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Pharmaceuticals, Volume 16, Issue 4 (April 2023) – 159 articles

Cover Story (view full-size image): With the increasing prevalence of obesity, the incidence of metabolic syndrome, a cluster of clinical manifestations such as insulin resistance, visceral adiposity and dyslipidemia, has increased dramatically. Adipose tissues (ATs) are dynamic tissues that play crucial physiological roles in maintaining health and metabolic homeostasis. Thyroid hormones (THs) and some of their derivatives, such as 3,5-diiodo-l-thyronine (T2), exert numerous effects in adipose tissues. In overweight rats, these effects include the induction of browning, changes in adipocyte morphology, tissue vascularization and the adipose inflammatory state. In this manuscript, we summarize the mechanism by which THs and thyroid hormone derivatives mediate adipose tissue activity and remodeling. View this paper
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21 pages, 422 KiB  
Review
Pharmacological Mechanism of Ketamine in Suicidal Behavior Based on Animal Models of Aggressiveness and Impulsivity: A Narrative Review
by Thi Mai Loan Nguyen, Fabrice Jollant, Laurent Tritschler, Romain Colle, Emmanuelle Corruble and Alain M. Gardier
Pharmaceuticals 2023, 16(4), 634; https://doi.org/10.3390/ph16040634 - 21 Apr 2023
Cited by 4 | Viewed by 2245
Abstract
Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures [...] Read more.
Around 700,000 people die from suicide each year in the world. Approximately 90% of suicides have a history of mental illness, and more than two-thirds occur during a major depressive episode. Specific therapeutic options to manage the suicidal crisis are limited and measures to prevent acting out also remain limited. Drugs shown to reduce the risk of suicide (antidepressants, lithium, or clozapine) necessitate a long delay of onset. To date, no treatment is indicated for the treatment of suicidality. Ketamine, a glutamate NMDA receptor antagonist, is a fast-acting antidepressant with significant effects on suicidal ideation in the short term, while its effects on suicidal acts still need to be demonstrated. In the present article, we reviewed the literature on preclinical studies in order to identify the potential anti-suicidal pharmacological targets of ketamine. Impulsive–aggressive traits are one of the vulnerability factors common to suicide in patients with unipolar and bipolar depression. Preclinical studies in rodent models with impulsivity, aggressiveness, and anhedonia may help to analyze, at least in part, suicide neurobiology, as well as the beneficial effects of ketamine/esketamine on reducing suicidal ideations and preventing suicidal acts. The present review focuses on disruptions in the serotonergic system (5-HTB receptor, MAO-A enzyme), neuroinflammation, and/or the HPA axis in rodent models with an impulsive/aggressive phenotype, because these traits are critical risk factors for suicide in humans. Ketamine can modulate these endophenotypes of suicide in human as well as in animal models. The main pharmacological properties of ketamine are then summarized. Finally, numerous questions arose regarding the mechanisms by which ketamine may prevent an impulsive–aggressive phenotype in rodents and suicidal ideations in humans. Animal models of anxiety/depression are important tools to better understand the pathophysiology of depressed patients, and in helping develop novel and fast antidepressant drugs with anti-suicidal properties and clinical utility. Full article
(This article belongs to the Special Issue Ketamine and Ketamine Metabolite Pharmacology)
10 pages, 313 KiB  
Article
Efficacy of Mentha aquatica L. Essential Oil (Linalool/Linalool Acetate Chemotype) against Insect Vectors and Agricultural Pests
by Marta Ferrati, Eleonora Spinozzi, Cecilia Baldassarri, Filippo Maggi, Roman Pavela, Angelo Canale, Riccardo Petrelli and Loredana Cappellacci
Pharmaceuticals 2023, 16(4), 633; https://doi.org/10.3390/ph16040633 - 21 Apr 2023
Viewed by 1666
Abstract
In recent years, agrochemical industries have been focused on the development of essential oil (EO)-based biopesticides, which can be considered valuable alternatives to traditional chemical products. The genus Mentha (Lamiaceae) comprises 30 species characterized by a wide range of biological activities, and some [...] Read more.
In recent years, agrochemical industries have been focused on the development of essential oil (EO)-based biopesticides, which can be considered valuable alternatives to traditional chemical products. The genus Mentha (Lamiaceae) comprises 30 species characterized by a wide range of biological activities, and some of their EOs showed good potential as pesticidal agents. In this regard, the aim of this study was to evaluate the insecticidal activity of the EO obtained from a rare linalool/linalool acetate chemotype of Mentha aquatica L. The EO was found to be highly effective against Culex quinquefasciatus (Say) 2nd instar larvae, Metopolophium dirhodum (Walker) adults, Spodoptera littoralis (Boisduval) 2nd instar larvae, and Tetranychus urticae (Koch) adults, showing lethal concentrations (LC50) or doses (LD50) of 31.5 ± 2.2 µL L−1, 4.9 ± 0.8 mL L−1, 18.5 ± 2.1 µg larvae−1, and 3.3 ± 0.5 mL L−1, respectively. On the contrary, Musca domestica L. adults and 3rd instar larvae of C. quinquefasciatus and S. littoralis were moderately affected by the treatment (LC50 or LD50: 71.4 ± 7.2 µg adult−1, 79.4 ± 5.2 µL L−1, 44.2 ± 5.8 µg larvae−1, respectively). The results obtained in this work demonstrated that various insects and pests could be differently sensible to the same EO and may lead to the exploitation of this plant or its major volatile compounds as novel ingredients of botanical insecticides and pesticides. Full article
(This article belongs to the Section Natural Products)
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17 pages, 4097 KiB  
Article
The First Anti-Snakebite and Hepatoprotective Characterization of a Trypsin Kunitz-like Inhibitor (EcTI) from the Plant Enterolobium contortisiliquum; A Case of Two Soul Mates Meeting
by Caroline R. C. Costa, Mariana N. Belchor, Airam Roggero, Laila L. Moraes, Ricardo Samelo, Isabelly Annunciato, Camila R. Bonturi, Maria L. V. Oliva, Sergio F. Sousa, Marcos A. de Oliveira and Marcos H. Toyama
Pharmaceuticals 2023, 16(4), 632; https://doi.org/10.3390/ph16040632 - 21 Apr 2023
Viewed by 1470
Abstract
Snake venom serine protease (SVSP) interferes with the regulation and control of important biological reactions in homeostasis and can be classified as an activator of the fibrinolytic system and platelet aggregation. Our group has recently isolated a new serine protease from Crotalus durissus [...] Read more.
Snake venom serine protease (SVSP) interferes with the regulation and control of important biological reactions in homeostasis and can be classified as an activator of the fibrinolytic system and platelet aggregation. Our group has recently isolated a new serine protease from Crotalus durissus terrificus total venom (Cdtsp-2). This protein exhibits edematogenic capacity and myotoxic activity. A Kunitz-like EcTI inhibitor protein with a molecular mass of 20 kDa was isolated from Enterolobium contortisiliquum and showed high trypsin inhibition. Thus, the objective of this work is to verify the possible inhibition of the pharmacological activities of Cdtsp-2 by the Kutinz-type inhibitor EcTI. To isolate Cdtsp-2 from total C. d. terrificus venom, we used three-step chromatographic HPLC. Using the mice paw edema model, we observed an edematogenic effect, myotoxicity and hepatotoxicity caused by Cdtsp-2. In vitro and in vivo experiments showed that the alterations in hemostasis caused by Cdtsp-2 are crucial for the development of marked hepatotoxicity and that EcTI significantly inhibits the enzymatic and pharmacological activities of Cdtsp-2. Kunitz-like inhibitor may be a viable alternative for the development of ancillary treatments against the biological activities of venoms. Full article
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13 pages, 1248 KiB  
Article
Pentoxifylline Effects on Hospitalized COVID-19 Patients with Cytokine Storm Syndrome: A Randomized Clinical Trial
by Rania M. Sarhan, Ahmed E. Altyar, Ahmed Essam Abou Warda, Yasmine Mohamed Saied, Haytham Soliman Ghareeb Ibrahim, Mona F. Schaalan, Shaimaa Fathy, Neven Sarhan and Marian S. Boshra
Pharmaceuticals 2023, 16(4), 631; https://doi.org/10.3390/ph16040631 - 21 Apr 2023
Cited by 1 | Viewed by 2708
Abstract
COVID-19 is a fatal, fast-spreading pandemic, and numerous attempts are being made around the world to understand and manage the disease. COVID-19 patients may develop a cytokine-release syndrome, which causes serious respiratory diseases and, in many cases, death. The study examined the feasibility [...] Read more.
