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Pharmaceuticals, Volume 16, Issue 6 (June 2023) – 131 articles

Cover Story (view full-size image): Over the past decades, peptides and proteins have been increasingly important in treating various human diseases and conditions. However, the practically impermeable blood–brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous system (CNS). Thus, developing effective localized delivery strategies for these therapeutics has gained extensive attention, owing to their ability to circumvent the physiological barrier to directly introduce macromolecules into the CNS to improve therapeutic effects and reduce systemic side effects. This review discusses various local administration and formulation strategies that have shown success in treating CNS diseases using peptide/protein therapeutics. Lastly, it discusses the challenges and future perspectives of these approaches. View this paper
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18 pages, 2521 KiB  
Article
Characteristics of Extracellular Vesicles from a High-Grade Serous Ovarian Cancer Cell Line Derived from a Platinum-Resistant Patient as a Potential Tool for Aiding the Prediction of Responses to Chemotherapy
by Katarina Černe, Nuša Kelhar, Nataša Resnik, Maruša Herzog, Lana Vodnik, Peter Veranič and Borut Kobal
Pharmaceuticals 2023, 16(6), 907; https://doi.org/10.3390/ph16060907 - 20 Jun 2023
Viewed by 1198
Abstract
Platinum-resistant high-grade serous ovarian cancer (HGSOC) is invariably a fatal disease. A central goal of ovarian cancer research is therefore to develop new strategies to overcome platinum resistance. Treatment is thus moving towards personalized therapy. However, validated molecular biomarkers that predict patients’ risk [...] Read more.
Platinum-resistant high-grade serous ovarian cancer (HGSOC) is invariably a fatal disease. A central goal of ovarian cancer research is therefore to develop new strategies to overcome platinum resistance. Treatment is thus moving towards personalized therapy. However, validated molecular biomarkers that predict patients’ risk of developing platinum resistance are still lacking. Extracellular vesicles (EVs) are promising candidate biomarkers. EpCAM-specific EVs are largely unexplored biomarkers for predicting chemoresistance. Using transmission electron microscopy, nanoparticle tracking analysis and flow cytometry, we compared the characteristics of EVs released from a cell line derived from a clinically confirmed cisplatin-resistant patient (OAW28) and EVs released from two cell lines from tumors sensitive to platinum-based chemotherapy (PEO1 and OAW42). We demonstrated that EVs released from the HGSOC cell line of chemoresistant patients exhibited greater size heterogeneity, a larger proportion of medium/large (>200 nm) Evs and a higher number of released EpCAM-positive EVs of different sizes, although the expression of EpCAM was predominant in EVs larger than 400 nm. We also found a strong positive correlation between the concentration of EpCAM-positive EVs and the expression of cellular EpCAM. These results may contribute to the prediction of platinum resistance in the future, although they should first be validated in clinical samples. Full article
(This article belongs to the Special Issue Personalized Medicine in Gynecological Cancer)
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18 pages, 3473 KiB  
Article
A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities
by Mohadeseh Namjoo, Hossein Ghafouri, Elham Assareh, Amir Reza Aref, Ebrahim Mostafavi, Ali Hamrahi Mohsen, Saeed Balalaie, Sylvain Broussy and S. Mohsen Asghari
Pharmaceuticals 2023, 16(6), 906; https://doi.org/10.3390/ph16060906 - 20 Jun 2023
Cited by 3 | Viewed by 1549
Abstract
Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear [...] Read more.
Vascular endothelial growth factor receptor 2 (VEGFR2) mediates VEGFA signaling mainly through the PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. Here we unveil a peptidomimetic (VGB3) based on the interaction between VEGFB and VEGFR1 that unexpectedly binds and neutralizes VEGFR2. Investigation of the cyclic and linear structures of VGB3 (named C-VGB3 and L-VGB3, respectively) using receptor binding and cell proliferation assays, molecular docking, and evaluation of antiangiogenic and antitumor activities in the 4T1 mouse mammary carcinoma tumor (MCT) model showed that loop formation is essential for peptide functionality. C-VGB3 inhibited proliferation and tubulogenesis of human umbilical vein endothelial cells (HUVECs), accounting for the abrogation of VEGFR2, p-VEGFR2 and, subsequently, PI3K/AKT/mTOR and PLCγ/ERK1/2 pathways. In 4T1 MCT cells, C-VGB3 inhibited cell proliferation, VEGFR2 expression and phosphorylation, the PI3K/AKT/mTOR pathway, FAK/Paxillin, and the epithelial-to-mesenchymal transition cascade. The apoptotic effects of C-VGB3 on HUVE and 4T1 MCT cells were inferred from annexin-PI and TUNEL staining and activation of P53, caspase-3, caspase-7, and PARP1, which mechanistically occurred through the intrinsic pathway mediated by Bcl2 family members, cytochrome c, Apaf-1 and caspase-9, and extrinsic pathway via death receptors and caspase-8. These data indicate that binding regions shared by VEGF family members may be important in developing novel pan-VEGFR inhibitors that are highly relevant in the pathogenesis of angiogenesis-related diseases. Full article
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19 pages, 17066 KiB  
Article
Lycopene from Red Guava (Psidium guajava L.): From Hepatoprotective Effect to Its Use as Promising Self-Emulsifying Drug Delivery System for Anti-Inflammatory and Antioxidant Applications
by Maíra Bernardes Alves, Andreanne Gomes Vasconcelos, Amandda Évelin Silva de Carvalho, Robson Camilotti Slompo, Bruno Silva Sá, Maria Júlia Lima Gonçalves, Liz Nayara Ribeiro da Costa Lima Moura, Ana Karolinne da Silva Brito, José Vinícius de Sousa França, Maria do Carmo de Carvalho e Martins, Márcia dos Santos Rizzo, Susana Soares, Verónica Bastos, Felipe Saldanha de Araujo, Bassam Felipe Mogharbel, Katherine Athayde Teixeira de Carvalho, Helena Oliveira, Alexandra Plácido, Daniel Dias Rufino Arcanjo, Eder Alves Barbosa and José Roberto de Souza de Almeida Leiteadd Show full author list remove Hide full author list
Pharmaceuticals 2023, 16(6), 905; https://doi.org/10.3390/ph16060905 - 20 Jun 2023
Viewed by 1598
Abstract
Lycopene is a carotenoid with potential use in the treatment of chronic illnesses. Here, different formulations of lycopene were studied: lycopene-rich extract from red guava (LEG), purified lycopene from red guava (LPG) and a self-emulsifying drug delivery system loaded with LPG (nanoLPG). The [...] Read more.
Lycopene is a carotenoid with potential use in the treatment of chronic illnesses. Here, different formulations of lycopene were studied: lycopene-rich extract from red guava (LEG), purified lycopene from red guava (LPG) and a self-emulsifying drug delivery system loaded with LPG (nanoLPG). The effects of administering orally various doses of LEG to hypercholesterolemic hamsters were evaluated regarding the liver function of the animals. The cytotoxicity of LPG in Vero cells was analyzed by a crystal violet assay and by fluorescence microscopy. In addition, nanoLPG was employed in stability tests. LPG and nanoLPG were tested for their cytotoxic effect on human keratinocytes and antioxidant capacity on cells in an endothelial dysfunction model in an isolated rat aorta. Finally, the effect of different nanoLPG concentrations on the expression of immune-related genes (IL-10, TNF-α, COX-2 and IFN-γ) from peripheral blood mononuclear cells (PBMC) using real-time PCR was also analyzed. Results suggest that LEG, despite not being able to improve blood markers indicative of liver function in hypercholesterolemic hamsters, reduced hepatic degenerative changes. Additionally, LPG did not show cytotoxicity in Vero cells. In relation to nanoLPG, the effects produced by heat stress evaluated by Dynamics Light Scattering (DLS) and visually were loss of color, texture change and phase separation after 15 days without interfering with the droplet size, so the formulation proved to be efficient in stabilizing the encapsulated lycopene. Although LPG and nanoLPG showed moderate toxicity to keratinocytes, which may be related to cell lineage characteristics, both revealed potent antioxidant activity. LPG and nanoLPG showed vasoprotective effects in aortic preparations. The gene expression assay indicates that, although no significant differences were observed in the expression of IL-10 and TNF-α, the PBMCs treated with nanoLPG showed a reduction in transcriptional levels of IFN-γ and an increased expression of COX-2. Thus, the work adds evidence to the safety of the use of lycopene by humans and shows that tested formulations, mainly nanoLPG due to its stability, stand out as promising and biosafe products for the treatment of diseases that have oxidative stress and inflammation in their etiopathology. Full article
(This article belongs to the Special Issue Pharmacotherapy of Dyslipidemias)
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14 pages, 2378 KiB  
Communication
Metformin Therapy Changes Gut Microbiota Alpha-Diversity in COVID-19 Patients with Type 2 Diabetes: The Role of SARS-CoV-2 Variants and Antibiotic Treatment
by Pavlo Petakh, Iryna Kamyshna, Valentyn Oksenych, Denis Kainov and Aleksandr Kamyshnyi
Pharmaceuticals 2023, 16(6), 904; https://doi.org/10.3390/ph16060904 - 20 Jun 2023
Cited by 7 | Viewed by 1898
Abstract
The gut microbiota play a crucial role in maintaining host health and have a significant impact on human health and disease. In this study, we investigated the alpha diversity of gut microbiota in COVID-19 patients and analyzed the impact of COVID-19 variants, antibiotic [...] Read more.
