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Pharmaceuticals, Volume 16, Issue 11 (November 2023) – 124 articles

Cover Story (view full-size image): Three-quarters of a million babies are born before 28 weeks of gestation world-wide. In high-income countries, 20% die in the newborn period, while a further 35% develop severe lung injury and 10% suffer from cerebral palsy. Currently, there is no prophylactic pharmacological treatment. In animal studies, activation of Peroxisome proliferator-activated receptors gamma (PPARγ) has been shown to be beneficial in diseases of prematurity, while reproductive toxicology studies support this finding. Observational studies of premature babies provide further supportive evidence. Paediatric formulation work is required before interventional clinical trials. Potential known side effects of PPARγ agonists may be avoided by short duration treatment, making this an exciting opportunity to reduce burden. View this paper
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27 pages, 6281 KiB  
Article
Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays
Pharmaceuticals 2023, 16(11), 1632; https://doi.org/10.3390/ph16111632 - 20 Nov 2023
Viewed by 1015
Abstract
Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by [...] Read more.
Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative–structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α2-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α2-ADR putative selectivity. These computational methods allowed the identification of the α2A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α2-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation. Full article
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34 pages, 4890 KiB  
Review
Quercetin as a Therapeutic Product: Evaluation of Its Pharmacological Action and Clinical Applications—A Review
Pharmaceuticals 2023, 16(11), 1631; https://doi.org/10.3390/ph16111631 - 20 Nov 2023
Cited by 1 | Viewed by 2143
Abstract
Quercetin is the major polyphenolic flavonoid that belongs to the class called flavanols. It is found in many foods, such as green tea, cranberry, apple, onions, asparagus, radish leaves, buckwheat, blueberry, broccoli, and coriander. It occurs in many different forms, but the most [...] Read more.
Quercetin is the major polyphenolic flavonoid that belongs to the class called flavanols. It is found in many foods, such as green tea, cranberry, apple, onions, asparagus, radish leaves, buckwheat, blueberry, broccoli, and coriander. It occurs in many different forms, but the most abundant quercetin derivatives are glycosides and ethers, namely, Quercetin 3-O-glycoside, Quercetin 3-sulfate, Quercetin 3-glucuronide, and Quercetin 3′-metylether. Quercetin has antioxidant, anti-inflammatory, cardioprotective, antiviral, and antibacterial effects. It is found to be beneficial against cardiovascular diseases, cancer, diabetes, neuro-degenerative diseases, allergy asthma, peptic ulcers, osteoporosis, arthritis, and eye disorders. In pre-clinical and clinical investigations, its impacts on various signaling pathways and molecular targets have demonstrated favorable benefits for the activities mentioned above, and some global clinical trials have been conducted to validate its therapeutic profile. It is also utilized as a nutraceutical due to its pharmacological properties. Although quercetin has several pharmacological benefits, its clinical use is restricted due to its poor water solubility, substantial first-pass metabolism, and consequent low bioavailability. To circumvent this limited bioavailability, a quercetin-based nanoformulation has been considered in recent times as it manifests increased quercetin uptake by the epithelial system and enhances the delivery of quercetin to the target site. This review mainly focuses on pharmacological action, clinical trials, patents, marketed products, and approaches to improving the bioavailability of quercetin with the use of a nanoformulation. Full article
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24 pages, 3136 KiB  
Article
The Cardiorenal Effects of Piper amalago Are Mediated by the Nitric Oxide/Cyclic Guanosine Monophosphate Pathway and the Voltage-Dependent Potassium Channels
Pharmaceuticals 2023, 16(11), 1630; https://doi.org/10.3390/ph16111630 - 20 Nov 2023
Viewed by 738
Abstract
Piper amalago L. is used in Brazilian traditional medicine to treat inflammation, chest pain, and anxiety. This study aimed to investigate the safety and the renal and cardiovascular effects of the volatile oil (VO) and the aqueous (AE) and hydroalcoholic (HE) extracts from [...] Read more.
Piper amalago L. is used in Brazilian traditional medicine to treat inflammation, chest pain, and anxiety. This study aimed to investigate the safety and the renal and cardiovascular effects of the volatile oil (VO) and the aqueous (AE) and hydroalcoholic (HE) extracts from P. amalago. The gas chromatography-mass spectrometry analyses identified 47 compounds in the VO, with β-cyclogermacrene, spathulenol, β-phellandrene, and α-pinene standing out. Among the 47 compounds also found in AE and HE by liquid chromatography-mass spectrometry, glycosylated flavones, organic acids, amino acids, and amides were highlighted. Some examples of these compounds are methoxy-methylenedioxy cis-cinnamoyl pyrrolidine, methoxy-methylenedioxy trans-cinnamoyl pyrrolidine, and cyclobutene-2,4-bis-(1,3-benzodioxol-5-methoxy-6-yl)-1,3-dicarboxapyrrolidide. The acute toxicity experiments were conducted on female rats (n = 5). The cardiorenal assays (n = 8) and evaluations of vasodilatory effects on the mesenteric vascular bed (n = 5) were conducted on male rats. In either extract or VO, there were no mortality or changes in relative weights or histopathological analysis of the organs. Urinary volume and renal electrolyte excretion were elevated significantly during repeated dose 7-day treatment with different preparations from P. amalago. None of the preparations induced hypotension or changes in cardiac electrical activity. Only HE promoted significant vasodilatory effects in rats’ isolated mesenteric vascular beds. These effects were completely abolished in the presence of L-NAME plus 4-aminopyridine. Therefore, P. amalago leaves are safe and present diuretic activity after acute and repeated dose administration over 7 days. Moreover, the HE induced significant vasodilator response in rats’ mesenteric vascular beds by NO/cGMP pathway and voltage-dependent K+ channels activation. Full article
(This article belongs to the Special Issue Pharmacological Advances for Treatment in Hypertension 2.0)
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17 pages, 4226 KiB  
Article
Discovery and Characterization of a Dual-Function Peptide Derived from Bitter Gourd Seed Protein Using Two Orthogonal Bioassay-Guided Fractionations Coupled with In Silico Analysis
Pharmaceuticals 2023, 16(11), 1629; https://doi.org/10.3390/ph16111629 - 20 Nov 2023
Viewed by 681
Abstract
The hydrolysate of bitter gourd seed protein, digested by the combined gastrointestinal proteases (BGSP-GPs), exhibited the most potent inhibition on angiotensin-I-converting enzyme (ACE) with an IC50 value of 48.1 ± 2.0 µg/mL. Using two independent bioassay-guided fractionations, fraction F5 from reversed-phase chromatography [...] Read more.