COVID-19 is a fatal, fast-spreading pandemic, and numerous attempts are being made around the world to understand and manage the disease. COVID-19 patients may develop a cytokine-release syndrome, which causes serious respiratory diseases and, in many cases, death. The study examined the feasibility of employing legally available anti-inflammatory pentoxifylline (PTX), a low toxicity and cost medication, to mitigate the hyper-inflammation caused by COVID-19. Thirty adult patients who tested positive for SARS-CoV2 were hospitalized owing to the cytokine storm syndrome. They were given 400 mg of pentoxifylline orally TID according to the standard COVID-19 protocol of the Egyptian Ministry of Health. Besides this, a group of thirty-eight hospitalized COVID-19 patients who received the standard COVID-19 protocol was included in the study as a control group. The outcomes included laboratory test parameters, clinical improvements, and number of deaths in both groups. After receiving PTX, all patients showed a significant improvement in C reactive protein (CRP), and interleukin-6 (IL-6) levels at p < 0.01 and p = 0.004, respectively, while there was an increase in total leukocyte count (TLC) and neutrophil-to-leucocyte ratio (NLR) at p < 0.01 compared to their baseline levels. The D-dimer level showed a significant increase in the treatment group at p < 0.01, while showing no statistically significant difference in the control group. The median initial ALT (42 U/L) in the treatment group showed a decrease compared to the control group (51 U/L). No statistical significance was reported regarding clinical improvement, length of stay, and death percentages between the two groups. Our results showed no significant improvement of PTX over controls in clinical outcomes of hospitalized COVID-19 patients. Nevertheless, PTX displayed a positive effect on certain inflammatory biomarkers. Full article
(This article belongs to the Section Pharmacology)
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11 pages, 730 KiB  
Article
Effectiveness and Safety Profile of Dupilumab in Chronic Rhinosinusitis with Nasal Polyps: Real-Life Data in Tertiary Care
by Cosimo Galletti, Maria Antonietta Barbieri, Francesco Ciodaro, Francesco Freni, Francesco Galletti, Edoardo Spina and Bruno Galletti
Pharmaceuticals 2023, 16(4), 630; https://doi.org/10.3390/ph16040630 - 21 Apr 2023
Cited by 9 | Viewed by 3168
Abstract
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines. Dupilumab radically changes the treatment of CRSwNP, but, considering its recent approval, it may be useful to evaluate its safety profile [...] Read more.
Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a type 2 pattern of inflammation resulting in the production of some cytokines. Dupilumab radically changes the treatment of CRSwNP, but, considering its recent approval, it may be useful to evaluate its safety profile in a real-world setting. This work aimed to prospectively highlight the effectiveness and safety profile of dupilumab in patients with CRSwNP enrolled in the Otorhinolaryngology Unit of the University Hospital of Messina. An observational cohort study was carried out considering all patients treated with dupilumab. A descriptive analysis was conducted reporting all demographic characteristics, endoscopic evaluations, and symptom conditions. A total of 66 patients were treated with dupilumab, but three patients were excluded due to a lack of adherence during the observational period. A statistically significant reduction in the Sino-Nasal Outcome Test 22 (SNOT-22) and nasal polyps score (NPS) was shown at the 6th and 12th months compared to baseline values (SNOT-22, −37 and −50, p < 0.001 for both comparisons; NPS, −3 and −4, p < 0.001 for both comparisons). During the follow-up, eight patients (12.7%) had a reaction at the site of injection, and seven (11.1%) had transient hypereosinophilia. Given the optimal treatment response and the minimal adverse effects observed, clinicians should consider dupilumab a safe and effective treatment. Further studies are necessary to better understand the long-term effects. Full article
(This article belongs to the Special Issue Drug Safety and Relevant Issues in the Real-World)
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14 pages, 3413 KiB  
Article
Clinical Confirmation of Pan-Amyloid Reactivity of Radioiodinated Peptide 124I-p5+14 (AT-01) in Patients with Diverse Types of Systemic Amyloidosis Demonstrated by PET/CT Imaging
by Emily B. Martin, Alan Stuckey, Dustin Powell, Ronald Lands, Bryan Whittle, Craig Wooliver, Sallie Macy, James S. Foster, Spencer Guthrie, Stephen J. Kennel and Jonathan S. Wall
Pharmaceuticals 2023, 16(4), 629; https://doi.org/10.3390/ph16040629 - 21 Apr 2023
Cited by 8 | Viewed by 1547
Abstract
There are at least 20 distinct types of systemic amyloidosis, all of which result in the organ-compromising accumulation of extracellular amyloid deposits. Amyloidosis is challenging to diagnose due to the heterogeneity of the clinical presentation, yet early detection is critical for favorable patient [...] Read more.
There are at least 20 distinct types of systemic amyloidosis, all of which result in the organ-compromising accumulation of extracellular amyloid deposits. Amyloidosis is challenging to diagnose due to the heterogeneity of the clinical presentation, yet early detection is critical for favorable patient outcomes. The ability to non-invasively and quantitatively detect amyloid throughout the body, even in at-risk populations, before clinical manifestation would be invaluable. To this end, a pan-amyloid-reactive peptide, p5+14, has been developed that is capable of binding all types of amyloid. Herein, we demonstrate the ex vivo pan-amyloid reactivity of p5+14 by using peptide histochemistry on animal and human tissue sections containing various types of amyloid. Furthermore, we present clinical evidence of pan-amyloid binding using iodine-124-labeled p5+14 in a cohort of patients with eight (n = 8) different types of systemic amyloidosis. These patients underwent PET/CT imaging as part of the first-in-human Phase 1/2 clinical trial evaluating this radiotracer (NCT03678259). The uptake of 124I-p5+14 was observed in abdominothoracic organs in patients with all types of amyloidosis evaluated and was consistent with the disease distribution described in the medical record and literature reports. On the other hand, the distribution in healthy subjects was consistent with radiotracer catabolism and clearance. The early and accurate diagnosis of amyloidosis remains challenging. These data support the utility of 124I-p5+14 for the diagnosis of varied types of systemic amyloidosis by PET/CT imaging. Full article
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12 pages, 8861 KiB  
Article
The Effects of Prolonged Treatment with Cemtirestat on Bone Parameters Reflecting Bone Quality in Non-Diabetic and Streptozotocin-Induced Diabetic Rats
by Monika Martiniakova, Veronika Kovacova, Vladimira Mondockova, Karol Svik, Piotr Londzin, Joanna Folwarczna, Marta Soltesova Prnova, Milan Stefek and Radoslav Omelka
Pharmaceuticals 2023, 16(4), 628; https://doi.org/10.3390/ph16040628 - 21 Apr 2023
Cited by 3 | Viewed by 1559
Abstract
Cemtirestat, a bifunctional drug acting as an aldose reductase inhibitor with antioxidant ability, is considered a promising candidate for the treatment of diabetic neuropathy. Our study firstly examined the effects of prolonged cemtirestat treatment on bone parameters reflecting bone quality in non-diabetic rats [...] Read more.