The gut microbiota play a crucial role in maintaining host health and have a significant impact on human health and disease. In this study, we investigated the alpha diversity of gut microbiota in COVID-19 patients and analyzed the impact of COVID-19 variants, antibiotic treatment, type 2 diabetes (T2D), and metformin therapy on gut microbiota composition and diversity. We used a culture-based method to analyze the gut microbiota and calculated alpha-diversity using the Shannon H′ and Simpson 1/D indices. We collected clinical data, such as the length of hospital stay (LoS), C-reactive protein (CRP) levels, and neutrophil-to-lymphocyte ratio. We found that patients with T2D had significantly lower alpha-diversity than those without T2D. Antibiotic use was associated with a reduction in alpha-diversity, while metformin therapy was associated with an increase. We did not find significant differences in alpha-diversity between the Delta and Omicron groups. The length of hospital stay, CRP levels, and NLR showed weak to moderate correlations with alpha diversity. Our findings suggest that maintaining a diverse gut microbiota may benefit COVID-19 patients with T2D. Interventions to preserve or restore gut microbiota diversity, such as avoiding unnecessary antibiotic use, promoting metformin therapy, and incorporating probiotics, may improve patient outcomes. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)
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14 pages, 1046 KiB  
Article
A Novel UHPLC-MS/MS Method for the Quantification of Seven Opioids in Different Human Tissues
by Alessandra Manca, Amedeo De Nicolò, Elisa Delia De Vivo, Micol Ferrara, Sharon Oh, Sahar Khalili, Niamh Higgins, Robert G. Deiss, Stefano Bonora, Jessica Cusato, Alice Palermiti, Jacopo Mula, Sara Gianella and Antonio D’Avolio
Pharmaceuticals 2023, 16(6), 903; https://doi.org/10.3390/ph16060903 - 19 Jun 2023
Viewed by 1630
Abstract
Background: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens [...] Read more.
Background: Opioids are considered the cornerstone of pain management: they show good efficacy as a first-line therapy for moderate to severe cancer pain. Since pharmacokinetic/pharmacodynamic information about the tissue-specific effect and toxicity of opioids is still scarce, their quantification in post-mortem autoptic specimens could give interesting insights. Methods: We describe an ultra-high-performance liquid chromatography coupled with tandem mass spectrometry method for the simultaneous quantification of methadone, morphine, oxycodone, hydrocodone, oxymorphone, hydromorphone and fentanyl in several tissues: liver, brain, kidney, abdominal adipose tissue, lung and blood plasma. The presented method has been applied on 28 autoptic samples from different organs obtained from four deceased PLWH who used opioids for palliative care during terminal disease. Results: Sample preparation was based on tissue weighing, disruption, sonication with drug extraction medium and a protein precipitation protocol. The extracts were then dried, reconstituted and injected onto the LX50 QSight 220 (Perkin Elmer, Milan, Italy) system. Separation was obtained by a 7 min gradient run at 40 °C with a Kinetex Biphenyl 2.6 µm, 2.1 × 100 mm. Concerning the analyzed samples, higher opioids concentrations were observed in tissues than in plasma. Particularly, O-MOR and O-COD showed higher concentrations in kidney and liver than other tissues (>15–20 times greater) and blood plasma (>100 times greater). Conclusions: Results in terms of linearity, accuracy, precision, recovery and matrix effect fitted the recommendations of FDA and EMA guidelines, and the sensitivity was high enough to allow successful application on human autoptic specimens from an ethically approved clinical study, confirming its eligibility for post-mortem pharmacological/toxicological studies. Full article
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14 pages, 3670 KiB  
Article
Asiatic Acid Inhibits Nasopharyngeal Carcinoma Cell Viability and Migration via Suppressing STAT3 and Claudin-1
by Supitchaya Pantia, Thaned Kangsamaksin, Tavan Janvilisri and Waraporn Komyod
Pharmaceuticals 2023, 16(6), 902; https://doi.org/10.3390/ph16060902 - 19 Jun 2023
Cited by 2 | Viewed by 1293
Abstract
Nasopharyngeal carcinoma (NPC) is a prevalent cancer in Southeast Asia, but effective treatment options remain limited, and chemotherapy has a high resistance rate. Asiatic acid (AA), a triterpenoid found in Centella asiatica, has shown anticancer activity in various cancers. Therefore, this study [...] Read more.
Nasopharyngeal carcinoma (NPC) is a prevalent cancer in Southeast Asia, but effective treatment options remain limited, and chemotherapy has a high resistance rate. Asiatic acid (AA), a triterpenoid found in Centella asiatica, has shown anticancer activity in various cancers. Therefore, this study aims to investigate the anticancer effects and mechanisms of AA in NPC cell lines. The effects of AA on NPC cytotoxicity, apoptosis, and migration were determined in TW-01 and SUNE5-8F NPC cell lines. Western blot analysis was performed to evaluate the protein expression levels affected by AA. The role of AA in proliferation and migration was investigated in STAT3 and claudin-1 knockdown cells. AA inhibited NPC cell viability and migration and induced cell death by increasing cleaved caspase-3 expression. Moreover, AA inhibited STAT3 phosphorylation and reduced claudin-1 expression in NPC cells. Although knockdown of STAT3 or claudin-1 slightly reduced cell viability, it did not enhance the anti-proliferative effect of AA. However, knockdown of STAT3 or claudin-1 increased the anti-migratory effect of AA in NPC cells. These results suggest that AA can be a promising candidate for drug development against NPC. Full article
(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)
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31 pages, 14193 KiB  
Review
Targeting Metalloenzymes: The “Achilles’ Heel” of Viruses and Parasites
by Dimitrios Moianos, Georgia-Myrto Prifti, Maria Makri and Grigoris Zoidis
Pharmaceuticals 2023, 16(6), 901; https://doi.org/10.3390/ph16060901 - 19 Jun 2023
Cited by 3 | Viewed by 1517
Abstract
Metalloenzymes are central to the regulation of a wide range of essential viral and parasitic functions, including protein degradation, nucleic acid modification, and many others. Given the impact of infectious diseases on human health, inhibiting metalloenzymes offers an attractive approach to disease therapy. [...] Read more.
Metalloenzymes are central to the regulation of a wide range of essential viral and parasitic functions, including protein degradation, nucleic acid modification, and many others. Given the impact of infectious diseases on human health, inhibiting metalloenzymes offers an attractive approach to disease therapy. Metal-chelating agents have been expansively studied as antivirals and antiparasitics, resulting in important classes of metal-dependent enzyme inhibitors. This review provides the recent advances in targeting the metalloenzymes of viruses and parasites that impose a significant burden on global public health, including influenza A and B, hepatitis B and C, and human immunodeficiency viruses as well as Trypanosoma brucei and Trypanosoma cruzi. Full article
(This article belongs to the Special Issue Feature Reviews in Medicinal Chemistry)
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11 pages, 473 KiB  
Article
Relation of Statin Use with Esophageal Cancer
by Sarang Jang, Hyo Geun Choi, Mi Jung Kwon, Ji Hee Kim, Joo-Hee Kim and So Young Kim
Pharmaceuticals 2023, 16(6), 900; https://doi.org/10.3390/ph16060900 - 19 Jun 2023
Viewed by 1076
Abstract
The present study evaluated the association of long-term statin use with the diagnosis and mortality of esophageal cancer in a Korean population. The Korean National Health Insurance Service-Health Screening Cohort from 2002 to 2019 was enrolled. Esophageal cancer patients were matched with control [...] Read more.