The hydrolysate of bitter gourd seed protein, digested by the combined gastrointestinal proteases (BGSP-GPs), exhibited the most potent inhibition on angiotensin-I-converting enzyme (ACE) with an IC50 value of 48.1 ± 2.0 µg/mL. Using two independent bioassay-guided fractionations, fraction F5 from reversed-phase chromatography and fraction S1 from strong cation exchange chromatography exhibited the highest ACE inhibitory (ACEI) activity. Three identical peptides were simultaneously detected from both fractions and, based on the in silico appraisal, APLVSW (AW6) was predicted as a promising ACEI peptide. Their dipeptidyl peptidase-IV (DPP4) inhibitory (DPP4I) activity was also explored. The IC50 values of AW6 against ACE and DPP4 were calculated to be 9.6 ± 0.3 and 145.4 ± 4.4 µM, respectively. The inhibitory kinetics and intermolecular interaction studies suggested that AW6 is an ACE competitive inhibitor and a DPP4 non-competitive inhibitor. The quantities of AW6 in BGSP-GP hydrolysate, fractions F5 and S1, were also analyzed using liquid chromatography–tandem mass spectrometry. Notably, AW6 could resist hydrolysis in the human gastrointestinal tract according to the result of the simulated gastrointestinal digestion. To the best of our knowledge, this is the first discovery and characterization of a dual-function (ACEI and DPP4I activities) peptide derived from bitter gourd seed protein. Full article
(This article belongs to the Section Biopharmaceuticals)
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21 pages, 357 KiB  
Review
Novel Immunotherapies and Combinations: The Future Landscape of Multiple Myeloma Treatment
Pharmaceuticals 2023, 16(11), 1628; https://doi.org/10.3390/ph16111628 - 19 Nov 2023
Viewed by 1411
Abstract
In multiple myeloma impressive outcomes have improved with the introduction of new therapeutic approaches, mainly those including naked monoclonal antibodies such as daratumumab and isatuximab. However, moving to earlier lines of therapy with effective anti-myeloma drugs led to an increase in the number [...] Read more.
In multiple myeloma impressive outcomes have improved with the introduction of new therapeutic approaches, mainly those including naked monoclonal antibodies such as daratumumab and isatuximab. However, moving to earlier lines of therapy with effective anti-myeloma drugs led to an increase in the number of patients who developed multi-refractoriness to them early on. Currently, triple- or multi-refractory MM represents an unmet medical need, and their management remains a complicated challenge. The recent approval of new immunotherapeutic approaches such as conjugated monoclonal antibodies, bispecific antibodies, and CAR T cells could be a turning point for these heavily pretreated patients. Nevertheless, several issues regarding their use are unsolved, such as how to select patients for each strategy or how to sequence these therapies within the MM therapeutic landscape. Here we provide an overview of the most recent data about approved conjugated monoclonal antibody belantamab, mafodotin, bispecific antibody teclistamab, and other promising compounds under development, mainly focusing on the ongoing clinical trials with monoclonal antibody combination approaches in advanced and earlier phases of MM treatment. Full article
0 pages, 2653 KiB  
Article
External Evaluation of Population Pharmacokinetics Models of Lithium in the Bipolar Population
Pharmaceuticals 2023, 16(11), 1627; https://doi.org/10.3390/ph16111627 - 18 Nov 2023
Viewed by 826
Abstract
Lithium has been used in the treatment of bipolar disorder for several decades. Treatment optimization is recommended for this drug, due to its narrow therapeutic range and a large pharmacokinetics (PK) variability. In addition to therapeutic drug monitoring, attempts have been made to [...] Read more.
Lithium has been used in the treatment of bipolar disorder for several decades. Treatment optimization is recommended for this drug, due to its narrow therapeutic range and a large pharmacokinetics (PK) variability. In addition to therapeutic drug monitoring, attempts have been made to predict individual lithium doses using population pharmacokinetics (popPK) models. This study aims to assess the clinical applicability of published lithium popPK models by testing their predictive performance on two different external datasets. Available PopPK models were identified and their predictive performance was determined using a clinical dataset (46 patients/samples) and the literature dataset (89 patients/samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated, and the results of both external evaluations compared. Only one model met the acceptability criteria for both datasets. Overall, there was a lack of predictability of models; median PE and median absolute PE, respectively, ranged from −6.6% to 111.2% and from 24.4% to 111.2% for the literature dataset, and from −4.5% to 137.6% and from 24.9% to 137.6% for the clinical dataset. Most models underpredicted the observed concentrations (7 out of 10 models presented a negative bias). Renal status was included as a covariate of lithium’s clearance in only two models. To conclude, most of lithium’s PopPK models had limited predictive performances related to the absence of covariates of interest included, such as renal status. A solution to this problem could be to improve the models with methodologies such as metamodeling. This could be useful in the perspective of model-informed precision dosing. Full article
(This article belongs to the Special Issue Population Pharmacokinetic and Pharmacodynamics)
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15 pages, 2888 KiB  
Article
URB937 Prevents the Development of Mechanical Allodynia in Male Rats with Trigeminal Neuralgia
Pharmaceuticals 2023, 16(11), 1626; https://doi.org/10.3390/ph16111626 - 18 Nov 2023
Cited by 1 | Viewed by 996
Abstract
Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment [...] Read more.