Cemtirestat, a bifunctional drug acting as an aldose reductase inhibitor with antioxidant ability, is considered a promising candidate for the treatment of diabetic neuropathy. Our study firstly examined the effects of prolonged cemtirestat treatment on bone parameters reflecting bone quality in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Experimental animals were assigned to four groups: non-diabetic rats, non-diabetic rats treated with cemtirestat, diabetic rats, and diabetic rats treated with cemtirestat. Higher levels of plasma glucose, triglycerides, cholesterol, glycated hemoglobin, magnesium, reduced femoral weight and length, bone mineral density and content, parameters characterizing trabecular bone mass and microarchitecture, cortical microarchitecture and geometry, and bone mechanical properties were determined in STZ-induced diabetic versus non-diabetic rats. Treatment with cemtirestat did not affect all aforementioned parameters in non-diabetic animals, suggesting that this drug is safe. In diabetic rats, cemtirestat supplementation reduced plasma triglyceride levels, increased the Haversian canal area and slightly, but insignificantly, improved bone mineral content. Nevertheless, the insufficient effect of cemtirestat treatment on diabetic bone disease does not support its use in the therapy of this complication of type 1 diabetes mellitus. Full article
(This article belongs to the Special Issue Therapeutic Targets for Diabetes and Associated Complications)
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14 pages, 5637 KiB  
Article
Fabrication and Characterization of Oxygen-Generating Polylactic Acid/Calcium Peroxide Composite Filaments for Bone Scaffolds
by Abdullah Mohammed, Abdu Saeed, Amr Elshaer, Ammar A. Melaibari, Adnan Memić, Hany Hassanin and Khamis Essa
Pharmaceuticals 2023, 16(4), 627; https://doi.org/10.3390/ph16040627 - 20 Apr 2023
Cited by 3 | Viewed by 1826
Abstract
The latest advancements in bone scaffold technology have introduced novel biomaterials that have the ability to generate oxygen when implanted, improving cell viability and tissue maturation. In this paper, we present a new oxygen-generating polylactic acid (PLA)/calcium peroxide (CPO) composite filament that can [...] Read more.
The latest advancements in bone scaffold technology have introduced novel biomaterials that have the ability to generate oxygen when implanted, improving cell viability and tissue maturation. In this paper, we present a new oxygen-generating polylactic acid (PLA)/calcium peroxide (CPO) composite filament that can be used in 3D printing scaffolds. The composite material was prepared using a wet solution mixing method, followed by drying and hot melting extrusion. The concentration of calcium peroxide in the composite varied from 0% to 9%. The prepared filaments were characterized in terms of the presence of calcium peroxide, the generated oxygen release, porosity, and antibacterial activities. Data obtained from scanning electron microscopy and X-ray diffraction showed that the calcium peroxide remained stable in the composite. The maximum calcium and oxygen release was observed in filaments with a 6% calcium peroxide content. In addition, bacterial inhibition was achieved in samples with a calcium peroxide content of 6% or higher. These results indicate that an optimized PLA filament with a 6% calcium peroxide content holds great promise for improving bone generation through bone cell oxygenation and resistance to bacterial infections. Full article
(This article belongs to the Special Issue 3D Printing of Drug Formulations)
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13 pages, 1315 KiB  
Article
Examination of Risk Factors and Expression Patterns of Atypical Femoral Fractures Using the Japanese Adverse Drug Event Report Database: A Retrospective Pharmacovigilance Study
by Shinya Toriumi, Ryuji Mimori, Haruhiko Sakamoto, Hitoshi Sueki, Munehiro Yamamoto and Yoshihiro Uesawa
Pharmaceuticals 2023, 16(4), 626; https://doi.org/10.3390/ph16040626 - 20 Apr 2023
Cited by 1 | Viewed by 1800
Abstract
Atypical femoral fracture (AFF) is a rare complication related to the use of bisphosphonates (BPs). Herein, we analyzed the risk factors and onset patterns of AFF using the Japanese Adverse Drug Event Report database and reported the findings. First, the independent risk factors [...] Read more.
Atypical femoral fracture (AFF) is a rare complication related to the use of bisphosphonates (BPs). Herein, we analyzed the risk factors and onset patterns of AFF using the Japanese Adverse Drug Event Report database and reported the findings. First, the independent risk factors for AFF were gender (female), high body mass index, and medical history of osteoporosis, arthritis, and systemic lupus erythematosus (SLE). Drug-related risk factors for AFF included BPs (i.e., alendronic acid, ibandronic acid, etidronic acid, zoledronic acid, minodronic acid, risedronic acid), denosumab, prednisolone, lansoprazole, rabeprazole, exemestane, letrozole, eldecalcitol, and menatetrenone. Therefore, it appears that AFF is influenced by a combination of patient backgrounds and drugs, and that the risk of developing AFF is particularly high in patients with fragile bones (e.g., osteoporosis, arthritis, and SLE). Second, in the analysis of AFF onset patterns, the onset of AFF from BPs and denosumab took a long time (>1 year) to develop. Analysis using a Weibull distribution showed wear-out failure-type AFF onset for BPs and denosumab, and both osteoporosis and cancer patients with long-term administration of these drugs showed a tendency to have an increased risk of onset. AFF developed earlier in osteoporosis patients with long-term administration of BPs and denosumab than in cancer patients. Full article
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14 pages, 585 KiB  
Protocol
Extensive CArdioVAscular Characterization and Follow-Up of Patients Receiving Immune Checkpoint Inhibitors: A Prospective Multicenter Study
by Danielle Delombaerde, Johan De Sutter, Lieselot Croes, Delphine Vervloet, Veronique Moerman, Nico Van de Veire, Anne-Marie Willems, Kristien Wouters, Marc Peeters, Hans Prenen and Christof Vulsteke
Pharmaceuticals 2023, 16(4), 625; https://doi.org/10.3390/ph16040625 - 20 Apr 2023
Cited by 1 | Viewed by 1773
Abstract
Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based [...] Read more.
Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based on anecdotal evidence and expert opinions, due to a lack of solid data and prospective studies. As many questions remain unanswered, cardiac monitoring, in patients receiving ICIs, is not always implemented by oncologists. Hence, an urgent need to investigate the possible short- and long-term CV effects of ICIs, as ICI approval is continuing to expand to the (neo)adjuvant setting. Methods: We have initiated a prospective, multicenter study, i.e., the CAVACI trial, in which a minimum of 276 patients with a solid tumor, eligible for ICI treatment, will be enrolled. The study consists of routine investigations of blood parameters (troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, in particular) and a thorough CV follow-up (electrocardiograms, transthoracic echocardiograms, and coronary calcium scoring) at fixed time points for a total period of two years. The primary endpoint is the cumulative incidence of troponin elevation in the first three months of ICI treatment, compared to baseline levels. Furthermore, secondary endpoints include incidence above the upper limit of normal of both troponin and NT-proBNP levels, evolution in troponin and NT-proBNP levels, the incidence of CV abnormalities/major adverse cardiac events, evaluation of associations between patient characteristics/biochemical parameters and CV events, transthoracic echocardiography parameters, electrocardiography parameters, and progression of coronary atherosclerosis. Recruitment of patients started in January 2022. Enrolment is ongoing in AZ Maria Middelares, Antwerp University Hospital, AZ Sint-Vincentius Deinze, and AZ Sint-Elisabeth Zottegem. Trial registration: ClinicalTrials.gov Identifier: NCT05699915, registered 26 January 2023. Full article
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12 pages, 1613 KiB  
Article
rAAV2-Mediated Restoration of GALC in Neural Stem Cells from Krabbe Patient-Derived iPSCs
by Guoshuai Tian, Chunyu Cao, Shuyue Li, Wei Wang, Ye Zhang and Yafeng Lv
Pharmaceuticals 2023, 16(4), 624; https://doi.org/10.3390/ph16040624 - 20 Apr 2023
Cited by 3 | Viewed by 1617
Abstract
Krabbe disease is a rare neurodegenerative fatal disease. It is caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which results in progressive accumulation of galactolipid substrates in myelin-forming cells. However, there is still a lack of appropriate neural models and effective approaches [...] Read more.