The present study evaluated the association of long-term statin use with the diagnosis and mortality of esophageal cancer in a Korean population. The Korean National Health Insurance Service-Health Screening Cohort from 2002 to 2019 was enrolled. Esophageal cancer patients were matched with control participants for demographic variables. The statin prescription histories were collected and grouped into <180 days, 180 to 545 days, and >545 days of duration. Propensity score overlap weighting was applied to minimize the bias between the esophageal cancer and control groups. The odds ratios (ORs) of the duration of statin use for esophageal cancer were analyzed using propensity score overlap weighted multivariable logistic regression analysis. The esophageal cancer group was classified as dead and surviving patients, and the ORs of the duration of statin use for the mortality of esophageal cancer were analyzed in an identical manner. Secondary analyses were conducted according to comorbid factors. Patients with esophageal cancer did not show lower odds for the duration of statin prescription in the overall study population (OR = 1.30, 95% CI = 1.03–1.65, p = 0.027 for 180 to 545 days and OR = 1.29, 95% CI = 1.08–1.55, p = 0.006 for >545 days). Subgroups of nonsmokers, past and current smokers, alcohol consumption ≥ 1 time a week, SBP < 140 mmHg and DBP < 90 mmHg, fasting blood glucose ≥ 100 mg/dL, total cholesterol ≥ 200 mg/dL, CCI score = 0, and nondyslipidemia history demonstrated low odds for the duration of statin prescription. Both types of statins, hydrophilic and lipophilic statins, were not related to a lower rate of esophageal cancer. The mortality of esophageal cancer was not associated with the duration of statin prescription. A subgroup with total cholesterol ≥ 200 mg/dL showed lower odds of statin prescription for mortality of esophageal cancer. The duration of statin prescription was not related to a lower rate or mortality of esophageal cancer in the adult Korean population. Full article
(This article belongs to the Special Issue Adjuvant Therapies for Cancer Treatment)
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33 pages, 2721 KiB  
Review
Nanotechnology-Aided Advancement in Combating the Cancer Metastasis
by Arun Kumar Singh, Rishabha Malviya, Bhupendra Prajapati, Sudarshan Singh, Deepika Yadav and Arvind Kumar
Pharmaceuticals 2023, 16(6), 899; https://doi.org/10.3390/ph16060899 - 19 Jun 2023
Cited by 2 | Viewed by 1599
Abstract
Modern medicine has been working to find a cure for cancer for almost a century, but thus far, they have not been very successful. Although cancer treatment has come a long way, more work has to be carried out to boost specificity and [...] Read more.
Modern medicine has been working to find a cure for cancer for almost a century, but thus far, they have not been very successful. Although cancer treatment has come a long way, more work has to be carried out to boost specificity and reduce systemic toxicity. The diagnostic industry is on the cusp of a technological revolution, and early diagnosis is essential for improving prognostic outlook and patient quality of life. In recent years, nanotechnology’s use has expanded, demonstrating its efficacy in enhancing fields such as cancer treatment, radiation therapy, diagnostics, and imaging. Applications for nanomaterials are diverse, ranging from enhanced radiation adjuvants to more sensitive early detection instruments. Cancer, particularly when it has spread beyond the original site of cancer, is notoriously tough to combat. Many people die from metastatic cancer, which is why it remains a huge issue. Cancer cells go through a sequence of events known as the “metastatic cascade” throughout metastasis, which may be used to build anti-metastatic therapeutic techniques. Conventional treatments and diagnostics for metastasis have their drawbacks and hurdles that must be overcome. In this contribution, we explore in-depth the potential benefits that nanotechnology-aided methods might offer to the detection and treatment of metastatic illness, either alone or in conjunction with currently available conventional procedures. Anti-metastatic drugs, which can prevent or slow the spread of cancer throughout the body, can be more precisely targeted and developed with the help of nanotechnology. Furthermore, we talk about how nanotechnology is being applied to the treatment of patients with cancer metastases. Full article
(This article belongs to the Special Issue Nanotechnology for Drug and Gene Delivery)
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13 pages, 786 KiB  
Review
Pharmacological Approaches to Modulate the Scarring Process after Glaucoma Surgery
by Debora Collotta, Simona Colletta, Virginia Carlucci, Claudia Fruttero, Antonio Maria Fea and Massimo Collino
Pharmaceuticals 2023, 16(6), 898; https://doi.org/10.3390/ph16060898 - 19 Jun 2023
Cited by 4 | Viewed by 1386
Abstract
Glaucoma is an acquired optic neuropathy that results in a characteristic optic nerve head appearance and visual field loss. Reducing the IOP is the only factor that can be modified, and the progression of the disease can be managed through medication, laser treatment, [...] Read more.
Glaucoma is an acquired optic neuropathy that results in a characteristic optic nerve head appearance and visual field loss. Reducing the IOP is the only factor that can be modified, and the progression of the disease can be managed through medication, laser treatment, or surgery. Filtering procedures are used when target pressure cannot be obtained with less invasive methods. Nevertheless, these procedures require accurate control of the fibrotic process, which can hamper filtration, thus, negatively affecting the surgical success. This review explores the available and potential pharmacological treatments that modulate the scarring process after glaucoma surgery, analyzing the most critical evidence available in the literature. The modulation of scarring is based on non-steroidal anti-inflammatory drugs (NSAIDs), mitomycin, and 5-fluorouracil. In the long term, the failure rate of filtering surgery is mainly due to the limitations of the current strategies caused by the complexity of the fibrotic process and the pharmacological and toxicological aspects of the drugs that are currently in use. Considering these limitations, new potential treatments were investigated. This review suggests that a better approach to tackle the fibrotic process may be to hit multiple targets, thus increasing the inhibitory potential against excessive scarring following surgery. Full article
(This article belongs to the Special Issue Pharmacology of Glaucoma)
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10 pages, 672 KiB  
Communication
Amantadine in Treatment of Dysthymia—The Pilot Case Series Study
by Marek Krzystanek, Ewa Martyniak, Artur Pałasz, Katarzyna Skałacka, Artur Chwalba and Piotr Wierzbiński
Pharmaceuticals 2023, 16(6), 897; https://doi.org/10.3390/ph16060897 - 19 Jun 2023
Viewed by 3269
Abstract
Dysthymia is a common chronic mood disorder in which isolated symptoms of depression persist for at least 2 years. Despite the many medications recommended for the treatment of dysthymia, no recommendations have yet been made for the treatment of patients who fail to [...] Read more.
Dysthymia is a common chronic mood disorder in which isolated symptoms of depression persist for at least 2 years. Despite the many medications recommended for the treatment of dysthymia, no recommendations have yet been made for the treatment of patients who fail to achieve clinical improvement. This justifies attempts to identify second-line drugs for the treatment of dysthymia. In an open and naturalistic case study, five patients diagnosed with dysthymia in whom at least one antidepressant treatment was ineffective were treated with amantadine. In the age- and gender-matched external control group, patients were treated with sertraline at 100 mg/day. Depressive symptoms were assessed using HDRS-17. Two men and three women were treated with 100 mg amantadine for 3 months with 3–5 months follow-up. After 1 month of treatment with amantadine, a significant reduction in the intensity of depressive symptoms was achieved in all patients, and the clinical improvement increased over the next 2 months of treatment. No deterioration in well-being was observed in any patient after discontinuation of amantadine. The effect of amantadine treatment was comparable to that of sertraline treatment in patients with dysthymia who improved with this drug. The present study indicates that amantadine is an effective and well-tolerated drug in the treatment of dysthymia. Amantadine may be associated with a quick improvement in symptoms in the treatment of dysthymia. Treatment with this drug seems to be associated with good tolerability and persistency of the therapeutic effect after the discontinuation of the treatment. Full article
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19 pages, 4309 KiB  
Article
Riluzole, a Derivative of Benzothiazole as a Potential Anti-Amoebic Agent against Entamoeba histolytica
by Maritza Velásquez-Torres, José Guadalupe Trujillo-Ferrara, Marycarmen Godínez-Victoria, Rosa Adriana Jarillo-Luna, Víctor Tsutsumi, Virginia Sánchez-Monroy, Araceli Posadas-Mondragón, Roberto Issac Cuevas-Hernández, José Angel Santiago-Cruz and Judith Pacheco-Yépez
Pharmaceuticals 2023, 16(6), 896; https://doi.org/10.3390/ph16060896 - 19 Jun 2023
Cited by 3 | Viewed by 1164
Abstract
Amoebiasis is produced by the parasite Entamoeba histolytica; this disease affects millions of people throughout the world who may suffer from amoebic colitis or amoebic liver abscess. Metronidazole is used to treat this protozoan, but it causes important adverse effects that limit [...] Read more.
