) showed anxiolytic and antidepressant actions in CD1 mice, being more effective at 20 mg/kg. Its administration did not induce anxiolytic actions in CB1KO mice, contrary to CB2KO and GPR55KO. In all of them, the lack of cannabinoid receptors did not modify the antidepressant activity of CBD. Interestingly, the administration of the CB1r antagonist SR141716A blocked the anxiolytic-like activity of CBD. Real-time PCR studies revealed a significant reduction in Cnr1 and GABA(A)α2 and γ2 gene expression in the HIPP and AMY of CD1 mice treated with CBD. Opposite changes were observed in the Cnr2. Indeed, Gpr55 was increased in the AMY and reduced in the HIPP. CB1r appears to play a relevant role in modulating the anxiolytic actions of CBD. Moreover, this study revealed that CBD also modified the gene expression of GABA(A) subunits α2 and γ2 and CB1r, CB2r and GPR55, in a dose- and brain-region-dependent manner, supporting a multimodal mechanism of action for CBD. Full article

(This article belongs to the Special Issue Seeking New Antidepressant Agents)

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63 pages, 23374 KiB

Open AccessReview

Lewis Acids and Heteropoly Acids in the Synthesis of Organic Peroxides

by Ivan A. Yaremenko, Peter S. Radulov, Yulia Yu. Belyakova, Dmitriy I. Fomenkov, Svetlana B. Tsogoeva and Alexander O. Terent’ev

Pharmaceuticals 2022, 15(4), 472; https://doi.org/10.3390/ph15040472 - 13 Apr 2022

Cited by 7 | Viewed by 4046

Abstract

Organic peroxides are an important class of compounds for organic synthesis, pharmacological chemistry, materials science, and the polymer industry. Here, for the first time, we summarize the main achievements in the synthesis of organic peroxides by the action of Lewis acids and heteropoly [...] Read more.

Organic peroxides are an important class of compounds for organic synthesis, pharmacological chemistry, materials science, and the polymer industry. Here, for the first time, we summarize the main achievements in the synthesis of organic peroxides by the action of Lewis acids and heteropoly acids. This review consists of three parts: (1) metal-based Lewis acids in the synthesis of organic peroxides; (2) the synthesis of organic peroxides promoted by non-metal-based Lewis acids; and (3) the application of heteropoly acids in the synthesis of organic peroxides. The information covered in this review will be useful for specialists in the field of organic synthesis, reactions and processes of oxygen-containing compounds, catalysis, pharmaceuticals, and materials engineering. Full article

(This article belongs to the Section Medicinal Chemistry)

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21 pages, 6907 KiB

Open AccessArticle

C16 Peptide and Ang-1 Improve Functional Disability and Pathological Changes in an Alzheimer’s Disease Model Associated with Vascular Dysfunction

by Xiaoxiao Fu, Jing Wang, Huaying Cai, Hong Jiang and Shu Han

Pharmaceuticals 2022, 15(4), 471; https://doi.org/10.3390/ph15040471 - 13 Apr 2022

Cited by 1 | Viewed by 2110

Abstract

Alzheimer’s disease (AD) is a neurological disorder characterized by neuronal cell death, tau pathology, and excessive inflammatory responses. Several vascular risk factors contribute to damage of the blood–brain barrier (BBB), secondary leak-out of blood vessels, and infiltration of inflammatory cells, which aggravate the [...] Read more.

Alzheimer’s disease (AD) is a neurological disorder characterized by neuronal cell death, tau pathology, and excessive inflammatory responses. Several vascular risk factors contribute to damage of the blood–brain barrier (BBB), secondary leak-out of blood vessels, and infiltration of inflammatory cells, which aggravate the functional disability and pathological changes in AD. Growth factor angiopoietin-1 (Ang-1) can stabilize the endothelium and reduce endothelial permeability by binding to receptor tyrosine kinase 2 (Tie2). C16 peptide (KAFDITYVRLKF) selectively binds to integrin ανβ3 and competitively inhibits leukocyte transmigration into the central nervous system by interfering with leukocyte ligands. In the present study, 45 male Sprague-Dawley (SD) rats were randomly divided into three groups: vehicle group, C16 peptide + Ang1 (C + A) group, and sham control group. The vehicle and C + A groups were subjected to two-vessel occlusion (2-VO) with artery ligation followed by Aβ1-42 injection into the hippocampus. The sham control group underwent sham surgery and injection with an equal amount of phosphate-buffered saline (PBS) instead of Aβ1-42. The C + A group was administered 1 mL of drug containing 2 mg of C16 and 400 µg of Ang-1 daily for 2 weeks. The sham control and vehicle groups were administered 1 mL of PBS for 2 weeks. Our results showed that treatment with Ang-1 plus C16 improved functional disability and reduced neuronal death by inhibiting inflammatory cell infiltration, protecting vascular endothelial cells, and maintaining BBB permeability. The results suggest that these compounds may be potential therapeutic agents for AD and warrant further investigation. Full article