Cannabinoids are proposed for alleviating neuropathic pain, but their use is limited by cannabimimetic side effects. The inhibition of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the endocannabinoid anandamide, has received attention as an alternative to cannabinoids in the treatment of neuropathic pain. Here, we investigated the effect of URB937, a blood–brain barrier impermeant FAAH inhibitor, on experimentally induced mechanical allodynia in an animal model of trigeminal neuralgia. Male Sprague-Dawley rats were subjected to chronic constriction injury of the infraorbital nerve (IoN-CCI); operated animals were treated sub-chronically with URB937 (1 mg/kg, i.p.) or vehicle before or after trigeminal mechanical allodynia establishment. We also assayed mRNA expression levels of the pain neuropeptide calcitonin gene-related peptide (CGRP) and cytokines in the medulla, cervical spinal cord, and trigeminal ganglion ipsilateral to IoN-CCI using rt-PCR. URB937 treatment prevented the development of mechanical allodynia and IoN-CCI-induced changes in mRNA expression levels of CGRP and cytokines in the evaluated areas. When administered after allodynia development, URB937 prevented IoN-CCI-induced changes in CGRP and cytokine gene expression; this was not associated with a significant abrogation of the mechanical allodynia. These findings suggest that URB937 may counteract, but not reverse, the development of allodynia in trigeminal neuralgia. Further research is needed to elucidate the underlying mechanisms. Full article
(This article belongs to the Special Issue Pharmacotherapy of Neuropathic Pain)
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22 pages, 9239 KiB  
Article
Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors
Pharmaceuticals 2023, 16(11), 1625; https://doi.org/10.3390/ph16111625 - 17 Nov 2023
Viewed by 873
Abstract
Dengue virus (DENV) is a major mosquito-borne human pathogen in tropical countries; however, there are currently no targeted antiviral treatments for DENV infection. Compounds 27 and 29 have been reported to be allosteric inhibitors of DENV RdRp with potent inhibitory effects. In this [...] Read more.
Dengue virus (DENV) is a major mosquito-borne human pathogen in tropical countries; however, there are currently no targeted antiviral treatments for DENV infection. Compounds 27 and 29 have been reported to be allosteric inhibitors of DENV RdRp with potent inhibitory effects. In this study, the structures of compounds 27 and 29 were optimized using computer-aided drug design (CADD) approaches. Nine novel compounds were synthesized based on rational considerations, including molecular docking scores, free energy of binding to receptor proteins, predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters, structural diversity, and feasibility of synthesis. Subsequently, the anti-DENV activity was assessed. In the cytopathic effect (CPE) assay conducted on BHK-21 cells using the DENV2 NGC strain, both SW-b and SW-d demonstrated comparable or superior activity against DENV2, with IC50 values of 3.58 ± 0.29 μM and 23.94 ± 1.00 μM, respectively, compared to that of compound 27 (IC50 = 19.67 ± 1.12 μM). Importantly, both SW-b and SW-d exhibited low cytotoxicity, with CC50 values of 24.65 μmol and 133.70 μmol, respectively, resulting in selectivity indices of 6.89 and 5.58, respectively. Furthermore, when compared to the positive control compound 3′-dATP (IC50 = 30.09 ± 8.26 μM), SW-b and SW-d displayed superior inhibitory activity in an enzyme inhibitory assay, with IC50 values of 11.54 ± 1.30 μM and 13.54 ± 0.32 μM, respectively. Molecular dynamics (MD) simulations elucidated the mode of action of SW-b and SW-d, highlighting their ability to enhance π–π packing interactions between benzene rings and residue W795 in the S1 fragment, compared to compounds 27 and 29. Although the transacylsulphonamide fragment reduced the interaction between T794 and NH, it augmented the interaction between R729 and T794. In summary, our study underscores the potential of SW-b and SW-d as allosteric inhibitors targeting the DENV NS5 RdRp domain. However, further in vivo studies are warranted to assess their pharmacology and toxicity profiles. Full article
(This article belongs to the Section Medicinal Chemistry)
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24 pages, 2703 KiB  
Review
Advances in Neuropathic Pain Research: Selected Intracellular Factors as Potential Targets for Multidirectional Analgesics
Pharmaceuticals 2023, 16(11), 1624; https://doi.org/10.3390/ph16111624 - 17 Nov 2023
Viewed by 1205
Abstract
Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. Unlike acute pain, which is short-term and starts suddenly in response to an injury, neuropathic pain arises from somatosensory nervous system damage or disease, is usually chronic, and makes [...] Read more.
Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. Unlike acute pain, which is short-term and starts suddenly in response to an injury, neuropathic pain arises from somatosensory nervous system damage or disease, is usually chronic, and makes every day functioning difficult, substantially reducing quality of life. The main reason for the lack of effective pharmacotherapies for neuropathic pain is its diverse etiology and the complex, still poorly understood, pathophysiological mechanism of its progression. Numerous experimental studies, including ours, conducted over the last several decades have shown that the development of neuropathic pain is based on disturbances in cell activity, imbalances in the production of pronociceptive factors, and changes in signaling pathways such as p38MAPK, ERK, JNK, NF-κB, PI3K, and NRF2, which could become important targets for pharmacotherapy in the future. Despite the availability of many different analgesics, relieving neuropathic pain is still extremely difficult and requires a multidirectional, individual approach. We would like to point out that an increasing amount of data indicates that nonselective compounds directed at more than one molecular target exert promising analgesic effects. In our review, we characterize four substances (minocycline, astaxanthin, fisetin, and peimine) with analgesic properties that result from a wide spectrum of actions, including the modulation of MAPKs and other factors. We would like to draw attention to these selected substances since, in preclinical studies, they show suitable analgesic properties in models of neuropathy of various etiologies, and, importantly, some are already used as dietary supplements; for example, astaxanthin and fisetin protect against oxidative stress and have anti-inflammatory properties. It is worth emphasizing that the results of behavioral tests also indicate their usefulness when combined with opioids, the effectiveness of which decreases when neuropathy develops. Moreover, these substances appear to have additional, beneficial properties for the treatment of diseases that frequently co-occur with neuropathic pain. Therefore, these substances provide hope for the development of modern pharmacological tools to not only treat symptoms but also restore the proper functioning of the human body. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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13 pages, 1689 KiB  
Article
OMNI: Gas Chromatograph Captures Seven Common PET Radiotracer Analytes in under 5 Minutes
Pharmaceuticals 2023, 16(11), 1623; https://doi.org/10.3390/ph16111623 - 17 Nov 2023
Viewed by 681
Abstract
A novel gas chromatography method was developed using automatic injections to identify and quantify the amount of residual solvents or analytes in samples of fluorine-18 and carbon-11 radiopharmaceuticals. This approach evaluates seven analytes in less than 5 versus 13 min of acquisition time. [...] Read more.