Amoebiasis is produced by the parasite Entamoeba histolytica; this disease affects millions of people throughout the world who may suffer from amoebic colitis or amoebic liver abscess. Metronidazole is used to treat this protozoan, but it causes important adverse effects that limit its use. Studies have shown that riluzole has demonstrated activity against some parasites. Thus, the present study aimed, for the first time, to demonstrate the in vitro and in silico anti-amoebic activity of riluzole. In vitro, the results of Entamoeba histolytica trophozoites treated with IC50 (319.5 μM) of riluzole for 5 h showed (i) a decrease of 48.1% in amoeba viability, (ii) ultrastructural changes such as a loss of plasma membrane continuity and alterations in the nuclei followed by lysis, (iii) apoptosis-like cell death, (iv) the triggering of the production of reactive oxygen species and nitric oxide, and (v) the downregulation of amoebic antioxidant enzyme gene expression. Interestingly, docking studies have indicated that riluzole presented a higher affinity than metronidazole for the antioxidant enzymes thioredoxin, thioredoxin reductase, rubrerythrin, and peroxiredoxin of Entamoeba histolytica, which are considered as possible candidates of molecular targets. Our results suggest that riluzole could be an alternative treatment against Entamoeba histolytica. Future studies should be conducted to analyze the in vivo riluzole anti-amoebic effect on the resolution of amebic liver abscess in a susceptible model, as this will contribute to developing new therapeutic agents with anti-amoebic activity. Full article
(This article belongs to the Special Issue Drug Discovery of Antiprotozoal Agents)
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21 pages, 4047 KiB  
Article
Isolation, Purification, and Structural Characterization of Polysaccharides from Codonopsis pilosula and Their Anti-Tumor Bioactivity by Immunomodulation
by Nan Li, Ying-Xia Xiong, Fan Ye, Bing Jin, Jin-Jia Wu, Miao-Miao Han, Tian Liu, Yi-Kai Fan, Cun-Yu Li, Jiu-Shi Liu, Ying-Hua Zhang, Gui-Bo Sun, Yun Zhang and Zheng-Qi Dong
Pharmaceuticals 2023, 16(6), 895; https://doi.org/10.3390/ph16060895 - 19 Jun 2023
Cited by 3 | Viewed by 1547
Abstract
The activity of polysaccharides is usually related to molecular weight. The molecular weight of polysaccharides is critical to their immunological effect in cancer therapy. Herein, the Codonopsis polysaccharides of different molecular weights were isolated using ultrafiltration membranes of 60- and 100-wDa molecular weight [...] Read more.
The activity of polysaccharides is usually related to molecular weight. The molecular weight of polysaccharides is critical to their immunological effect in cancer therapy. Herein, the Codonopsis polysaccharides of different molecular weights were isolated using ultrafiltration membranes of 60- and 100-wDa molecular weight cut-off to determine the relationship between molecular weight and antitumor activities. First, three water-soluble polysaccharides CPPS-I (<60 wDa), CPPS-II (60–100 wDa), and CPPS-III (>100 wDa) from Codonopsis were isolated and purified using a combination of macroporous adsorption resin chromatography and ultrafiltration. Their structural characteristics were determined through chemical derivatization, GPC, HPLC, FT–IR, and NMR techniques. In vitro experiments indicated that all Codonopsis polysaccharides exhibited significant antitumor activities, with the tumor inhibition rate in the following order: CPPS-II > CPPS-I > CPPS-III. The treatment of CPPS-II exhibited the highest inhibition rate at a high concentration among all groups, which was almost as efficient as that of the DOX·HCL (10 μg/mL) group at 125 μg/mL concentration. Notably, CPPS-II demonstrated the ability to enhance NO secretion and the antitumor ability of macrophages relative to the other two groups of polysaccharides. Finally, in vivo experiments revealed that CPPS-II increased the M1/M2 ratio in immune system regulation and that the tumor inhibition effect of CPPS-II + DOX was superior to that of DOX monotherapy, implying that CPPS-II + DOX played a synergistic role in regulating the immune system function and the direct tumor-killing ability of DOX. Therefore, CPPS-II is expected to be applied as an effective cancer treatment or adjuvant therapy. Full article
(This article belongs to the Special Issue Polysaccharides as Drug Candidates)
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17 pages, 3439 KiB  
Article
Baricitinib Lipid-Based Nanosystems as a Topical Alternative for Atopic Dermatitis Treatment
by Núria Garrós, Paola Bustos-Salgados, Òscar Domènech, María José Rodríguez-Lagunas, Negar Beirampour, Roya Mohammadi-Meyabadi, Mireia Mallandrich, Ana C. Calpena and Helena Colom
Pharmaceuticals 2023, 16(6), 894; https://doi.org/10.3390/ph16060894 - 18 Jun 2023
Cited by 1 | Viewed by 1822
Abstract
Atopic dermatitis (AD) is a chronic autoimmune inflammatory skin disorder which causes a significant clinical problem due to its prevalence. The ongoing treatment for AD is aimed at improving the patient’s quality of life. Additionally, glucocorticoids or immunosuppressants are being used in systemic [...] Read more.
Atopic dermatitis (AD) is a chronic autoimmune inflammatory skin disorder which causes a significant clinical problem due to its prevalence. The ongoing treatment for AD is aimed at improving the patient’s quality of life. Additionally, glucocorticoids or immunosuppressants are being used in systemic therapy. Baricitinib (BNB) is a reversible Janus-associated kinase (JAK)-inhibitor; JAK is an important kinase involved in different immune responses. We aimed at developing and evaluating new topical liposomal formulations loaded with BNB for the treatment of flare ups. Three liposomal formulations were elaborated using POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), CHOL (Cholesterol) and CER (Ceramide) in different proportions: (i) POPC, (ii) POPC:CHOL (8:2, mol/mol) and (iii) POPC:CHOL:CER (3.6:2.4:4.0 mol/mol/mol). They were physiochemically characterized over time. In addition, an in vitro release study, ex vivo permeation and retention studies in altered human skin (AHS) were also performed. Histological analysis was used to study the tolerance of the formulations on the skin. Lastly, the HET-CAM test was also performed to evaluate the irritancy capacity of the formulations, and the modified Draize test was performed to evaluate the erythema and edema capacity of the formulations on the altered skin. All liposomes showed good physicochemical properties and were stable for at least one month. POPC:CHOL:CER had the highest flux and permeation, and the retention in the skin was equal to that of POPC:CHOL. The formulations exhibited no harmful or irritating effects, and the histological examination revealed no changes in structure. The three liposomes have shown promising results for the aim of the study. Full article
(This article belongs to the Special Issue Current Insights on Lipid-Based Nanosystems 2023)
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18 pages, 717 KiB  
Article
Assessment of Physicochemical Parameters and Contaminants in Herbal Dietary Supplements Used in the Treatment of Inflammatory Bowel Disease
by Daniela Amidžić Klarić, Jelena Kovačić, Mario-Livio Jeličić, Snježana Zubčić, Vladimir Stankov, Marija Gulan Čičak, Boris Bučar, Ilija Klarić and Ana Mornar
Pharmaceuticals 2023, 16(6), 893; https://doi.org/10.3390/ph16060893 - 18 Jun 2023
Viewed by 1550
Abstract
Inflammatory bowel disease is a complex disorder characterized by chronic gastrointestinal inflammation. Thus, patients prefer to use herbal dietary supplements containing turmeric, Indian frankincense, green chiretta, and black pepper in an attempt to cope better with their chronic condition. The dietary supplements’ dosage [...] Read more.