(This article belongs to the Special Issue New Applications and Developments in Synthetic Peptide Chemistry)

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11 pages, 444 KiB

Open AccessArticle

Antiplasmodial Activity of Vachellia xanthophloea (Benth.) P.J.H. Hurter (African Fever Tree) and Its Constituents

by Nasir Tajuddeen, Tarryn Swart, Heinrich C. Hoppe and Fanie R. van Heerden

Pharmaceuticals 2022, 15(4), 470; https://doi.org/10.3390/ph15040470 - 13 Apr 2022

Cited by 4 | Viewed by 2725

Abstract

Vachellia xanthophloea is used in Zulu traditional medicine as an antimalarial remedy. A moderate antiplasmodial activity was previously reported for extracts of the plant against D10 Plasmodium falciparum. This study aimed to identify the phytochemicals responsible for the antiplasmodial activity of the [...] Read more.

Vachellia xanthophloea is used in Zulu traditional medicine as an antimalarial remedy. A moderate antiplasmodial activity was previously reported for extracts of the plant against D10 Plasmodium falciparum. This study aimed to identify the phytochemicals responsible for the antiplasmodial activity of the leaf extract. The compounds were isolated by chromatography and their structures were determined using spectroscopic and spectrometric methods. The antiplasmodial activity was evaluated using a parasite lactate dehydrogenase assay and cytotoxicity was determined using a resazurin assay. The ethyl acetate fraction inhibited P. falciparum with IC₅₀ = 10.6 µg/mL and showed minimal cytotoxicity (98% cell viability at 33 µg/mL). The chromatographic purification of this fraction afforded sixteen compounds, including two new flavonoids. A 1:1 mixture of phytol and lupeol was also isolated from the hexane fraction. All the compounds were reported from V. xanthophloea for the first time. Among the isolated metabolites, methyl gallate displayed the best activity against P. falciparum (IC₅₀ = 1.2 µg/mL), with a 68% viability of HeLa cells at 10 µg/mL. Therefore, methyl gallate was responsible for the antiplasmodial activity of the V. xanthophloea leaf extract and its presence in the leaf extract might account for the folkloric use of the plant as an antimalarial remedy. Full article

(This article belongs to the Special Issue Selected Papers from the 7th International Electronic Conference on Medicinal Chemistry (ECMC2021))

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18 pages, 4342 KiB

Open AccessArticle

Rutaecarpine Promotes Adipose Thermogenesis and Protects against HFD-Induced Obesity via AMPK/PGC-1α Pathway

by Dandan Chen, Yanan Duan, Shuxiang Yu, Xinwen Zhang, Ni Li and Jingya Li

Pharmaceuticals 2022, 15(4), 469; https://doi.org/10.3390/ph15040469 - 13 Apr 2022

Cited by 3 | Viewed by 2393

Abstract

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, [...] Read more.

Pharmacological activation of adaptive thermogenesis to increase energy expenditure is considered to be a novel strategy for obesity. Peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α), which serves as an inducible co-activator in energy expenditure, is highly expressed in brown adipose tissues (BAT). In this study, we found a PGC-1α transcriptional activator, natural compound rutaecarpine (Rut), which promoted brown adipocytes mitochondrial biogenesis and thermogenesis in vitro. Chronic Rut treatment reduced the body weight gain and mitigated insulin sensitivity through brown and beige adipocyte thermogenesis. Mechanistic study showed that Rut activated the energy metabolic pathway AMP-activated protein kinase (AMPK)/PGC-1α axis, and deficiency of AMPK abolished the beneficial metabolic phenotype of the Rut treatment in vitro and in vivo. In summary, a PGC-1α transcriptional activator Rut was found to activate brown and beige adipose thermogenesis to resist diet-induced obesity through AMPK pathway. Our findings serve as a further understanding of the natural compound in adipose tissue and provides a possible strategy to combat obesity and related metabolic disorders. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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19 pages, 6508 KiB