Krabbe disease is a rare neurodegenerative fatal disease. It is caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which results in progressive accumulation of galactolipid substrates in myelin-forming cells. However, there is still a lack of appropriate neural models and effective approaches for Krabbe disease. We generated induced pluripotent stem cells (iPSCs) from a Krabbe patient previously. Here, Krabbe patient-derived neural stem cells (K-NSCs) were induced from these iPSCs. By using nine kinds of recombinant adeno-associated virus (rAAV) vectors to infect K-NSCs, we found that the rAAV2 vector has high transduction efficiency for K-NSCs. Most importantly, rAAV2-GALC rescued GALC enzymatic activity in K-NSCs. Our findings not only establish a novel patient NSC model for Krabbe disease, but also firstly indicate the potential of rAAV2-mediated gene therapy for this devastating disease. Full article
(This article belongs to the Special Issue AdV and AAV Mediated Gene Delivery)
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12 pages, 1710 KiB  
Article
A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of ALS-L1023 in Non-Alcoholic Fatty Liver Disease
by Gi-Ae Kim, Hyun Chin Cho, Soung Won Jeong, Bo-Kyeong Kang, Mimi Kim, Seungwon Jung, Jungwook Hwang, Eileen L. Yoon and Dae Won Jun
Pharmaceuticals 2023, 16(4), 623; https://doi.org/10.3390/ph16040623 - 20 Apr 2023
Cited by 1 | Viewed by 1453
Abstract
Preclinical data have shown that the herbal extract, ALS-L1023, from Melissa officinalis reduces visceral fat and hepatic steatosis. We aimed to assess the safety and efficacy of ALS-L1023 as the treatment of non-alcoholic fatty liver disease (NAFLD). We conducted a 24-week randomized, double-blind, [...] Read more.
Preclinical data have shown that the herbal extract, ALS-L1023, from Melissa officinalis reduces visceral fat and hepatic steatosis. We aimed to assess the safety and efficacy of ALS-L1023 as the treatment of non-alcoholic fatty liver disease (NAFLD). We conducted a 24-week randomized, double-blind, placebo-controlled 2a study in patients with NAFLD (MRI-proton density fat fraction [MRI-PDFF] ≥ 8% and liver fibrosis ≥ 2.5 kPa on MR elastography [MRE]) in Korea. Patients were randomly assigned to 1800 mg ALS-L1023 (n = 19), 1200 mg ALS-L1023 (n = 21), or placebo (n = 17) groups. Efficacy endpoints included changes in liver fat on MRI-PDFF, liver stiffness on MRE, and liver enzymes. For the full analysis set, a relative hepatic fat reduction from baseline was significant in the 1800 mg ALS-L1023 group (−15.0%, p = 0.03). There was a significant reduction in liver stiffness from baseline in the 1200 mg ALS-L1023 group (−10.7%, p = 0.03). Serum alanine aminotransferase decreased by −12.4% in the 1800 mg ALS-L1023 group, −29.8% in the 1200 mg ALS-L1023 group, and −4.9% in the placebo group. ALS-L1023 was well tolerated and there were no differences in the incidence of adverse events among the study groups. ALS-L1023 could reduce hepatic fat content in patients with NAFLD. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 3724 KiB  
Article
Multitargeted Virtual Screening and Molecular Simulation of Natural Product-like Compounds against GSK3β, NMDA-Receptor, and BACE-1 for the Management of Alzheimer’s Disease
by Danish Iqbal, Md Tabish Rehman, Mohamed F. Alajmi, Mohammed Alsaweed, Qazi Mohammad Sajid Jamal, Sharifa M. Alasiry, Awatif B. Albaker, Munerah Hamed, Mehnaz Kamal and Hind Muteb Albadrani
Pharmaceuticals 2023, 16(4), 622; https://doi.org/10.3390/ph16040622 - 20 Apr 2023
Cited by 4 | Viewed by 2131
Abstract
The complexity of Alzheimer’s disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3β, NMDA receptor, and BACE-1 [...] Read more.
The complexity of Alzheimer’s disease (AD) and several side effects of currently available medication inclined us to search for a novel natural cure by targeting multiple key regulatory proteins. We initially virtually screened the natural product-like compounds against GSK3β, NMDA receptor, and BACE-1 and thereafter validated the best hit through molecular dynamics simulation (MDS). The results demonstrated that out of 2029 compounds, only 51 compounds exhibited better binding interactions than native ligands, with all three protein targets (NMDA, GSK3β, and BACE) considered multitarget inhibitors. Among them, F1094-0201 is the most potent inhibitor against multiple targets with binding energy −11.7, −10.6, and −12 kcal/mol, respectively. ADME-T analysis results showed that F1094-0201 was found to be suitable for CNS drug-likeness in addition to their other drug-likeness properties. The MDS results of RMSD, RMSF, Rg, SASA, SSE and residue interactions indicated the formation of a strong and stable association in the complex of ligands (F1094-0201) and proteins. These findings confirm the F1094-0201’s ability to remain inside target proteins’ binding pockets while forming a stable complex of protein-ligand. The free energies (MM/GBSA) of BACE-F1094-0201, GSK3β-F1094-0201, and NMDA-F1094-0201 complex formation were −73.78 ± 4.31 kcal mol−1, −72.77 ± 3.43 kcal mol−1, and −52.51 ± 2.85 kcal mol−1, respectively. Amongst the target proteins, F1094-0201 have a more stable association with BACE, followed by NMDA and GSK3β. These attributes of F1094-0201 indicate it as a possible option for the management of pathophysiological pathways associated with AD. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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21 pages, 14097 KiB  
Article
Oleoylethanolamide Protects against Acute Ischemic Stroke by Promoting PPARα-Mediated Microglia/Macrophage M2 Polarization
by Ying Li, Yanan Zhang, Qing Wang, Chuang Wu, Guicheng Du and Lichao Yang
Pharmaceuticals 2023, 16(4), 621; https://doi.org/10.3390/ph16040621 - 20 Apr 2023
Cited by 2 | Viewed by 1740
Abstract
Oleoylethanolamide (OEA) has been demonstrated to be a feasible protectant in ischemic stroke. However, the mechanism for OEA-afforded neuroprotection remains elusive. The present study aimed to investigate the neuroprotective effects of OEA on peroxisome proliferator-activated receptor α (PPARα)-mediated microglia M2 polarization after cerebral [...] Read more.
Oleoylethanolamide (OEA) has been demonstrated to be a feasible protectant in ischemic stroke. However, the mechanism for OEA-afforded neuroprotection remains elusive. The present study aimed to investigate the neuroprotective effects of OEA on peroxisome proliferator-activated receptor α (PPARα)-mediated microglia M2 polarization after cerebral ischemia. Transient middle cerebral artery occlusion (tMCAO) was induced for 1 h in wild-type (WT) or PPARα-knock-out (KO) mice. Mouse small glioma cells (BV2) microglia and primary microglia cultures were used to evaluate the direct effect of OEA on microglia. A coculture system was used to further elucidate the effect of OEA on microglial polarization and ischemic neurons’ fate. OEA promoted the microglia switch from an inflammatory M1 phenotype to the protective M2 phenotype and enhanced the binding of PPARα with the arginase1 (Arg1) and Ym1 promoter in WT mice but not in KO mice after MCAO. Notably, the increased M2 microglia caused by OEA treatment were strongly linked to neuron survival after ischemic stroke. In vitro studies confirmed that OEA shifted BV2 microglia from (lipopolysaccharide) LPS-induced M1-like to M2-like phenotype through PPARα. Additionally, the activation of PPARα in primary microglia by OEA led to an M2 protective phenotype that enhanced neuronal survival against oxygen-glucose deprivation (OGD) in the coculture systems. Our findings demonstrate the novel effects of OEA in enhancing microglia M2 polarization to protect neighboring neurons by activating the PPARα signal, which is a new mechanism of OEA against cerebral ischemic injury. Therefore, OEA might be a promising therapeutic drug for stroke and targeting PPARα-mediated M2 microglia may represent a new strategy to treat ischemic stroke. Full article
(This article belongs to the Section Pharmacology)
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17 pages, 3326 KiB  
Review
Advanced Therapy Medicinal Products for Age-Related Macular Degeneration; Scaffold Fabrication and Delivery Methods
by Hanieh Khalili, Hamid Heidari Kashkoli, David Edward Weyland, Sama Pirkalkhoran and Wiktoria Roksana Grabowska
Pharmaceuticals 2023, 16(4), 620; https://doi.org/10.3390/ph16040620 - 20 Apr 2023
Cited by 2 | Viewed by 2653
Abstract
Retinal degenerative diseases such as age-related macular degeneration (AMD) represent a leading cause of blindness, resulting in permanent damage to retinal cells that are essential for maintaining normal vision. Around 12% of people over the age of 65 have some form of retinal [...] Read more.