Inflammatory bowel disease is a complex disorder characterized by chronic gastrointestinal inflammation. Thus, patients prefer to use herbal dietary supplements containing turmeric, Indian frankincense, green chiretta, and black pepper in an attempt to cope better with their chronic condition. The dietary supplements’ dosage forms and herbal ingredients were assessed in terms of the products’ physicochemical parameters (weight uniformity, friability, disintegration, rupture test, tablet’s breaking force, and powder flowability) in view of the USP-NF requirements. In addition, contaminants such as organic solvents and ethylene oxide were evaluated using gas chromatography. Assessment of gluten via an Enzyme-Linked Immunosorbent Assay was also performed. Most of the products met USP requirements. The high average weight of one multicomponent tablet sample with a high breaking force value can explain the observed negative results of the disintegration test. A total of 26% of samples tested positive for gluten, but the most alarming fact is that the ethylene oxide levels found in two samples were up to 30 times higher than the EU limit. Accordingly, dietary supplement quality control is of fundamental importance. Full article
(This article belongs to the Section Natural Products)
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21 pages, 2590 KiB  
Review
Cyclic Peptides with Antifungal Properties Derived from Bacteria, Fungi, Plants, and Synthetic Sources
by Naiera M. Helmy and Keykavous Parang
Pharmaceuticals 2023, 16(6), 892; https://doi.org/10.3390/ph16060892 - 18 Jun 2023
Cited by 6 | Viewed by 1759
Abstract
Fungal infections remain a significant concern for human health. The emergence of microbial resistance, the improper use of antimicrobial drugs, and the need for fewer toxic antifungal treatments in immunocompromised patients have sparked substantial interest in antifungal research. Cyclic peptides, classified as antifungal [...] Read more.
Fungal infections remain a significant concern for human health. The emergence of microbial resistance, the improper use of antimicrobial drugs, and the need for fewer toxic antifungal treatments in immunocompromised patients have sparked substantial interest in antifungal research. Cyclic peptides, classified as antifungal peptides, have been in development as potential antifungal agents since 1948. In recent years, there has been growing attention from the scientific community to explore cyclic peptides as a promising strategy for combating antifungal infections caused by pathogenic fungi. The identification of antifungal cyclic peptides from various sources has been possible due to the widespread interest in peptide research in recent decades. It is increasingly important to evaluate narrow- to broad-spectrum antifungal activity and the mode of action of synthetic and natural cyclic peptides for both synthesized and extracted peptides. This short review aims to highlight some of the antifungal cyclic peptides isolated from bacteria, fungi, and plants. This brief review is not intended to present an exhaustive catalog of all known antifungal cyclic peptides but rather seeks to showcase selected cyclic peptides with antifungal properties that have been isolated from bacteria, fungi, plants, and synthetic sources. The addition of commercially available cyclic antifungal peptides serves to corroborate the notion that cyclic peptides can serve as a valuable source for the development of antifungal drugs. Additionally, this review discusses the potential future of utilizing combinations of antifungal peptides from different sources. The review underscores the need for the further exploration of the novel antifungal therapeutic applications of these abundant and diverse cyclic peptides. Full article
(This article belongs to the Special Issue Recent Trends in Cyclic Peptides as Therapeutic Agents)
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11 pages, 912 KiB  
Review
The Role of AI in Drug Discovery: Challenges, Opportunities, and Strategies
by Alexandre Blanco-González, Alfonso Cabezón, Alejandro Seco-González, Daniel Conde-Torres, Paula Antelo-Riveiro, Ángel Piñeiro and Rebeca Garcia-Fandino
Pharmaceuticals 2023, 16(6), 891; https://doi.org/10.3390/ph16060891 - 18 Jun 2023
Cited by 52 | Viewed by 19582
Abstract
Artificial intelligence (AI) has the potential to revolutionize the drug discovery process, offering improved efficiency, accuracy, and speed. However, the successful application of AI is dependent on the availability of high-quality data, the addressing of ethical concerns, and the recognition of the limitations [...] Read more.
Artificial intelligence (AI) has the potential to revolutionize the drug discovery process, offering improved efficiency, accuracy, and speed. However, the successful application of AI is dependent on the availability of high-quality data, the addressing of ethical concerns, and the recognition of the limitations of AI-based approaches. In this article, the benefits, challenges, and drawbacks of AI in this field are reviewed, and possible strategies and approaches for overcoming the present obstacles are proposed. The use of data augmentation, explainable AI, and the integration of AI with traditional experimental methods, as well as the potential advantages of AI in pharmaceutical research, are also discussed. Overall, this review highlights the potential of AI in drug discovery and provides insights into the challenges and opportunities for realizing its potential in this field. Note from the human authors: This article was created to test the ability of ChatGPT, a chatbot based on the GPT-3.5 language model, in terms of assisting human authors in writing review articles. The text generated by the AI following our instructions (see Supporting Information) was used as a starting point, and its ability to automatically generate content was evaluated. After conducting a thorough review, the human authors practically rewrote the manuscript, striving to maintain a balance between the original proposal and the scientific criteria. The advantages and limitations of using AI for this purpose are discussed in the last section. Full article
(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)
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19 pages, 5252 KiB  
Article
Inhibition of TRPA1, Endoplasmic Reticulum Stress, Human Airway Epithelial Cell Damage, and Ectopic MUC5AC Expression by Vasaka (Adhatoda vasica; Malabar Nut) Tea
by Tosifa A. Memon, Lili Sun, Marysol Almestica-Roberts, Cassandra E. Deering-Rice, Philip J. Moos and Christopher A. Reilly
Pharmaceuticals 2023, 16(6), 890; https://doi.org/10.3390/ph16060890 - 17 Jun 2023
Viewed by 1246
Abstract
This study tested whether a medicinal plant, Vasaka, typically consumed as a tea to treat respiratory malaise, could protect airway epithelial cells (AECs) from wood smoke particle-induced damage and prevent pathological mucus production. Wood/biomass smoke is a pneumotoxic air pollutant. Mucus normally protects [...] Read more.
This study tested whether a medicinal plant, Vasaka, typically consumed as a tea to treat respiratory malaise, could protect airway epithelial cells (AECs) from wood smoke particle-induced damage and prevent pathological mucus production. Wood/biomass smoke is a pneumotoxic air pollutant. Mucus normally protects the airways, but excessive production can obstruct airflow and cause respiratory distress. Vasaka tea pre- and co-treatment dose-dependently inhibited mucin 5AC (MUC5AC) mRNA induction by AECs treated with wood smoke particles. This correlated with transient receptor potential ankyrin-1 (TRPA1) inhibition, an attenuation of endoplasmic reticulum (ER) stress, and AEC damage/death. Induction of mRNA for anterior gradient 2, an ER chaperone/disulfide isomerase required for MUC5AC production, and TRP vanilloid-3, a gene that suppresses ER stress and wood smoke particle-induced cell death, was also attenuated. Variable inhibition of TRPA1, ER stress, and MUC5AC mRNA induction was observed using selected chemicals identified in Vasaka tea including vasicine, vasicinone, apigenin, vitexin, isovitexin, isoorientin, 9-oxoODE, and 9,10-EpOME. Apigenin and 9,10-EpOME were the most cytoprotective and mucosuppressive. Cytochrome P450 1A1 (CYP1A1) mRNA was also induced by Vasaka tea and wood smoke particles. Inhibition of CYP1A1 enhanced ER stress and MUC5AC mRNA expression, suggesting a possible role in producing protective oxylipins in stressed cells. The results provide mechanistic insights and support for the purported benefits of Vasaka tea in treating lung inflammatory conditions, raising the possibility of further development as a preventative and/or restorative therapy. Full article
(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)
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15 pages, 330 KiB  
Review
Pharmacogenetic Testing for the Pediatric Gastroenterologist: Actionable Drug–Gene Pairs to Know
by Tracy Sandritter, Rachel Chevalier, Rebecca Abt and Valentina Shakhnovich
Pharmaceuticals 2023, 16(6), 889; https://doi.org/10.3390/ph16060889 - 16 Jun 2023
Cited by 1 | Viewed by 1215
Abstract
Gastroenterologists represent some of the earlier adopters of precision medicine through pharmacogenetic testing by embracing upfront genotyping for thiopurine S-methyltransferase nucleotide diphosphatase (TPMT) before prescribing 6-mercaptopurine or azathioprine for the treatment of inflammatory bowel disease. Over the last two decades, pharmacogenetic [...] Read more.