Open AccessArticle

Synthesis and Antiproliferative Activity of Novel Imipridone–Ferrocene Hybrids with Triazole and Alkyne Linkers

by Tamás Czuczi, József Murányi, Péter Bárány, István Móra, Adina Borbély, Miklós Csala and Antal Csámpai

Pharmaceuticals 2022, 15(4), 468; https://doi.org/10.3390/ph15040468 - 12 Apr 2022

Cited by 2 | Viewed by 3006

Abstract

Imipridones, including ONC201, ONC206 and ONC212 (which are emblematic members of this class of compounds developed by Oncoceutics) constitute a novel class of anticancer agents, with promising results in clinical trials. With the aim of increasing the ROS (reactive oxygen species) responsivity of [...] Read more.

Imipridones, including ONC201, ONC206 and ONC212 (which are emblematic members of this class of compounds developed by Oncoceutics) constitute a novel class of anticancer agents, with promising results in clinical trials. With the aim of increasing the ROS (reactive oxygen species) responsivity of the synthesized molecules, a set of novel ferrocene–imipridone hybrids were designed and synthesized. Our strategy was motivated by the documented interplay between the imipridone-triggered activation of TRAIL (the tumor necrosis factor-related apoptosis-inducing ligand) and mitochondrial ClpP (Caseinolytic protease P) and the ROS-mediated effect of ferrocene-containing compounds. In order to obtain novel hybrids with multitarget characters, the ferrocene moiety was tethered to the imipridone scaffold through ethynylene and 1,2,3-triazolyl linkers by using Sonogashira coupling of Cu(I)- and Ru(II)-catalyzed azide–alkyne cycloadditions. The biological activities of the new hybrids were examined by using in vitro cell viability assays on four malignant cell lines (PANC-1, A2058, EBC-1 and Fadu), along with colony formation assays on the most resistant PANC-1 cell line. Several hybrids caused a significantly greater drop in the cell viability compared to ONC201, and two of them completely overcame the resistance, with IC₅₀ values comparable to those produced by ONC201. The two most potent hybrids, but not ONC201, induced apoptosis/necrosis in PANC-1 and A2058 cells after 24 h of treatment. Full article

(This article belongs to the Special Issue Heterocyclic Compounds and Their Application in Therapy)

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33 pages, 8193 KiB

Open AccessArticle

Mapping Molecular Networks within Clitoria ternatea Linn. against LPS-Induced Neuroinflammation in Microglial Cells, with Molecular Docking and In Vivo Toxicity Assessment in Zebrafish

by Nurul Farah Adni Mat Zian, Puspanjali Swain, Siti Munirah Mohd Faudzi, Norzalina Zakaria, Wan Norhamidah Wan Ibrahim, Noraini Abu Bakar, Khozirah Shaari, Johnson Stanslas, Tae-Ik Choi and Cheol-Hee Kim

Pharmaceuticals 2022, 15(4), 467; https://doi.org/10.3390/ph15040467 - 12 Apr 2022

Cited by 2 | Viewed by 3241

Abstract

Clitoria ternatea Linn. (CT), or butterfly pea, is an Ayurvedic plant traditionally used as a brain tonic. Recently, it was reported to be of use in treating central nervous system (CNS) disorders, i.e., as an antistress treatment and antidepressant. In the present study, [...] Read more.

Clitoria ternatea Linn. (CT), or butterfly pea, is an Ayurvedic plant traditionally used as a brain tonic. Recently, it was reported to be of use in treating central nervous system (CNS) disorders, i.e., as an antistress treatment and antidepressant. In the present study, we report a detailed phytochemical profile of the ethyl acetate fraction of the flower of CT (CTF_EA) with significant neuroprotective and anti-neuroinflammatory properties in both LPS-activated BV-2 and SK-N-SH cells. Concurrently, the molecular network (MN) derived from the CTF_EA metabolome allows putative identification of flavonol 3-O-glycosides, hydrocinnamic acids, and primary metabolites. Molecular docking studies suggest that CTF_EA preferentially targets iNOS, resulting in a decrease in nitric oxide (NO). Furthermore, no toxic effects on normal embryonic development, blood vessel formation, and apoptosis are observed when CTF_EA is tested for in vivo toxicity in zebrafish models. The overall preliminary results suggest the anti-neuroinflammatory and neuroprotective effects of CT and provide scientific support for the efficacy of this medicinal plant at local and traditional levels. However, studies on the targeted isolation of bioactive metabolites, in-depth pharmacological efficacy, and safety in mammalian models are urgently needed to expand our understanding of this plant before it is developed into a promising therapeutic agent for brain-related diseases. Full article