Retinal degenerative diseases such as age-related macular degeneration (AMD) represent a leading cause of blindness, resulting in permanent damage to retinal cells that are essential for maintaining normal vision. Around 12% of people over the age of 65 have some form of retinal degenerative disease. Whilst antibody-based drugs have revolutionised treatment of neovascular AMD, they are only effective at an early stage and cannot prevent eventual progression or allow recovery of previously lost vision. Hence, there is a clear unmet need to find innovative treatment strategies to develop a long-term cure. The replacement of damaged retinal cells is thought to be the best therapeutic strategy for the treatment of patients with retinal degeneration. Advanced therapy medicinal products (ATMPs) are a group of innovative and complex biological products including cell therapy medicinal products, gene therapy medicinal products, and tissue engineered products. Development of ATMPs for the treatment of retinal degeneration diseases has become a fast-growing field of research because it offers the potential to replace damaged retinal cells for long-term treatment of AMD. While gene therapy has shown encouraging results, its effectiveness for treatment of retinal disease may be hampered by the body’s response and problems associated with inflammation in the eye. In this mini-review, we focus on describing ATMP approaches including cell- and gene-based therapies for treatment of AMD along with their applications. We also aim to provide a brief overview of biological substitutes, also known as scaffolds, that can be used for delivery of cells to the target tissue and describe biomechanical properties required for optimal delivery. We describe different fabrication methods for preparing cell-scaffolds and explain how the use of artificial intelligence (AI) can aid with the process. We predict that combining AI with 3D bioprinting for 3D cell-scaffold fabrication could potentially revolutionise retinal tissue engineering and open up new opportunities for developing innovative platforms to deliver therapeutic agents to the target tissues. Full article
(This article belongs to the Special Issue Recent Advances in Ocular Drug Delivery Systems)
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12 pages, 298 KiB  
Perspective
Cardiovascular Safety and Benefits of Testosterone Implant Therapy in Postmenopausal Women: Where Are We?
by Guilherme Renke and Francisco Tostes
Pharmaceuticals 2023, 16(4), 619; https://doi.org/10.3390/ph16040619 - 20 Apr 2023
Cited by 3 | Viewed by 2853
Abstract
We discuss the CV safety and efficacy data for subcutaneous testosterone therapy (STT) in postmenopausal women. We also highlight new directions and applications of correct dosages performed in a specialized center. To recommend STT, we propose innovative criteria (IDEALSTT) according to total testosterone [...] Read more.
We discuss the CV safety and efficacy data for subcutaneous testosterone therapy (STT) in postmenopausal women. We also highlight new directions and applications of correct dosages performed in a specialized center. To recommend STT, we propose innovative criteria (IDEALSTT) according to total testosterone (T) level, carotid artery intima-media thickness, and calculated SCORE for a 10-year risk of fatal cardiovascular disease (CVD). Despite all the controversies, hormone replacement therapy (HRT) with T has gained prominence in treating pre and postmenopausal women in the last decades. HRT with silastic and bioabsorbable testosterone hormone implants has gained prominence recently due to its practicality and effectiveness in treating menopausal symptoms and hypoactive sexual desire disorder. A recent publication on the complications of STT, looking at a large cohort of patients over seven years, demonstrated its long-term safety. However, the cardiovascular (CV) risk and safety of STT in women are still controversial. Full article
(This article belongs to the Special Issue State of the Art of Pharmaceutical Research in Brazil)
19 pages, 2706 KiB  
Article
Super Carbonate Apatite-miR-497a-5p Complex Is a Promising Therapeutic Option against Inflammatory Bowel Disease
by Naoto Tsujimura, Takayuki Ogino, Masayuki Hiraki, Taisei Kai, Hiroyuki Yamamoto, Haruka Hirose, Yuhki Yokoyama, Yuki Sekido, Tsuyoshi Hata, Norikatsu Miyoshi, Hidekazu Takahashi, Mamoru Uemura, Tsunekazu Mizushima, Yuichiro Doki, Hidetoshi Eguchi and Hirofumi Yamamoto
Pharmaceuticals 2023, 16(4), 618; https://doi.org/10.3390/ph16040618 - 19 Apr 2023
Viewed by 1775
Abstract
The incidence of inflammatory bowel disease (IBD) is increasing worldwide. It is reported that TGF-β/Smad signal pathway is inactivated in patients with Crohn’s disease by overexpression of Smad 7. With expectation of multiple molecular targeting by microRNAs (miRNAs), we currently attempted to identify [...] Read more.
The incidence of inflammatory bowel disease (IBD) is increasing worldwide. It is reported that TGF-β/Smad signal pathway is inactivated in patients with Crohn’s disease by overexpression of Smad 7. With expectation of multiple molecular targeting by microRNAs (miRNAs), we currently attempted to identify certain miRNAs that activate TGF-β/Smad signal pathway and aimed to prove in vivo therapeutic efficacy in mouse model. Through Smad binding element (SBE) reporter assays, we focused on miR-497a-5p. This miRNA is common between mouse and human species and enhanced the activity of TGF-β/Smad signal pathway, decreased Smad 7 and/or increased phosphorylated Smad 3 expression in non-tumor cell line HEK293, colorectal cancer cell line HCT116 and mouse macrophage J774a.1 cells. MiR-497a-5p also suppressed the production of inflammatory cytokines TNF-α, IL-12p40, a subunit of IL-23, and IL-6 when J774a.1 cells were stimulated by lipopolysaccharides (LPS). In a long-term therapeutic model for mouse dextran sodium sulfate (DSS)-induced colitis, systemic delivery of miR-497a-5p load on super carbonate apatite (sCA) nanoparticle as a vehicle restored epithelial structure of the colonic mucosa and suppressed bowel inflammation compared with negative control miRNA treatment. Our data suggest that sCA-miR-497a-5p may potentially have a therapeutic ability against IBD although further investigation is essential. Full article
(This article belongs to the Special Issue Drug Treatments for Inflammatory Bowel Diseases)
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18 pages, 1960 KiB  
Review
Patient-Centric Design of Topical Dermatological Medicines
by Rita Oliveira and Isabel F. Almeida
Pharmaceuticals 2023, 16(4), 617; https://doi.org/10.3390/ph16040617 - 19 Apr 2023
Cited by 2 | Viewed by 2296
Abstract
Topical treatments are essential approaches to skin diseases but are associated with poor adherence. Topical vehicles have the primary purpose of ensuring drug effectiveness (by modulating drug stability and delivery, as well as skin properties) but have a marked impact on treatment outcomes [...] Read more.