Gastroenterologists represent some of the earlier adopters of precision medicine through pharmacogenetic testing by embracing upfront genotyping for thiopurine S-methyltransferase nucleotide diphosphatase (TPMT) before prescribing 6-mercaptopurine or azathioprine for the treatment of inflammatory bowel disease. Over the last two decades, pharmacogenetic testing has become more readily available for other genes relevant to drug dose individualization. Common medications prescribed by gastroenterologists for conditions other than inflammatory bowel disease now have actionable guidelines, which can improve medication efficacy and safety; however, a clear understanding of how to interpret the results remains a challenge for many clinicians, precluding wide implementation of genotype-guided dosing for drugs other than 6-mercaptopurine and azathioprine. Our goal is to provide a practical tutorial on the currently available pharmacogenetic testing options and a results interpretation for drug–gene pairs important to medications commonly used in pediatric gastroenterology. We focus on evidence-based clinical guidelines published by the Clinical Pharmacogenetics Implementation Consortium (CPIC®) to highlight relevant drug–gene pairs, including proton pump inhibitors and selective serotonin reuptake inhibitors and cytochrome P450 (CYP) 2C19, ondansetron and CYP2D6, 6-mercaptopurine and TMPT and Nudix hydrolase 15 (NUDT15), and budesonide and tacrolimus and CYP3A5. Full article
(This article belongs to the Special Issue Pharmacology of Pediatric Medicines)
31 pages, 3979 KiB  
Article
Phenothiazine- and Carbazole-Cyanochalcones as Dual Inhibitors of Tubulin Polymerization and Human Farnesyltransferase
by Andreea Zubaș, Alina Ghinet, Amaury Farce, Joëlle Dubois and Elena Bîcu
Pharmaceuticals 2023, 16(6), 888; https://doi.org/10.3390/ph16060888 - 16 Jun 2023
Viewed by 1217
Abstract
In the search for innovative approaches to cancer chemotherapy, a chemical library of 49 cyanochalcones, 1a-r, 2a-o, and 3a-p, was designed as dual inhibitors of human farnesyltransferase (FTIs) and tubulin polymerization (MTIs) (FTIs/MTIs), two important biological targets in oncology. This [...] Read more.
In the search for innovative approaches to cancer chemotherapy, a chemical library of 49 cyanochalcones, 1a-r, 2a-o, and 3a-p, was designed as dual inhibitors of human farnesyltransferase (FTIs) and tubulin polymerization (MTIs) (FTIs/MTIs), two important biological targets in oncology. This approach is innovative since the same molecule would be able to interfere with two different mitotic events of the cancer cells and prevent these cells from developing an emergency route and becoming resistant to anticancer agents. Compounds were synthesized by the Claisen–Schmidt condensation of aldehydes with N-3-oxo-propanenitriles under classical magnetic stirring and under sonication. Newly synthesized compounds were screened for their potential to inhibit human farnesyltransferase, tubulin polymerization, and cancer cell growth in vitro. This study allowed for the identification of 22 FTIs and 8 dual FTIs/MTIs inhibitors. The most effective molecule was carbazole-cyanochalcone 3a, bearing a 4-dimethylaminophenyl group (IC50 (h-FTase) = 0.12 µM; IC50 (tubulin) = 0.24 µM) with better antitubulin activity than the known inhibitors that were previously reported, phenstatin and (-)-desoxypodophyllotoxin. The docking of the dual inhibitors was realized in both the active site of FTase and in the colchicine binding site of tubulin. Such compounds with a dual inhibitory profile are excellent clinical candidates for the treatment of human cancers and offer new research perspectives in the search for new anti-cancer drugs. Full article
(This article belongs to the Section Medicinal Chemistry)
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27 pages, 2549 KiB  
Review
Hypericum perforatum L. and the Underlying Molecular Mechanisms for Its Choleretic, Cholagogue, and Regenerative Properties
by Ala Mohagheghzadeh, Parmis Badr, Abdolali Mohagheghzadeh and Shiva Hemmati
Pharmaceuticals 2023, 16(6), 887; https://doi.org/10.3390/ph16060887 - 15 Jun 2023
Cited by 1 | Viewed by 2438
Abstract
Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its [...] Read more.
Any defects in bile formation, secretion, or flow may give rise to cholestasis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. As the pathogenesis of hepatic disorders is multifactorial, targeting parallel pathways potentially increases the outcome of therapy. Hypericum perforatum has been famed for its anti-depressive effects. However, according to traditional Persian medicine, it helps with jaundice and acts as a choleretic medication. Here, we will discuss the underlying molecular mechanisms of Hypericum for its use in hepatobiliary disorders. Differentially expressed genes retrieved from microarray data analysis upon treatment with safe doses of Hypericum extract and intersection with the genes involved in cholestasis are identified. Target genes are located mainly at the endomembrane system with integrin-binding ability. Activation of α5β1 integrins, as osmo-sensors in the liver, activates a non-receptor tyrosine kinase, c-SRC, which leads to the insertion of bile acid transporters into the canalicular membrane to trigger choleresis. Hypericum upregulates CDK6 that controls cell proliferation, compensating for the bile acid damage to hepatocytes. It induces ICAM1 to stimulate liver regeneration and regulates nischarin, a hepatoprotective receptor. The extract targets the expression of conserved oligomeric Golgi (COG) and facilitates the movement of bile acids toward the canalicular membrane via Golgi-derived vesicles. In addition, Hypericum induces SCP2, an intracellular cholesterol transporter, to maintain cholesterol homeostasis. We have also provided a comprehensive view of the target genes affected by Hypericum’s main metabolites, such as hypericin, hyperforin, quercitrin, isoquercitrin, quercetin, kaempferol, rutin, and p-coumaric acid to enlighten a new scope in the management of chronic liver disorders. Altogether, standard trials using Hypericum as a neo-adjuvant or second-line therapy in ursodeoxycholic-acid-non-responder patients define the future trajectories of cholestasis treatment with this product. Full article
(This article belongs to the Special Issue Multi-Targeted Natural Products as Therapeutics)
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17 pages, 3834 KiB  
Article
Evaluation of Brain Targeting and Antipsychotic Activity of Nasally Administrated Ziprasidone Lipid–Polymer Hybrid Nanocarriers
by Hadel A. Abo El-Enin, Alaa S. Tulbah, Hany W. Darwish, Rania Salama, Ibrahim A. Naguib, Heba A. Yassin and Hend Mohamed Abdel-Bar
Pharmaceuticals 2023, 16(6), 886; https://doi.org/10.3390/ph16060886 - 15 Jun 2023
Viewed by 1328
Abstract
The feasibility of using lipid–polymer hybrid (LPH) nanocarriers as a potential platform for the intranasal delivery of ziprasidone (ZP), a second-generation antipsychotic, was explored. Different ZP-loaded LPH composed of a PLGA core and cholesterol-lecithin lipid coat were prepared using a single step nano-precipitation [...] Read more.
The feasibility of using lipid–polymer hybrid (LPH) nanocarriers as a potential platform for the intranasal delivery of ziprasidone (ZP), a second-generation antipsychotic, was explored. Different ZP-loaded LPH composed of a PLGA core and cholesterol-lecithin lipid coat were prepared using a single step nano-precipitation self-assembly technique. Modulation of polymer, lipid and drug amounts, as well as stirring-speed-optimized LPH with a particle size of 97.56 ± 4.55 nm and a ZP entrapment efficiency (EE%) of 97.98 ± 1.22%. The brain deposition and pharmacokinetics studies proved the efficiency of LPH to traverse the blood–brain barrier (BBB) following intranasal delivery with a 3.9-fold increase in targeting efficiency compared to the intravenous (IV) ZP solution with a direct nose-to-brain transport percentage (DTP) of 74.68%. The ZP-LPH showed enhanced antipsychotic activity in terms of animals’ hypermobility over an IV drug solution in schizophrenic rats. The obtained results showed that the fabricated LPH was able to improve ZP brain uptake and proved its antipsychotic efficiency. Full article
(This article belongs to the Special Issue Pharmaceutical Excipients in Formulation Design and Drug Delivery)
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17 pages, 12533 KiB  
Article
Hydrogen Attenuates Inflammation by Inducing Early M2 Macrophage Polarization in Skin Wound Healing
by Pengxiang Zhao, Zisong Cai, Xujuan Zhang, Mengyu Liu, Fei Xie, Ziyi Liu, Shidong Lu and Xuemei Ma
Pharmaceuticals 2023, 16(6), 885; https://doi.org/10.3390/ph16060885 - 15 Jun 2023
Cited by 2 | Viewed by 1570
Abstract
The heterogeneous and highly plastic cell populations of macrophages are important mediators of cellular responses during all stages of wound healing, especially in the inflammatory stage. Molecular hydrogen (H2), which has potent antioxidant and anti-inflammatory effects, has been shown to promote [...] Read more.