A novel gas chromatography method was developed using automatic injections to identify and quantify the amount of residual solvents or analytes in samples of fluorine-18 and carbon-11 radiopharmaceuticals. This approach evaluates seven analytes in less than 5 versus 13 min of acquisition time. The method additionally includes a 3 min bakeout to aid in the removal and carry-over of higher-boiling impurities. Chromatographic parameters such as column temperature, hold time, column pressure, flow rate, and split ratios were adjusted and optimized to analyze radioactive drug samples containing analytes which include methanol, ethanol, acetone, acetonitrile, triethylamine, N,N-dimethylformamide, and dimethyl sulfoxide. The relative standard deviation for each solvent was determined to be no greater than 1.6%. The method limit of detection (LOD) and limit of quantification (LOQ) were between 0.053 and 0.163 and 0.000 (5.791 × 10−6) and 0.520 mg/mL, respectively. This GC technique, using flame ionization detection (FID), was validated and is currently employed for the routine quality control of all approved IND and RDRC PET radiopharmaceuticals at our center. Full article
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20 pages, 4305 KiB  
Review
Theranostic Imaging Surrogates for Targeted Alpha Therapy: Progress in Production, Purification, and Applications
Pharmaceuticals 2023, 16(11), 1622; https://doi.org/10.3390/ph16111622 - 17 Nov 2023
Cited by 2 | Viewed by 1055
Abstract
This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It [...] Read more.
This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate. Thirteen surrogates for TAT are explored: 133La, 132La, 134Ce/134La, and 226Ac for 225Ac TAT; 203Pb for 212Pb TAT; 131Ba for 223Ra and 224Ra TAT; 123I, 124I, 131I and 209At for 211At TAT; 134Ce/134La for 227Th TAT; and 155Tb and 152Tb for 149Tb TAT. Full article
(This article belongs to the Special Issue Therapeutic Radionuclides in Nuclear Medicine)
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16 pages, 1774 KiB  
Article
QSAR Studies, Synthesis, and Biological Evaluation of New Pyrimido-Isoquinolin-Quinone Derivatives against Methicillin-Resistant Staphylococcus aureus
Pharmaceuticals 2023, 16(11), 1621; https://doi.org/10.3390/ph16111621 - 17 Nov 2023
Viewed by 751
Abstract
According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections [...] Read more.
According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds. Full article
(This article belongs to the Special Issue Application of 2D and 3D-QSAR Models in Drug Design)
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18 pages, 8507 KiB  
Article
Preclinical Studies of Canagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, and Donepezil Combined Therapy in Alzheimer’s Disease
Pharmaceuticals 2023, 16(11), 1620; https://doi.org/10.3390/ph16111620 - 16 Nov 2023
Viewed by 942
Abstract
The incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), is continuously growing worldwide, which leads to a heavy economic and societal burden. The lack of a safe and effective causal therapy in cognitive decline is an aggravating factor and requires investigations into [...] Read more.
The incidence of neurodegenerative diseases, such as Alzheimer’s disease (AD), is continuously growing worldwide, which leads to a heavy economic and societal burden. The lack of a safe and effective causal therapy in cognitive decline is an aggravating factor and requires investigations into the repurposing of commonly used drugs. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new and efficient class of hypoglycemic drugs and, due to their pleiotropic effects, have indications that go beyond diabetes. There is emerging data from murine studies that SGLT2i can cross the blood–brain barrier and may have neuroprotective effects, such as increasing the brain-derived neurotrophic factor (BDNF), reducing the amyloid burden, inhibiting acetylcholinesterase (AChE) and restoring the circadian rhythm in the mammalian target of rapamycin (mTOR) activation. The current study investigates the effect of an SGLT2i and donepezil, under a separate or combined 21-day treatment on AD-relevant behaviors and brain pathology in mice. The SGLT2i canagliflozin was found to significantly improve the novelty preference index and the percentage of time spent in the open arms of the maze in the novel object recognition and elevated plus maze test, respectively. In addition, canagliflozin therapy decreased AChE activity, mTOR and glial fibrillary acidic protein expression. The results also recorded the acetylcholine M1 receptor in canagliflozin-treated mice compared to the scopolamine group. In the hippocampus, the SGLT2i canagliflozin reduced the microgliosis and astrogliosis in males, but not in female mice. These findings emphasize the value of SGLT2i in clinical practice. By inhibiting AChE activity, canagliflozin represents a compound that resembles AD-registered therapies in this respect, supporting the need for further evaluation in dementia clinical trials. Full article
(This article belongs to the Special Issue Multi-target Drug Treatments for Neurodegenerative Disease)
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17 pages, 1866 KiB  
Article
Exploring CD39 and CD73 Expression as Potential Biomarkers in Prostate Cancer
Pharmaceuticals 2023, 16(11), 1619; https://doi.org/10.3390/ph16111619 - 16 Nov 2023
Viewed by 1312
Abstract
Prostate cancer (PC) is the most diagnosed tumor in males and ranks as the second leading cause of male mortality in the western world. The CD39 and CD73 enzymes play a crucial role in cancer regulation by degrading nucleotides and forming nucleosides. This [...] Read more.