Topical treatments are essential approaches to skin diseases but are associated with poor adherence. Topical vehicles have the primary purpose of ensuring drug effectiveness (by modulating drug stability and delivery, as well as skin properties) but have a marked impact on treatment outcomes as they influence patient satisfaction and, consequently, adherence to topical treatments. There is also a wide variety of vehicles available for topical formulations, which can complicate the decisions of clinicians regarding the most appropriate treatments for specific skin disorders. One of the possible strategies to improve topical-treatment adherence is the implementation of patient-centric drug-product design. In this process, the patient’s needs (e.g., those related to motor impairment), the needs associated with the disease (according to the skin lesions’ characteristics), and the patient’s preferences are taken into consideration and translated into a target product profile (TPP). Herein, an overview of topical vehicles and their properties is presented, along with a discussion of the patient-centric design of topical dermatological medicines and the proposal of TPPs for some of the most common skin diseases. Full article
(This article belongs to the Special Issue Feature Reviews in Pharmaceutical Technology)
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18 pages, 3573 KiB  
Article
Disruption of Proteostasis by Natural Products and Synthetic Compounds That Induce Pervasive Unfolding of Proteins: Therapeutic Implications
by Nuria Vilaboa, Juan Antonio Lopez, Marco de Mesa, Clara Escudero-Duch, Natalie Winfield, Melanie Bayford and Richard Voellmy
Pharmaceuticals 2023, 16(4), 616; https://doi.org/10.3390/ph16040616 - 19 Apr 2023
Cited by 1 | Viewed by 1550
Abstract
Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells [...] Read more.
Exposure of many cancer cells, including multiple myeloma cells, to cytotoxic concentrations of natural products celastrol and withaferin A or synthetic compounds of the IHSF series resulted in denaturation of a luciferase reporter protein. Proteomic analysis of detergent-insoluble extract fractions from HeLa-derived cells revealed that withaferin A, IHSF058 and IHSF115 caused denaturation of 915, 722 and 991 of 5132 detected cellular proteins, respectively, of which 440 were targeted by all three compounds. Western blots showed that important fractions of these proteins, in some cases approaching half of total protein amounts, unfolded. Relatively indiscriminate covalent modification of target proteins was observed; 1178 different proteins were modified by IHSF058. Further illustrating the depth of the induced proteostasis crisis, only 13% of these proteins detectably aggregated, and 79% of the proteins that aggregated were not targets of covalent modification. Numerous proteostasis network components were modified and/or found in aggregates. Proteostasis disruption caused by the study compounds may be more profound than that mediated by proteasome inhibitors. The compounds act by a different mechanism that may be less susceptible to resistance development. Multiple myeloma cells were particularly sensitive to the compounds. Development of an additional proteostasis-disrupting therapy of multiple myeloma is suggested. Full article
(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)
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29 pages, 4578 KiB  
Article
Brain Kynurenine Pathway Metabolite Levels May Reflect Extent of Neuroinflammation in ALS, FTD and Early Onset AD
by Annelies Heylen, Yannick Vermeiren, Ido P. Kema, Martijn van Faassen, Claude van der Ley, Debby Van Dam and Peter P. De Deyn
Pharmaceuticals 2023, 16(4), 615; https://doi.org/10.3390/ph16040615 - 19 Apr 2023
Cited by 1 | Viewed by 1593
Abstract
Objectives: Despite distinct clinical profiles, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients share a remarkable portion of pathological features, with a substantial percentage of patients displaying a mixed disease phenotype. Kynurenine metabolism seems to play a role in dementia-associated neuroinflammation and [...] Read more.
Objectives: Despite distinct clinical profiles, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients share a remarkable portion of pathological features, with a substantial percentage of patients displaying a mixed disease phenotype. Kynurenine metabolism seems to play a role in dementia-associated neuroinflammation and has been linked to both diseases. We aimed to explore dissimilarities in kynurenine pathway metabolites in these early onset neurodegenerative disorders in a brain-region-specific manner. Methods: Using liquid chromatography mass spectrometry (LC-MS/MS), kynurenine metabolite levels were determined in the brain samples of 98 healthy control subjects (n = 20) and patients with early onset Alzheimer’s disease (EOAD) (n = 23), ALS (n = 20), FTD (n = 24) or a mixed FTD–ALS (n = 11) disease profile. Results: Overall, the kynurenine pathway metabolite levels were significantly lower in patients with ALS compared to FTD, EOAD and control subjects in the frontal cortex, substantia nigra, hippocampus and neostriatum. Anthranilic acid levels and kynurenine-to-tryptophan ratios were consistently lower in all investigated brain regions in ALS compared to the other diagnostic groups. Conclusions: These results suggest that the contribution of kynurenine metabolism in neuroinflammation is lower in ALS than in FTD or EOAD and may also be traced back to differences in the age of onset between these disorders. Further research is necessary to confirm the potential of the kynurenine system as a therapeutic target in these early onset neurodegenerative disorders. Full article
(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)
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24 pages, 1363 KiB  
Review
Agnostic Approvals in Oncology: Getting the Right Drug to the Right Patient with the Right Genomics
by Valentina Tateo, Paola Valeria Marchese, Veronica Mollica, Francesco Massari, Razelle Kurzrock and Jacob J. Adashek
Pharmaceuticals 2023, 16(4), 614; https://doi.org/10.3390/ph16040614 - 19 Apr 2023
Cited by 19 | Viewed by 6036
Abstract
(1) Background: The oncology field has drastically changed with the advent of precision medicine, led by the discovery of druggable genes or immune targets assessed through next-generation sequencing. Biomarker-based treatments are increasingly emerging, and currently, six tissue-agnostic therapies are FDA-approved. (2) Methods: We [...] Read more.
(1) Background: The oncology field has drastically changed with the advent of precision medicine, led by the discovery of druggable genes or immune targets assessed through next-generation sequencing. Biomarker-based treatments are increasingly emerging, and currently, six tissue-agnostic therapies are FDA-approved. (2) Methods: We performed a review of the literature and reported the trials that led to the approval of tissue-agnostic treatments and ongoing clinical trials currently investigating novel biomarker-based approaches. (3) Results: We discussed the approval of agnostic treatments: pembrolizumab and dostarlimab for MMRd/MSI-H, pembrolizumab for TMB-H, larotrectinib and entrectinib for NTRK-fusions, dabrafenib plus trametinib for BRAF V600E mutation, and selpercatinib for RET fusions. In addition, we reported novel clinical trials of biomarker-based approaches, including ALK, HER2, FGFR, and NRG1. (4) Conclusions: Precision medicine is constantly evolving, and with the improvement of diagnostic tools that allow a wider genomic definition of the tumor, tissue-agnostic targeted therapies are a promising treatment strategy tailored to the specific tumor genomic profile, leading to improved survival outcomes. Full article
(This article belongs to the Special Issue Immune Checkpoint Inhibitor in Cancer Therapy: Recent Advances)
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32 pages, 2555 KiB  
Review
Combination of Two Photosensitisers in Anticancer, Antimicrobial and Upconversion Photodynamic Therapy
by Martina Mušković, Rafaela Pokrajac and Nela Malatesti
Pharmaceuticals 2023, 16(4), 613; https://doi.org/10.3390/ph16040613 - 19 Apr 2023
Cited by 3 | Viewed by 2660
Abstract
Photodynamic therapy (PDT) is a special form of phototherapy in which oxygen is needed, in addition to light and a drug called a photosensitiser (PS), to create cytotoxic species that can destroy cancer cells and various pathogens. PDT is often used in combination [...] Read more.