The heterogeneous and highly plastic cell populations of macrophages are important mediators of cellular responses during all stages of wound healing, especially in the inflammatory stage. Molecular hydrogen (H2), which has potent antioxidant and anti-inflammatory effects, has been shown to promote M2 polarization in injury and disease. However, more in vivo time series studies of the role of M1-to-M2 polarization in wound healing are needed. In the current study, we performed time series experiments on a dorsal full-thickness skin defect mouse model in the inflammatory stage to examine the effects of H2 inhalation. Our results revealed that H2 could promote very early M1-to-M2 polarization (on days 2–3 post wounding, 2–3 days earlier than in conventional wound healing), without disturbing the functions of the M1 phenotype. Time series analysis of the transcriptome, blood cell counts, and multiple cytokines further indicated that peripheral blood monocytes were a source of H2-induced M2 macrophages and that the functions of H2 in macrophage polarization were not only dependent on its antioxidant effects. Therefore, we believe that H2 could reduce inflammation in wound care by shifting early macrophage polarization in clinical settings. Full article
(This article belongs to the Special Issue Therapeutic Potential of Molecular Hydrogen)
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14 pages, 2417 KiB  
Article
Thymoquinone Enhances Apoptosis of K562 Chronic Myeloid Leukemia Cells through Hypomethylation of SHP-1 and Inhibition of JAK/STAT Signaling Pathway
by Futoon Abedrabbu Al-Rawashde, Ola M. Al-Sanabra, Moath Alqaraleh, Ahmad Q. Jaradat, Abdullah Saleh Al-Wajeeh, Muhammad Farid Johan, Wan Rohani Wan Taib, Imilia Ismail and Hamid Ali Nagi Al-Jamal
Pharmaceuticals 2023, 16(6), 884; https://doi.org/10.3390/ph16060884 - 15 Jun 2023
Cited by 1 | Viewed by 1956
Abstract
The epigenetic silencing of tumor suppressor genes (TSGs) is critical in the development of chronic myeloid leukemia (CML). SHP-1 functions as a TSG and negatively regulates JAK/STAT signaling. Enhancement of SHP-1 expression by demethylation provides molecular targets for the treatment of various cancers. [...] Read more.
The epigenetic silencing of tumor suppressor genes (TSGs) is critical in the development of chronic myeloid leukemia (CML). SHP-1 functions as a TSG and negatively regulates JAK/STAT signaling. Enhancement of SHP-1 expression by demethylation provides molecular targets for the treatment of various cancers. Thymoquinone (TQ), a constituent of Nigella sativa seeds, has shown anti-cancer activities in various cancers. However, TQs effect on methylation is not fully clear. Therefore, the aim of this study is to assess TQs ability to enhance the expression of SHP-1 through modifying DNA methylation in K562 CML cells. The activities of TQ on cell cycle progression and apoptosis were evaluated using a fluorometric-red cell cycle assay and Annexin V-FITC/PI, respectively. The methylation status of SHP-1 was studied by pyrosequencing analysis. The expression of SHP-1, TET2, WT1, DNMT1, DNMT3A, and DNMT3B was determined using RT-qPCR. The protein phosphorylation of STAT3, STAT5, and JAK2 was assessed using Jess Western analysis. TQ significantly downregulated the DNMT1 gene, DNMT3A gene, and DNMT3B gene and upregulated the WT1 gene and TET2 gene. This led to hypomethylation and restoration of SHP-1 expression, resulting in inhibition of JAK/STAT signaling, induction of apoptosis, and cell cycle arrest. The observed findings imply that TQ promotes apoptosis and cell cycle arrest in CML cells by inhibiting JAK/STAT signaling via restoration of the expression of JAK/STAT-negative regulator genes. Full article
(This article belongs to the Section Natural Products)
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13 pages, 1675 KiB  
Article
Proof-of-Principle Study of Inflammasome Signaling Proteins as Diagnostic Biomarkers of the Inflammatory Response in Parkinson’s Disease
by Erika d. l. R. M. Cabrera Ranaldi, Karen Nuytemans, Anisley Martinez, Corneliu C. Luca, Robert W. Keane and Juan Pablo de Rivero Vaccari
Pharmaceuticals 2023, 16(6), 883; https://doi.org/10.3390/ph16060883 - 15 Jun 2023
Cited by 5 | Viewed by 1289
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder marked by the death of dopaminergic neurons in the midbrain, the accumulation of α-synuclein aggregates, and motor deficits. A major contributor to dopaminergic neuronal loss is neuroinflammation. The inflammasome is a multiprotein complex that perpetuates neuroinflammation [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disorder marked by the death of dopaminergic neurons in the midbrain, the accumulation of α-synuclein aggregates, and motor deficits. A major contributor to dopaminergic neuronal loss is neuroinflammation. The inflammasome is a multiprotein complex that perpetuates neuroinflammation in neurodegenerative disorders including PD. Increases in inflammasome proteins are associated with worsened pathology. Thus, the inhibition of inflammatory mediators has the potential to aid in PD treatment. Here, we investigated inflammasome signaling proteins as potential biomarkers of the inflammatory response in PD. Plasma from PD subjects and healthy age-matched controls were evaluated for levels of the inflammasome protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin (IL)-18. This was carried out using Simple Plex technology to identify changes in inflammasome proteins in the blood of PD subjects. The area under the curve (AUC) was obtained through calculation of the receiver operating characteristics (ROC) to obtain information on biomarker reliability and traits. Additionally, we completed a stepwise regression selected from the lowest Akaike information criterion (AIC) to assess how the inflammasome proteins caspase-1 and ASC contribute to IL-18 levels in people with PD. PD subjects demonstrated elevated caspase-1, ASC, and IL-18 levels when compared to controls; each of these proteins were found to be promising biomarkers of inflammation in PD. Furthermore, inflammasome proteins were determined to significantly contribute to and predict IL-18 levels in subjects with PD. Thus, we demonstrated that inflammasome proteins serve as reliable biomarkers of inflammation in PD and that inflammasome proteins provide significant contributions to IL-18 levels in PD. Full article
(This article belongs to the Special Issue Inflammasomes as the Target of Pharmacotherapy)
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18 pages, 2104 KiB  
Article
Radiochemical and Biological Evaluation of 3p-C-NETA-ePSMA-16, a Promising PSMA-Targeting Agent for Radiotheranostics
by Erika Murce, Stephen Ahenkorah, Savanne Beekman, Maryana Handula, Debra Stuurman, Corrina de Ridder, Frederik Cleeren and Yann Seimbille
Pharmaceuticals 2023, 16(6), 882; https://doi.org/10.3390/ph16060882 - 15 Jun 2023
Viewed by 1443
Abstract
Bifunctional chelators (BFCs) are a key element in the design of radiopharmaceuticals. By selecting a BFC that efficiently complexes diagnostic and therapeutic radionuclides, a theranostic pair possessing almost similar biodistribution and pharmacokinetic properties can be developed. We have previously reported 3p-C-NETA [...] Read more.
Bifunctional chelators (BFCs) are a key element in the design of radiopharmaceuticals. By selecting a BFC that efficiently complexes diagnostic and therapeutic radionuclides, a theranostic pair possessing almost similar biodistribution and pharmacokinetic properties can be developed. We have previously reported 3p-C-NETA as a promising theranostic BFC, and the encouraging preclinical outcomes obtained with [18F]AlF-3p-C-NETA-TATE led us to conjugate this chelator to a PSMA-targeting vector for imaging and treatment of prostate cancer. In this study, we synthesized 3p-C-NETA-ePSMA-16 and radiolabeled it with different diagnostic (111In, 18F) and therapeutic (177Lu, 213Bi) radionuclides. 3p-C-NETA-ePSMA-16 showed high affinity to PSMA (IC50 = 4.61 ± 1.33 nM), and [111In]In-3p-C-NETA-ePSMA-16 showed specific cell uptake (1.41 ± 0.20% ID/106 cells) in PSMA expressing LS174T cells. Specific tumor uptake of [111In]In-3p-C-NETA-ePSMA-16 was observed up to 4 h p.i. (1.62 ± 0.55% ID/g at 1 h p.i.; 0.89 ± 0.58% ID/g at 4 h p.i.) in LS174T tumor-bearing mice. Only a faint signal could be seen at 1 h p.i. in the SPECT/CT scans, whereas dynamic PET/CT scans performed after administration of [18F]AlF-3p-C-NETA-ePSMA-16 in PC3-Pip tumor xenografted mice resulted in a better tumor visualization and imaging contrast. Therapy studies with short-lived radionuclides such as 213Bi could further elucidate the therapeutic potential of 3p-C-NETA-ePSMA-16 as a radiotheranostic. Full article
(This article belongs to the Special Issue Novel Imaging Probes: From Design to Applications)
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56 pages, 9845 KiB  
Review
Phytochemicals as Antimicrobials: Prospecting Himalayan Medicinal Plants as Source of Alternate Medicine to Combat Antimicrobial Resistance
by Mohammad Vikas Ashraf, Shreekar Pant, M. A. Hannan Khan, Ali Asghar Shah, Sazada Siddiqui, Mouna Jeridi, Heba Waheeb Saeed Alhamdi and Shoeb Ahmad
Pharmaceuticals 2023, 16(6), 881; https://doi.org/10.3390/ph16060881 - 15 Jun 2023
Cited by 8 | Viewed by 3375
Abstract
Among all available antimicrobials, antibiotics hold a prime position in the treatment of infectious diseases. However, the emergence of antimicrobial resistance (AMR) has posed a serious threat to the effectiveness of antibiotics, resulting in increased morbidity, mortality, and escalation in healthcare costs causing [...] Read more.