Prostate cancer (PC) is the most diagnosed tumor in males and ranks as the second leading cause of male mortality in the western world. The CD39 and CD73 enzymes play a crucial role in cancer regulation by degrading nucleotides and forming nucleosides. This study aimed to investigate the expression of the CD39 and CD73 enzymes as potential therapeutic targets for PC. The initial part of this study retrospectively analyzed tissue samples from 23 PC patients. Using the TissueFAXSTM cytometry platform, we found significantly higher levels of CD39—labeling its intensity compared to CD73. Additionally, we observed a correlation between the Gleason score and the intensity of CD39 expression. In the prospective arm, blood samples were collected from 25 patients at the time of diagnosis and after six months of treatment to determine the expression of CD39 and CD73 in the serum extracellular vesicles (EVs) and to analyze nucleotide hydrolysis. Notably, the expression of CD39 in the EVs was significantly increased compared to the CD73 and/or combined CD39/CD73 expression levels at initial collection. Furthermore, our results demonstrated positive correlations between ADP hydrolysis and the transurethral resection and Gleason score. Understanding the role of ectonucleotidases is crucial for identifying new biomarkers in PC. Full article
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15 pages, 2769 KiB  
Article
Esterase-Responsive Polyglycerol-Based Nanogels for Intracellular Drug Delivery in Rare Gastrointestinal Stromal Tumors
Pharmaceuticals 2023, 16(11), 1618; https://doi.org/10.3390/ph16111618 - 16 Nov 2023
Viewed by 742
Abstract
Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that [...] Read more.
Rare gastrointestinal stromal tumors (GISTs) are caused by mutations in the KIT and PDGFRA genes. Avapritinib (BLU-285) is a targeted selective inhibitor for mutated KIT and PDGFRA receptors that can be used to treat these tumors. However, there are subtypes of GISTs that exhibit resistance against BLU-285 and thus require other treatment strategies. This can be addressed by employing a drug delivery system that transports a combination of drugs with distinct cell targets. In this work, we present the synthesis of esterase-responsive polyglycerol-based nanogels (NGs) to overcome drug resistance in rare GISTs. Using inverse nanoprecipitation mediated with inverse electron-demand Diels–Alder cyclizations (iEDDA) between dPG-methyl tetrazine and dPG-norbornene, multi-drug-loaded NGs were formed based on a surfactant-free encapsulation protocol. The obtained NGs displayed great stability in the presence of fetal bovine serum (FBS) and did not trigger hemolysis in red blood cells over a period of 24 h. Exposing the NGs to Candida Antarctica Lipase B (CALB) led to the degradation of the NG network, indicating the capability of targeted drug release. The bioactivity of the loaded NGs was tested in vitro on various cell lines of the GIST-T1 family, which exhibit different drug resistances. Cell internalization with comparable uptake kinetics of the NGs could be confirmed by confocal laser scanning microscopy (CLSM) and flow cytometry for all cell lines. Cell viability and live cell imaging studies revealed that the loaded NGs are capable of intracellular drug release by showing similar IC50 values to those of the free drugs. Furthermore, multi-drug-loaded NGs were capable of overcoming BLU-285 resistance in T1-α-D842V + G680R cells, demonstrating the utility of this carrier system. Full article
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24 pages, 2298 KiB  
Project Report
An Overview of Cancer in Djibouti: Current Status, Therapeutic Approaches, and Promising Endeavors in Local Essential Oil Treatment
Pharmaceuticals 2023, 16(11), 1617; https://doi.org/10.3390/ph16111617 - 16 Nov 2023
Viewed by 979
Abstract
Djibouti, a developing economy, grapples with significant socioeconomic obstacles and the prevalence of infectious pathologies, including certain forms of neoplasms. These challenges are exacerbated by limited access to affordable medical technologies for diagnosis, coupled with a lack of preventive interventions, particularly in disadvantaged [...] Read more.
Djibouti, a developing economy, grapples with significant socioeconomic obstacles and the prevalence of infectious pathologies, including certain forms of neoplasms. These challenges are exacerbated by limited access to affordable medical technologies for diagnosis, coupled with a lack of preventive interventions, particularly in disadvantaged areas. The attention devoted to local phytotherapeutic treatments underscores the uniqueness of Djibouti’s flora, resulting from its distinctive geographical position. International focus specifically centers on harnessing this potential as a valuable resource, emphasizing the phytoconstituents used to counter pathologies, notably carcinomas. This comprehensive overview covers a broad spectrum, commencing with an examination of the current state of knowledge, namely an in-depth investigation of oncological risk factors. Essential elements of control are subsequently studied, highlighting the fundamental prerequisites for effective management. The significance of dietary habits in cancer prevention and support is explored in depth, while traditional methods are examined, highlighting the cultural significance of indigenous essential oil therapies and encouraging further research based on the promising results. Full article
(This article belongs to the Section Natural Products)
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14 pages, 1202 KiB  
Review
Study of lncRNAs in Pediatric Neurological Diseases: Methods, Analysis of the State-of-Art and Possible Therapeutic Implications
Pharmaceuticals 2023, 16(11), 1616; https://doi.org/10.3390/ph16111616 - 16 Nov 2023
Cited by 1 | Viewed by 628
Abstract
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various cellular processes, and their roles in pediatric neurological diseases are increasingly being explored. This review provides an overview of lncRNA implications in the central nervous system, both in its physiological state and [...] Read more.
Long non-coding RNAs (lncRNAs) have emerged as crucial regulators in various cellular processes, and their roles in pediatric neurological diseases are increasingly being explored. This review provides an overview of lncRNA implications in the central nervous system, both in its physiological state and when a pathological condition is present. We describe the role of lncRNAs in neural development, highlighting their significance in processes such as neural stem cell proliferation, differentiation, and synaptogenesis. Dysregulation of specific lncRNAs is associated with multiple pediatric neurological diseases, such as neurodevelopmental or neurodegenerative disorders and brain tumors. The collected evidence indicates that there is a need for further research to uncover the full spectrum of lncRNA involvement in pediatric neurological diseases and brain tumors. While challenges exist, ongoing advancements in technology and our understanding of lncRNA biology offer hope for future breakthroughs in the field of pediatric neurology, leveraging lncRNAs as potential therapeutic targets and biomarkers. Full article
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54 pages, 1769 KiB  
Review
Origin of Antibiotics and Antibiotic Resistance, and Their Impacts on Drug Development: A Narrative Review
Pharmaceuticals 2023, 16(11), 1615; https://doi.org/10.3390/ph16111615 - 15 Nov 2023
Cited by 2 | Viewed by 3351
Abstract
Antibiotics have revolutionized medicine, saving countless lives since their discovery in the early 20th century. However, the origin of antibiotics is now overshadowed by the alarming rise in antibiotic resistance. This global crisis stems from the relentless adaptability of microorganisms, driven by misuse [...] Read more.