Photodynamic therapy (PDT) is a special form of phototherapy in which oxygen is needed, in addition to light and a drug called a photosensitiser (PS), to create cytotoxic species that can destroy cancer cells and various pathogens. PDT is often used in combination with other antitumor and antimicrobial therapies to sensitise cells to other agents, minimise the risk of resistance and improve overall outcomes. Furthermore, the aim of combining two photosensitising agents in PDT is to overcome the shortcomings of the monotherapeutic approach and the limitations of individual agents, as well as to achieve synergistic or additive effects, which allows the administration of PSs in lower concentrations, consequently reducing dark toxicity and preventing skin photosensitivity. The most common strategies in anticancer PDT use two PSs to combine the targeting of different organelles and cell-death mechanisms and, in addition to cancer cells, simultaneously target tumour vasculature and induce immune responses. The use of PDT with upconversion nanoparticles is a promising approach to the treatment of deep tissues and the goal of using two PSs is to improve drug loading and singlet oxygen production. In antimicrobial PDT, two PSs are often combined to generate various reactive oxygen species through both Type I and Type II processes. Full article
(This article belongs to the Section Medicinal Chemistry)
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13 pages, 2130 KiB  
Article
Preparation and Bioevaluation of a Novel 99mTc-Labeled Glucose Derivative Containing Cyclohexane as a Promising Tumor Imaging Agent
by Junhong Feng, Xuran Zhang, Yuhao Jiang, Qing Ruan, Qianna Wang and Junbo Zhang
Pharmaceuticals 2023, 16(4), 612; https://doi.org/10.3390/ph16040612 - 18 Apr 2023
Viewed by 1082
Abstract
To develop novel tumor imaging agents with high tumor uptake and excellent tumor/non-target ratios, a glucose derivative containing cyclohexane (CNMCHDG) was synthesized and labeled with Tc-99m. [99mTc]Tc-CNMCHDG was prepared by a kit formulation that was straightforward to operate and fast. Without [...] Read more.
To develop novel tumor imaging agents with high tumor uptake and excellent tumor/non-target ratios, a glucose derivative containing cyclohexane (CNMCHDG) was synthesized and labeled with Tc-99m. [99mTc]Tc-CNMCHDG was prepared by a kit formulation that was straightforward to operate and fast. Without purification, [99mTc]Tc-CNMCHDG had a high radiochemical purity of over 95% and great in vitro stability and hydrophilicity (log P = −3.65 ± 0.10). In vitro cellular uptake studies showed that the uptake of [99mTc]Tc-CNMCHDG was significantly inhibited by pre-treatment with D-glucose and increased by pre-treatment with insulin. Preliminary cellular studies have demonstrated that the mechanism by which the complex enters into cells may be related to GLUTs. The results of biodistribution and SPECT imaging studies displayed high tumor uptake and good retention of [99mTc]Tc-CNMCHDG in A549 tumor-bearing mice (4.42 ± 0.36%ID/g at 120 min post-injection). Moreover, [99mTc]Tc-CNMCHDG exhibited excellent tumor-to-non-target ratios and a clean imaging background and is a potential candidate for clinical transformation. Full article
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21 pages, 2667 KiB  
Review
An Updated Review on the Multifaceted Therapeutic Potential of Calendula officinalis L.
by Kiran Shahane, Madhuri Kshirsagar, Srushti Tambe, Divya Jain, Srutee Rout, Maria Karolina Martins Ferreira, Suraj Mali, Purnima Amin, Prem Prakash Srivastav, Jorddy Cruz and Rafael Rodrigues Lima
Pharmaceuticals 2023, 16(4), 611; https://doi.org/10.3390/ph16040611 - 18 Apr 2023
Cited by 21 | Viewed by 5472
Abstract
Calendula officinalis Linn. (CO) is a popular medicinal plant from the plant kingdom’s Asteraceae family that has been used for millennia. This plant contains flavonoids, triterpenoids, glycosides, saponins, carotenoids, volatile oil, amino acids, steroids, sterols, and quinines. These chemical constituents confer multifaceted biological [...] Read more.
Calendula officinalis Linn. (CO) is a popular medicinal plant from the plant kingdom’s Asteraceae family that has been used for millennia. This plant contains flavonoids, triterpenoids, glycosides, saponins, carotenoids, volatile oil, amino acids, steroids, sterols, and quinines. These chemical constituents confer multifaceted biological effects such as anti-inflammatory, anti-cancer, antihelminthic, antidiabetes, wound healing, hepatoprotective, and antioxidant activities. Additionally, it is employed in cases of certain burns and gastrointestinal, gynecological, ocular, and skin conditions. In this review, we have discussed recent research from the last five years on the therapeutic applications of CO and emphasized its myriad capabilities as a traditional medicine. We have also elucidated CO’s molecular mechanisms and recent clinical studies. Overall, this review intends to summarize, fill in the gaps in the existing research, and provide a wealth of possibilities for researchers working to validate traditional claims and advance the safe and effective use of CO in treating various ailments. Full article
(This article belongs to the Section Natural Products)
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21 pages, 2685 KiB  
Review
Asialo-rhuEPO as a Potential Neuroprotectant for Ischemic Stroke Treatment
by Farooqahmed S. Kittur, Chiu-Yueh Hung, P. Andy Li, David C. Sane and Jiahua Xie
Pharmaceuticals 2023, 16(4), 610; https://doi.org/10.3390/ph16040610 - 18 Apr 2023
Cited by 1 | Viewed by 1490
Abstract
Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently [...] Read more.
Neuroprotective drugs to protect the brain against cerebral ischemia and reperfusion (I/R) injury are urgently needed. Mammalian cell-produced recombinant human erythropoietin (rhuEPOM) has been demonstrated to have excellent neuroprotective functions in preclinical studies, but its neuroprotective properties could not be consistently translated in clinical trials. The clinical failure of rhuEPOM was thought to be mainly due to its erythropoietic activity-associated side effects. To exploit its tissue-protective property, various EPO derivatives with tissue-protective function only have been developed. Among them, asialo-rhuEPO, lacking terminal sialic acid residues, was shown to be neuroprotective but non-erythropoietic. Asialo-rhuEPO can be prepared by enzymatic removal of sialic acid residues from rhuEPOM (asialo-rhuEPOE) or by expressing human EPO gene in glycoengineered transgenic plants (asialo-rhuEPOP). Both types of asialo-rhuEPO, like rhuEPOM, displayed excellent neuroprotective effects by regulating multiple cellular pathways in cerebral I/R animal models. In this review, we describe the structure and properties of EPO and asialo-rhuEPO, summarize the progress on neuroprotective studies of asialo-rhuEPO and rhuEPOM, discuss potential reasons for the clinical failure of rhuEPOM with acute ischemic stroke patients, and advocate future studies needed to develop asialo-rhuEPO as a multimodal neuroprotectant for ischemic stroke treatment. Full article
(This article belongs to the Special Issue Emerging Therapeutic Candidates for Stroke Treatment)
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25 pages, 10387 KiB  
Review
Curcumin and Its Derivatives as Potential Antimalarial and Anti-Inflammatory Agents: A Review on Structure–Activity Relationship and Mechanism of Action
by Siti Nur Hidayah Jamil, Amatul Hamizah Ali, Shevin Rizal Feroz, Su Datt Lam, Hani Kartini Agustar, Mohd Ridzuan Mohd Abd Razak and Jalifah Latip
Pharmaceuticals 2023, 16(4), 609; https://doi.org/10.3390/ph16040609 - 18 Apr 2023
Cited by 7 | Viewed by 2931
Abstract
Curcumin, one of the major ingredients of turmeric (Curcuma longa), has been widely reported for its diverse bioactivities, including against malaria and inflammatory-related diseases. However, curcumin’s low bioavailability limits its potential as an antimalarial and anti-inflammatory agent. Therefore, research on the [...] Read more.