Among all available antimicrobials, antibiotics hold a prime position in the treatment of infectious diseases. However, the emergence of antimicrobial resistance (AMR) has posed a serious threat to the effectiveness of antibiotics, resulting in increased morbidity, mortality, and escalation in healthcare costs causing a global health crisis. The overuse and misuse of antibiotics in global healthcare setups have accelerated the development and spread of AMR, leading to the emergence of multidrug-resistant (MDR) pathogens, which further limits treatment options. This creates a critical need to explore alternative approaches to combat bacterial infections. Phytochemicals have gained attention as a potential source of alternative medicine to address the challenge of AMR. Phytochemicals are structurally and functionally diverse and have multitarget antimicrobial effects, disrupting essential cellular activities. Given the promising results of plant-based antimicrobials, coupled with the slow discovery of novel antibiotics, it has become highly imperative to explore the vast repository of phytocompounds to overcome the looming catastrophe of AMR. This review summarizes the emergence of AMR towards existing antibiotics and potent phytochemicals having antimicrobial activities, along with a comprehensive overview of 123 Himalayan medicinal plants reported to possess antimicrobial phytocompounds, thus compiling the existing information that will help researchers in the exploration of phytochemicals to combat AMR. Full article
(This article belongs to the Special Issue Small Molecules as Antimicrobials 2022)
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20 pages, 2379 KiB  
Article
Molecular Multi-Target Approach for Human Acetylcholinesterase, Butyrylcholinesterase and β-Secretase 1: Next Generation for Alzheimer’s Disease Treatment
by Géssica Oliveira Mendes, Samuel Silva da Rocha Pita, Paulo Batista de Carvalho, Michel Pires da Silva, Alex Gutterres Taranto and Franco Henrique Andrade Leite
Pharmaceuticals 2023, 16(6), 880; https://doi.org/10.3390/ph16060880 - 15 Jun 2023
Cited by 1 | Viewed by 1400
Abstract
Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect and being incapable of stopping or [...] Read more.
Alzheimer’s Disease (AD) is a neurodegenerative condition characterized by progressive memory loss and other affected cognitive functions. Pharmacological therapy of AD relies on inhibitors of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), offering only a palliative effect and being incapable of stopping or reversing the neurodegenerative process. However, recent studies have shown that inhibiting the enzyme β-secretase 1 (BACE-1) may be able to stop neurodegeneration, making it a promising target. Considering these three enzymatic targets, it becomes feasible to apply computational techniques to guide the identification and planning of molecules capable of binding to all of them. After virtually screening 2119 molecules from a library, 13 hybrids were built and further screened by triple pharmacophoric model, molecular docking, and molecular dynamics (t = 200 ns). The selected hybrid G meets all stereo-electronic requirements to bind to AChE, BChE, and BACE-1 and offers a promising structure for future synthesis, enzymatic testing, and validation. Full article
(This article belongs to the Special Issue New Perspectives on Chemoinformatics and Drug Design)
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24 pages, 3259 KiB  
Article
Discovery of a New Chalcone-Trimethoxycinnamide Hybrid with Antimitotic Effect: Design, Synthesis, and Structure—Activity Relationship Studies
by Joana Moreira, Patrícia M. A. Silva, Matilde Barros, Lucília Saraiva, Madalena Pinto, Hassan Bousbaa and Honorina Cidade
Pharmaceuticals 2023, 16(6), 879; https://doi.org/10.3390/ph16060879 - 14 Jun 2023
Viewed by 1461
Abstract
In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (7) based on the combination of subunits of two promising antiproliferative compounds (CM-M345 (1) and BP-M345 (2)), previously obtained by our research group, are [...] Read more.
In this work, the design and synthesis of a new chalcone-trimethoxycinnamide hybrid (7) based on the combination of subunits of two promising antiproliferative compounds (CM-M345 (1) and BP-M345 (2)), previously obtained by our research group, are reported. In order to expand the structure–activity relationship (SAR) knowledge, a new series of 7-analogues was also designed and synthetized. All the compounds were evaluated for their antitumor activity against melanoma (A375-C5), breast adenocarcinoma (MCF-7), and colorectal carcinoma (HCT116) cell lines, as well as non-tumor HPAEpiC cells. Three of the newly synthesized compounds (6, 7, and 13) exhibited potent antiproliferative activity, mainly on colorectal tumor cells (GI50 = 2.66–3.26 μM), showing hybrid 7 selectivity for tumor cells. We performed molecular mechanism studies to evaluate the potential interference of compounds with the p53 pathway, namely, p53–MDM2 interaction and mitosis in HCT116 cells. The antiproliferative activities of compounds were shown to be p53-independent. Compound 7 emerged as an antimitotic agent by inducing the mitotic arrest of colorectal tumor cells, and subsequently, cell death. Full article
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15 pages, 12226 KiB  
Article
Annona muricata Leaf as an Anti-Cryptosporidial Agent: An In Silico Molecular Docking Analysis and In Vivo Studies
by Eman S. El-Wakil, Hagar F. Abdelmaksoud, Majed H. Wakid, Muslimah N. Alsulami, Olfat Hammam, Haleema H. Albohiri and Marwa M. I. Ghallab
Pharmaceuticals 2023, 16(6), 878; https://doi.org/10.3390/ph16060878 - 14 Jun 2023
Cited by 1 | Viewed by 1188
Abstract
Cryptosporidiosis is a serious parasitic diarrheal disease linked to the occurrence of colorectal cancer in immunocompromised patients. The FDA-approved drug nitazoxanide (NTZ) achieved a temporary effect, and relapses occur. Annona muricata leaf is widely used in traditional medicine to treat a wide range [...] Read more.
Cryptosporidiosis is a serious parasitic diarrheal disease linked to the occurrence of colorectal cancer in immunocompromised patients. The FDA-approved drug nitazoxanide (NTZ) achieved a temporary effect, and relapses occur. Annona muricata leaf is widely used in traditional medicine to treat a wide range of disorders, including antiparasitic and anticancer effects. So, this study aimed to investigate Annona muricata leaf antiparasitic and anticancer properties compared to NTZ in Cryptosporidium parvum (C. parvum) acutely and chronically infected immunosuppressed mice. A molecular docking analysis was performed to evaluate the effectiveness of some biologically active compounds that represented the pharmacological properties of Annona muricata leaf-rich extract toward C. parvum lactate dehydrogenase compared to NTZ. For the in vivo study, eighty immunosuppressed albino mice were classified into four groups as follows: group I: infected and treated with A. muricata; group II: infected and treated with nitazoxanide; group III: infected and received no treatment; and group IV: were neither infected nor treated. Furthermore, half of the mice in groups I and II received the drugs on the 10th day post-infection (dpi), and the other half received treatment on the 90th day post-infection. Parasitological, histopathological, and immunohistochemical evaluations were performed. The docking analysis showed that the lowest estimated free energy of binding of annonacin, casuarine, L-epigallocatechin, P-coumaric acid, and ellagic acid toward C. parvum LDH, were −6.11, −6.32, −7.51, −7.81, and −9.64 kcal/mol, respectively, while NTZ was −7.03 kcal/mol. Parasitological examination displayed a significantly high difference in C. parvum oocyst mean counts in groups I and II compared to group III (p-value < 0.001), with group I demonstrating the highest efficacy. The analyses of histopathological and immunohistochemical results revealed that group I showed restoration of the normal villous pattern without evidence of dysplasia or malignancy. A. muricata leaf has proved to be a reliable agent for Cryptosporidium treatment. This paper argues for its promising use as an antiparasitic agent and for the prevention of neoplastic sequels of Cryptosporidium infection. Full article
(This article belongs to the Special Issue Drug Discovery of Antiprotozoal Agents)
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