Antibiotics have revolutionized medicine, saving countless lives since their discovery in the early 20th century. However, the origin of antibiotics is now overshadowed by the alarming rise in antibiotic resistance. This global crisis stems from the relentless adaptability of microorganisms, driven by misuse and overuse of antibiotics. This article explores the origin of antibiotics and the subsequent emergence of antibiotic resistance. It delves into the mechanisms employed by bacteria to develop resistance, highlighting the dire consequences of drug resistance, including compromised patient care, increased mortality rates, and escalating healthcare costs. The article elucidates the latest strategies against drug-resistant microorganisms, encompassing innovative approaches such as phage therapy, CRISPR-Cas9 technology, and the exploration of natural compounds. Moreover, it examines the profound impact of antibiotic resistance on drug development, rendering the pursuit of new antibiotics economically challenging. The limitations and challenges in developing novel antibiotics are discussed, along with hurdles in the regulatory process that hinder progress in this critical field. Proposals for modifying the regulatory process to facilitate antibiotic development are presented. The withdrawal of major pharmaceutical firms from antibiotic research is examined, along with potential strategies to re-engage their interest. The article also outlines initiatives to overcome economic challenges and incentivize antibiotic development, emphasizing international collaborations and partnerships. Finally, the article sheds light on government-led initiatives against antibiotic resistance, with a specific focus on the Middle East. It discusses the proactive measures taken by governments in the region, such as Saudi Arabia and the United Arab Emirates, to combat this global threat. In the face of antibiotic resistance, a multifaceted approach is imperative. This article provides valuable insights into the complex landscape of antibiotic development, regulatory challenges, and collaborative efforts required to ensure a future where antibiotics remain effective tools in safeguarding public health. Full article
(This article belongs to the Section Pharmacology)
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16 pages, 2411 KiB  
Review
A Review of Childhood Acute Myeloid Leukemia: Diagnosis and Novel Treatment
Pharmaceuticals 2023, 16(11), 1614; https://doi.org/10.3390/ph16111614 - 15 Nov 2023
Viewed by 1171
Abstract
Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, [...] Read more.
Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, management, and prognosis prediction is much more important than before. Disease classifications and risk group classifications, such as the WHO classification, the international consensus classification (ICC), and the European LeukemiaNet (ELN) classification, were revised in 2022. The application of the new information in childhood AML will be upcoming in the next few years. The frequency of each genetic abnormality in adult and childhood AML is different; therefore, in this review, we emphasize well-known genetic subtypes in childhood AML, including core-binding factor AML (CBF AML), KMT2Ar (KMT2A/11q23 rearrangement) AML, normal karyotype AML with somatic mutations, unbalanced cytogenetic abnormalities AML, NUP98 11p15/NUP09 rearrangement AML, and acute promyelocytic leukemia (APL). Current risk group classification, the management algorithm in childhood AML, and novel treatment modalities such as targeted therapy, immune therapy, and chimeric antigen receptor (CAR) T-cell therapy are reviewed. Finally, the indications of hematopoietic stem cell transplantation (HSCT) in AML are discussed. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 3246 KiB  
Article
The Metabolic Fingerprint of Doxorubicin-Induced Cardiotoxicity in Male CD-1 Mice Fades Away with Time While Autophagy Increases
Pharmaceuticals 2023, 16(11), 1613; https://doi.org/10.3390/ph16111613 - 15 Nov 2023
Cited by 1 | Viewed by 708
Abstract
The cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients’ quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) [...] Read more.
The cardiotoxicity of doxorubicin (DOX) may manifest at the beginning/during treatment or years after, compromising patients’ quality of life. We intended to study the cardiac pathways one week (short-term, control 1 [CTRL1] and DOX1 groups) or five months (long-term, CTRL2 and DOX2 groups) after DOX administration in adult male CD-1 mice. Control groups were given saline, and DOX groups received a 9.0 mg/Kg cumulative dose. In the short-term, DOX decreased the content of AMP-activated protein kinase (AMPK) while the electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) increased compared to CTRL1, suggesting the upregulation of fatty acids oxidation. Moreover, mitofusin1 (Mfn1) content was decreased in DOX1, highlighting decreased mitochondrial fusion. In addition, increased B-cell lymphoma-2 associated X-protein (BAX) content in DOX1 pointed to the upregulation of apoptosis. Conversely, in the long-term, DOX decreased the citrate synthase (CS) activity and the content of Beclin1 and autophagy protein 5 (ATG5) compared to CTRL2, suggesting decreased mitochondrial density and autophagy. Our study demonstrates that molecular mechanisms elicited by DOX are modulated at different extents over time, supporting the differences on clinic cardiotoxic manifestations with time. Moreover, even five months after DOX administration, meaningful heart molecular changes occurred, reinforcing the need for the continuous cardiac monitoring of patients and determination of earlier biomarkers before clinical cardiotoxicity is set. Full article
(This article belongs to the Special Issue Current Frames on Cardiotoxicology of New and Old Anticancer Drugs)
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16 pages, 751 KiB  
Article
A Real-World Data Driven Pharmacovigilance Investigation on Drug-Induced Arrhythmia Using KAERS DB, a Korean Nationwide Adverse Drug Reporting System
Pharmaceuticals 2023, 16(11), 1612; https://doi.org/10.3390/ph16111612 - 15 Nov 2023
Cited by 1 | Viewed by 1006
Abstract
This study aims to investigate the prevalence and seriousness of drug-induced arrhythmia and to identify predictors associated with the seriousness of arrhythmia. Drug-induced arrhythmia cases reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were [...] Read more.