Curcumin, one of the major ingredients of turmeric (Curcuma longa), has been widely reported for its diverse bioactivities, including against malaria and inflammatory-related diseases. However, curcumin’s low bioavailability limits its potential as an antimalarial and anti-inflammatory agent. Therefore, research on the design and synthesis of novel curcumin derivatives is being actively pursued to improve the pharmacokinetic profile and efficacy of curcumin. This review discusses the antimalarial and anti-inflammatory activities and the structure–activity relationship (SAR), as well as the mechanisms of action of curcumin and its derivatives in malarial treatment. This review provides information on the identification of the methoxy phenyl group responsible for the antimalarial activity and the potential sites and functional groups of curcumin for structural modification to improve its antimalarial and anti-inflammatory actions, as well as potential molecular targets of curcumin derivatives in the context of malaria and inflammation. Full article
(This article belongs to the Special Issue Natural Products for Treatment of Parasitic Diseases)
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20 pages, 4832 KiB  
Article
Design of Potent Inhibitors Targeting the Main Protease of SARS-CoV-2 Using QSAR Modeling, Molecular Docking, and Molecular Dynamics Simulations
by Mehdi Oubahmane, Ismail Hdoufane, Christelle Delaite, Adlane Sayede, Driss Cherqaoui and Achraf El Allali
Pharmaceuticals 2023, 16(4), 608; https://doi.org/10.3390/ph16040608 - 18 Apr 2023
Cited by 5 | Viewed by 2146
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a serious global public health threat. The evolving strains of SARS-CoV-2 have reduced the effectiveness of vaccines. Therefore, antiviral drugs against SARS-CoV-2 are urgently needed. The main protease (Mpro) of SARS-CoV-2 is an extremely [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a serious global public health threat. The evolving strains of SARS-CoV-2 have reduced the effectiveness of vaccines. Therefore, antiviral drugs against SARS-CoV-2 are urgently needed. The main protease (Mpro) of SARS-CoV-2 is an extremely potent target due to its pivotal role in virus replication and low susceptibility to mutation. In the present study, a quantitative structure–activity relationship (QSAR) study was performed to design new molecules that might have higher inhibitory activity against SARS-CoV-2 Mpro. In this context, a set of 55 dihydrophenanthrene derivatives was used to build two 2D-QSAR models using the Monte Carlo optimization method and the Genetic Algorithm Multi-Linear Regression (GA-MLR) method. From the CORAL QSAR model outputs, the promoters responsible for the increase/decrease in inhibitory activity were extracted and interpreted. The promoters responsible for an increase in activity were added to the lead compound to design new molecules. The GA-MLR QSAR model was used to ensure the inhibitory activity of the designed molecules. For further validation, the designed molecules were subjected to molecular docking analysis and molecular dynamics simulations along with an absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. The results of this study suggest that the newly designed molecules have the potential to be developed as effective drugs against SARS-CoV-2. Full article
(This article belongs to the Special Issue Protease-Based Drug Discovery)
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19 pages, 10547 KiB  
Article
Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans
by Shuang Liang, Danyang Liu, Zhengwu Xiao, Jonathan Greenbaum, Hui Shen, Hongmei Xiao and Hongwen Deng
Pharmaceuticals 2023, 16(4), 607; https://doi.org/10.3390/ph16040607 - 18 Apr 2023
Cited by 2 | Viewed by 2050
Abstract
Sarcopenia, characterized by age-related loss of muscle mass, strength, and decreased physical performance, is a growing public health challenge amid the rapidly ageing population. As there are no approved drugs that target sarcopenia, it has become increasingly urgent to identify promising pharmacological interventions. [...] Read more.
Sarcopenia, characterized by age-related loss of muscle mass, strength, and decreased physical performance, is a growing public health challenge amid the rapidly ageing population. As there are no approved drugs that target sarcopenia, it has become increasingly urgent to identify promising pharmacological interventions. In this study, we conducted an integrative drug repurposing analysis utilizing three distinct approaches. Firstly, we analyzed skeletal muscle transcriptomic sequencing data in humans and mice using gene differential expression analysis, weighted gene co-expression analysis, and gene set enrichment analysis. Subsequently, we employed gene expression profile similarity assessment, hub gene expression reversal, and disease-related pathway enrichment to identify and repurpose candidate drugs, followed by the integration of findings with rank aggregation algorithms. Vorinostat, the top-ranking drug, was also validated in an in vitro study, which demonstrated its efficacy in promoting muscle fiber formation. Although still requiring further validation in animal models and human clinical trials, these results suggest a promising drug repurposing prospect in the treatment and prevention of sarcopenia. Full article
(This article belongs to the Special Issue Drug Discovery: Genomic and Transcriptomic Approaches)
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15 pages, 10155 KiB  
Review
PET Imaging in Bladder Cancer: An Update and Future Direction
by Jules Zhang-Yin, Antoine Girard, Etienne Marchal, Thierry Lebret, Marie Homo Seban, Marine Uhl and Marc Bertaux
Pharmaceuticals 2023, 16(4), 606; https://doi.org/10.3390/ph16040606 - 17 Apr 2023
Cited by 1 | Viewed by 2613
Abstract
Molecular imaging with positron emission tomography is a powerful tool in bladder cancer management. In this review, we aim to address the current place of the PET imaging in bladder cancer care and offer perspectives on potential future radiopharmaceutical and technological advancements. A [...] Read more.
Molecular imaging with positron emission tomography is a powerful tool in bladder cancer management. In this review, we aim to address the current place of the PET imaging in bladder cancer care and offer perspectives on potential future radiopharmaceutical and technological advancements. A special focus is given to the following: the role of [18F] 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography in the clinical management of bladder cancer patients, especially for staging and follow-up; treatment guided by [18F]FDG PET/CT; the role of [18F]FDG PET/MRI, the other PET radiopharmaceuticals beyond [18F]FDG, such as [68Ga]- or [18F]-labeled fibroblast activation protein inhibitor; and the application of artificial intelligence. Full article
(This article belongs to the Section Radiopharmaceutical Sciences)
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19 pages, 2855 KiB  
Review
The Role of Natural Flavonoids as Telomerase Inhibitors in Suppressing Cancer Growth
by Neel Parekh, Ashish Garg, Renuka Choudhary, Madhu Gupta, Ginpreet Kaur, Seema Ramniwas, Moyad Shahwan, Hardeep Singh Tuli and Gautam Sethi
Pharmaceuticals 2023, 16(4), 605; https://doi.org/10.3390/ph16040605 - 17 Apr 2023
Cited by 5 | Viewed by 2403
Abstract
Cancer is a complex and multifaceted group of diseases characterized by the uncontrolled growth and spread of abnormal cells. While cancer can be challenging and life-altering, advances in research and development have led to the identification of new promising anti-cancer targets. Telomerase is [...] Read more.
Cancer is a complex and multifaceted group of diseases characterized by the uncontrolled growth and spread of abnormal cells. While cancer can be challenging and life-altering, advances in research and development have led to the identification of new promising anti-cancer targets. Telomerase is one such target that is overexpressed in almost all cancer cells and plays a critical role in maintaining telomere length, which is essential for cell proliferation and survival. Inhibiting telomerase activity can lead to telomere shortening and eventual cell death, thus presenting itself as a potential target for cancer therapy. Naturally occurring flavonoids are a class of compounds that have already been shown to possess different biological properties, including the anti-cancer property. They are present in various everyday food sources and richly present in fruits, nuts, soybeans, vegetables, tea, wine, and berries, to name a few. Thus, these flavonoids could inhibit or deactivate telomerase expression in cancer cells by different mechanisms, which include inhibiting the expression of hTERT, mRNA, protein, and nuclear translocation, inhibiting the binding of transcription factors to hTERT promoters, and even telomere shortening. Numerous cell line studies and in vivo experiments have supported this hypothesis, and this development could serve as a vital and innovative therapeutic option for cancer. In this light, we aim to elucidate the role of telomerase as a potential anti-cancer target. Subsequently, we have illustrated that how commonly found natural flavonoids demonstrate their anti-cancer activity via telomerase inactivation in different cancer types, thus proving the potential of these naturally occurring flavonoids as useful therapeutic agents. Full article
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