(This article belongs to the Special Issue Zebrafish as a Powerful Tool for Drug Discovery 2021)

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11 pages, 3984 KiB

Open AccessArticle

Evening Primrose Oil Improves Chemotherapeutic Effects in Human Pancreatic Ductal Adenocarcinoma Cell Lines—A Preclinical Study

by Laura Zeppa, Cristina Aguzzi, Giorgia Versari, Margherita Luongo, Maria Beatrice Morelli, Federica Maggi, Consuelo Amantini, Giorgio Santoni, Oliviero Marinelli and Massimo Nabissi

Pharmaceuticals 2022, 15(4), 466; https://doi.org/10.3390/ph15040466 - 12 Apr 2022

Cited by 1 | Viewed by 2317

Abstract

Evening Primrose oil (EPO), obtained from the seeds of Evening Primrose (Oenothera L.), is largely used as a dietary supplement, especially after cancer diagnosis. Human pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease correlated with poor clinical prognosis and a very low [...] Read more.

Evening Primrose oil (EPO), obtained from the seeds of Evening Primrose (Oenothera L.), is largely used as a dietary supplement, especially after cancer diagnosis. Human pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease correlated with poor clinical prognosis and a very low response rate to common chemotherapy. The aim of this work was to study the potential ability of EPO to improve the effects of chemotherapeutic drugs in PANC-1 and MIAPaCa-2 cell lines. Cytotoxicity, cell death, reactive oxygen species (ROS) production and EPO anticancer activity associated with the main chemotherapeutic drugs commonly used in therapy were investigated. Results showed that EPO reduced PDAC cell viability and increased paclitaxel efficacy. This evidence suggests that EPO may be used as a potential supplement to increase chemotherapeutic efficacy in PDAC therapy. Full article

(This article belongs to the Special Issue Synergistic Effects of Plant Derivatives with Other Drugs)

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20 pages, 3918 KiB

Open AccessArticle

Effects of a Short-Term Lipopolysaccharides Challenge on Mouse Brain and Liver Peroxisomal Antioxidant and β-oxidative Functions: Protective Action of Argan Oil

by Soukaina Essadek, Habiba Bouchab, Riad El Kebbaj, Catherine Gondcaille, Soufiane El Kamouni, Stéphane Savary, Joseph Vamecq, Abdelkhalid Essamadi, Mustapha Cherkaoui-Malki, Boubker Nasser and Pierre Andreoletti

Pharmaceuticals 2022, 15(4), 465; https://doi.org/10.3390/ph15040465 - 12 Apr 2022

Cited by 4 | Viewed by 2606

Abstract

During sepsis, the imbalance between oxidative insult and body antioxidant response causes the dysfunction of organs, including the brain and liver. Exposing mice to bacterial lipopolysaccharides (LPS) results in a similar pathophysiological outcome. The protection offered by argan oil was studied against LPS-induced [...] Read more.

During sepsis, the imbalance between oxidative insult and body antioxidant response causes the dysfunction of organs, including the brain and liver. Exposing mice to bacterial lipopolysaccharides (LPS) results in a similar pathophysiological outcome. The protection offered by argan oil was studied against LPS-induced oxidative stress, dysregulation of peroxisomal antioxidants, and β-oxidation activities in the brain and liver. In a short-term LPS treatment, lipid peroxidation (malonaldehyde assay) increased in the brain and liver with upregulations of proinflammatory tumor necrosis factor (Tnf)-α and anti-inflammatory interleukin (Il)-10 genes, especially in the liver. Although exposure to olive oil (OO), colza oil (CO), and argan oil (AO) prevented LPS-induced lipid peroxidation in the brain and liver, only AO exposure protected against liver inflammation. Remarkably, only exposure to AO prevented LPS-dependent glutathione (GSH) dysregulation in the brain and liver. Furthermore, exposure to AO increased more efficiently than OO and CO in both organs, peroxisomal antioxidant capacity via induction of catalase (Cat) gene, protein and activity expression levels, and superoxide dismutase (Sod1) mRNA and activity levels. Interestingly, LPS decreased protein levels of the peroxisomal fatty acid-ATP binding cassette (ABC) transporters, ABCD1 and ABCD2, and increased acyl-CoA oxidase 1 (ACOX1) protein expression. Moreover, these LPS effects were attenuated for ABCD1 and ACOX1 in the brain of mice pretreated with AO. Our data collectively highlight the protective effects of AO against early oxidative stress caused by LPS in the brain and liver and their reliance on the preservation of peroxisomal functions, including antioxidant and β-oxidation activities, making AO a promising candidate for the prevention and management of sepsis. Full article

(This article belongs to the Section Natural Products)

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33 pages, 1609 KiB

Open AccessEditor’s ChoiceReview

Physiological Effects and Human Health Benefits of Hibiscus sabdariffa: A Review of Clinical Trials

by Efigenia Montalvo-González, Zuamí Villagrán, Sughey González-Torres, Laura Elena Iñiguez-Muñoz, Mario Alberto Isiordia-Espinoza, José Martín Ruvalcaba-Gómez, Ramón Ignacio Arteaga-Garibay, José Luis Acosta, Napoleón González-Silva and Luis Miguel Anaya-Esparza

Pharmaceuticals 2022, 15(4), 464; https://doi.org/10.3390/ph15040464 - 12 Apr 2022

Cited by 15 | Viewed by 8845

Abstract

Hibiscus sabdariffa Linn. Malvaceae (HS) is characterized by its edible calyxes. The HS calyxes are widely used for cosmetic, food, and medicinal applications. According to ethnobotanical evidence, decoction, infusion, or maceration extracts from HS calyxes have been used in folk medicine to treat [...] Read more.

Hibiscus sabdariffa Linn. Malvaceae (HS) is characterized by its edible calyxes. The HS calyxes are widely used for cosmetic, food, and medicinal applications. According to ethnobotanical evidence, decoction, infusion, or maceration extracts from HS calyxes have been used in folk medicine to treat many ailments. Moreover, several in vitro and in vivo studies have demonstrated the pharmacological properties and potential human health benefits of HS consumption. On the other hand, the evaluation of the physiological effects and health benefits of HS in clinical studies is most challenging. Therefore, this narrative review summarizes and discusses the physiological effects and health benefits of HS calyxes reported in clinical trials. Preparations obtained from HS calyxes (extracts, infusions, decoction, teas, beverages, capsules, and pills) are used as non-pharmacological therapies to prevent/control diverse chronic non-communicable diseases. The most-reported HS health benefits are its antihypertensive, antidyslipidemic, hypoglycemic, body fat mass reduction, nephroprotective, antianemic, antioxidant, anti-inflammatory, and anti-xerostomic activities; these effects are associated with the phytochemicals found in HS. Moreover, no adverse effects were reported during the clinical trials. However, clinical studies exhibited some limitations; thus, further studies are required to validate the clinical efficacy of HS in large-scale studies with higher doses and a good experimental design Full article

(This article belongs to the Special Issue Bioactive Compounds from Plants and Foods with Pharmaceutical Interest 2022)

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25 pages, 1657 KiB

Open AccessReview

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

by Luigi Principe, Tommaso Lupia, Lilia Andriani, Floriana Campanile, Davide Carcione, Silvia Corcione, Francesco Giuseppe De Rosa, Roberto Luzzati, Giacomo Stroffolini, Marina Steyde, Giuliana Decorti and Stefano Di Bella

Pharmaceuticals 2022, 15(4), 463; https://doi.org/10.3390/ph15040463 - 12 Apr 2022

Cited by 14 | Viewed by 5590

Abstract

Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for [...] Read more.

Bacterial resistance mechanisms are continuously and rapidly evolving. This is particularly true for Gram-negative bacteria. Over the last decade, the strategy to develop new β-lactam/β-lactamase inhibitors (BLs/BLIs) combinations has paid off and results from phase 3 and real-world studies are becoming available for several compounds. Cefiderocol warrants a separate discussion for its peculiar mechanism of action. Considering the complexity of summarizing and integrating the emerging literature data of clinical outcomes, microbiological mechanisms, and pharmacokinetic/pharmacodynamic properties of the new BL/BLI and cefiderocol, we aimed to provide an overview of data on the following compounds: aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, cefiderocol, ceftaroline/avibactam, ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam, meropenem/nacubactam and meropenem/vaborbactam. Each compound is described in a dedicated section by experts in infectious diseases, microbiology, and pharmacology, with tables providing at-a-glance information. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents 2022)

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