This study aims to investigate the prevalence and seriousness of drug-induced arrhythmia and to identify predictors associated with the seriousness of arrhythmia. Drug-induced arrhythmia cases reported to the Korean Adverse Event Reporting System Database (KAERS DB) from January 2012 to December 2021 were investigated. A disproportionality test was performed to detect the association of the etiologic medication classes and types, along with patient demographic information, with the seriousness of drug-induced arrhythmia. Logistic regression was performed to investigate the predictors that increase the risk of serious arrhythmia. The most common etiologic agent for drug-induced arrhythmia was sevoflurane, whereas serious arrhythmia was most prevalent with narcotics. Antibiotics (reporting odds ratio (ROR) 4.125; 95% CI 1.438–11.835), chemotherapy (ROR 6.994; 95% CI 2.239–21.542), and iodinated contrast media (ROR 8.273; 95% CI 3.062–22.352) had a strong association with the seriousness of drug-induced arrhythmia. Among numerous etiologic agents, ioversol (ROR 16.490; 95% CI 3.589–75.772) and lidocaine (ROR 12.347; 95% CI 2.996–50.884) were more likely to be reported with serious arrhythmia. Aging and comorbidity, primarily cancer, are the most contributing predictors associated with serious arrhythmia. Further studies on the clinical significance of patient-specific predictors for the increased risk of serious drug-induced arrhythmia are warranted to promote drug safety. Full article
(This article belongs to the Section Pharmacology)
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14 pages, 611 KiB  
Article
Skin Toxicities Associated with Botulin Toxin Injection for Aesthetic Procedures: Data from the European Spontaneous Reporting System
Pharmaceuticals 2023, 16(11), 1611; https://doi.org/10.3390/ph16111611 - 15 Nov 2023
Viewed by 852
Abstract
Botulinum toxin is a protein deriving from the bacteria Clostridium botulinum and it is widely used for the treatment of a variety of muscle hyperactivity syndromes and for cosmetic indications. Having a long-lasting effect, Botulinum toxin type A (BTA) is one of the [...] Read more.
Botulinum toxin is a protein deriving from the bacteria Clostridium botulinum and it is widely used for the treatment of a variety of muscle hyperactivity syndromes and for cosmetic indications. Having a long-lasting effect, Botulinum toxin type A (BTA) is one of the most botulin toxin products used. Even if BTA has shown benefits in reducing the vertical lines between the eyebrows, Adverse Drug Reactions (ADRs) have been experienced as well, of which the most common ones are headache and drooping eyelids. In addition, since other local and systemic risks have been identified, a non-interventional post-authorization safety study (PASS) has been started. The aim of the present study was to report cases of skin toxicity associated with this drug, considering Individual Case Safety Reports (ICSRs) existing on the Eudravigilance website. Among 1464 ICSRs sent to the EV database, 718 ICSRs, including 5154 PTs, reported BTA as a suspected drug associated with cutaneous toxicity. The majority of patients experiencing BTA-induced skin toxicity were female (92.1%) belonging mostly to the age group of 18–64 years. The most serious criteria, when reported, were “Other Medically Important Condition” and “Caused/prolonged hospitalization”, although the outcome was mainly reported as “Unknown”. The most reported PTs, related to skin disorders, were: “Erythema”, “Rash”, “Pruritus”, “Urticaria”, “Swelling face”, “Brow ptosis”, “Eyelid ptosis”, “Injection site pain”, and “Angioedema”. Considering that in most ICSRs, ADRs related to skin disorders were symptoms of hypersensitivity reactions which in some conditions could be life-threatening, further studies are required to better define the safety profile of BTA used for aesthetic procedures. Full article
(This article belongs to the Section Pharmacology)
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21 pages, 422 KiB  
Review
Safety of Immunomodulatory Systemic Therapies Used in the Management of Immune-Related Cutaneous Adverse Events
Pharmaceuticals 2023, 16(11), 1610; https://doi.org/10.3390/ph16111610 - 15 Nov 2023
Viewed by 914
Abstract
Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies [...] Read more.
Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies can cause several adverse events which may limit their use. In addition, immunomodulatory agents should be used with particular caution in patients receiving immunotherapy, as the efficacy of the oncologic regimen may potentially be undermined. In this review, we summarize the safety of systemic therapies that are used in the management of ircAEs, with a particular focus on the resultant risk of secondary tumor progression in patients with active cancer. Full article
16 pages, 772 KiB  
Article
Comprehensive Observational Study in a Large Cohort of Asthma Patients after Adding LAMA to ICS/LABA
Pharmaceuticals 2023, 16(11), 1609; https://doi.org/10.3390/ph16111609 - 14 Nov 2023
Viewed by 853
Abstract
Introduction: Adding LAMA to LABA/ICS is recommended to improve control in patients with persistent asthma. Methods: This observational, retrospective, before-and-after study considered patients diagnosed with asthma who started LABA/ICS + LAMA treatment (triple therapy, TT) between 1 January 2017 and 31 December 2018 [...] Read more.
Introduction: Adding LAMA to LABA/ICS is recommended to improve control in patients with persistent asthma. Methods: This observational, retrospective, before-and-after study considered patients diagnosed with asthma who started LABA/ICS + LAMA treatment (triple therapy, TT) between 1 January 2017 and 31 December 2018 and had been treated with LABA/ICS (dual therapy, DT) in the year before. Changes in lung function and exacerbation rates, healthcare resource utilization, and healthcare and non-healthcare costs (€2019) were estimated in patients with asthma in clinical practices in Spain. Data from computerized medical records from seven Spanish regions were collected ±1 year of LAMA addition. Results: 4740 patients (64.1 years old [SD: 16.3]) were included. TT reduced the incidence of exacerbations by 16.7% (p < 0.044) and the number of patients with exacerbations by 8.5% (p < 0.001) compared to previous DT. The rate of patients with severe exacerbations requiring systemic corticosteroids and their hospitalization rates significantly decreased by 22.5% and 29.5%. TT significantly improved FEV1, FVC, and FEV1/FVC, saving €571/patient for society. Younger patients with asthma (18–44 years old) and patients with severe asthma (FEV1 < 60%) performed better upon the initiation of TT. Conclusions: TT reduced asthma exacerbations, improved lung function and reduced healthcare costs vs. DT, particularly in patients requiring systemic corticosteroids to treat severe exacerbations. Full article
(This article belongs to the Special Issue Pharmacology and Therapeutics of Asthma)
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20 pages, 4850 KiB  
Article
Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives
Pharmaceuticals 2023, 16(11), 1608; https://doi.org/10.3390/ph16111608 - 14 Nov 2023
Viewed by 1507
Abstract
Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, [...] Read more.
Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source “Turkish DeLight” to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors. Full article
(This article belongs to the Special Issue Structural and Computational-Driven Molecule Design in Drug Discovery)
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21 pages, 9047 KiB  
Article
Integrating Metabolomics and Network Pharmacology to Explore the Mechanism of Xiao-Yao-San in the Treatment of Inflammatory Response in CUMS Mice
Pharmaceuticals 2023, 16(11), 1607; https://doi.org/10.3390/ph16111607 - 14 Nov 2023
Viewed by 898
Abstract
Depression can trigger an inflammatory response that affects the immune system, leading to the development of other diseases related to inflammation. Xiao-Yao-San (XYS) is a commonly used formula in clinical practice for treating depression. However, it remains unclear whether XYS has a modulating [...] Read more.
Depression can trigger an inflammatory response that affects the immune system, leading to the development of other diseases related to inflammation. Xiao-Yao-San (XYS) is a commonly used formula in clinical practice for treating depression. However, it remains unclear whether XYS has a modulating effect on the inflammatory response associated with depression. The objective of this study was to examine the role and mechanism of XYS in regulating the anti-inflammatory response in depression. A chronic unpredictable mild stress (CUMS) mouse model was established to evaluate the antidepressant inflammatory effects of XYS. Metabolomic assays and network pharmacology were utilized to analyze the pathways and targets associated with XYS in its antidepressant inflammatory effects. In addition, molecular docking, immunohistochemistry, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), and Western Blot were performed to verify the expression of relevant core targets. The results showed that XYS significantly improved depressive behavior and attenuated the inflammatory response in CUMS mice. Metabolomic analysis revealed the reversible modulation of 21 differential metabolites by XYS in treating depression-related inflammation. Through the combination of liquid chromatography and network pharmacology, we identified seven active ingredients and seven key genes. Furthermore, integrating the predictions from network pharmacology and the findings from metabolomic analysis, Vascular Endothelial Growth Factor A (VEGFA) and Peroxisome Proliferator-Activated Receptor-γ (PPARG) were identified as the core targets. Molecular docking and related molecular experiments confirmed these results. The present study employed metabolomics and network pharmacology analyses to provide evidence that XYS has the ability to alleviate the inflammatory response in depression through the modulation of multiple metabolic pathways and targets. Full article
(This article belongs to the Special Issue Metabolomics and Metabolism of Traditional Chinese Medicine)
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19 pages, 2868 KiB  
Article
Neuroprotective Effects of Davallia mariesii Roots and Its Active Constituents on Scopolamine-Induced Memory Impairment in In Vivo and In Vitro Studies
Pharmaceuticals 2023, 16(11), 1606; https://doi.org/10.3390/ph16111606 - 14 Nov 2023
Cited by 1 | Viewed by 749
Abstract
Beta-amyloid (Aβ) proteins, major contributors to Alzheimer’s disease (AD), are overproduced and accumulate as oligomers and fibrils. These protein accumulations lead to significant changes in neuronal structure and function, ultimately resulting in the neuronal cell death observed in AD. Consequently, substances that can [...] Read more.
Beta-amyloid (Aβ) proteins, major contributors to Alzheimer’s disease (AD), are overproduced and accumulate as oligomers and fibrils. These protein accumulations lead to significant changes in neuronal structure and function, ultimately resulting in the neuronal cell death observed in AD. Consequently, substances that can inhibit Aβ production and/or accumulation are of great interest for AD prevention and treatment. In the course of an ongoing search for natural products, the roots of Davallia mariesii T. Moore ex Baker were selected as a promising candidate with anti-amyloidogenic effects. The ethanol extract of D. mariesii roots, along with its active constituents, not only markedly reduced Aβ production by decreasing β-secretase expression in APP–CHO cells (Chinese hamster ovary cells which stably express amyloid precursor proteins), but also exhibited the ability to diminish Aβ aggregation while enhancing the disaggregation of Aβ aggregates, as determined through the Thioflavin T (Th T) assay. Furthermore, in an in vivo study, the extract of D. mariesii roots showed potential (a tendency) for mitigating scopolamine-induced memory impairment, as evidenced by results from the Morris water maze test and the passive avoidance test, which correlated with reduced Aβ deposition. Additionally, the levels of acetylcholine were significantly elevated, and acetylcholinesterase levels significantly decreased in the brains of mice (whole brains). The treatment with the extract of D. mariesii roots also led to upregulated brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding protein (p-CREB) in the hippocampal region. These findings suggest that the extract of D. mariesii roots, along with its active constituents, may offer neuroprotective effects against AD. Consequently, there is potential for the development of the extract of D. mariesii roots and its active constituents as effective therapeutic or preventative agents for AD. Full article
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11 pages, 2460 KiB  
Article
Influence of the Molar Activity of 203/212Pb-PSC-PEG2-TOC on Somatostatin Receptor Type 2-Binding and Cell Uptake
Pharmaceuticals 2023, 16(11), 1605; https://doi.org/10.3390/ph16111605 - 14 Nov 2023
Viewed by 644
Abstract
(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as [177Lu]Lu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴,-tetraacetic acid-[Tyr3,Thr8]-octreotide (177Lu-DOTA-TOC) and, [...] Read more.
(1) Background: In neuroendocrine tumors (NETs), somatostatin receptor subtype 2 is highly expressed, which can be targeted by a radioactive ligand such as [177Lu]Lu-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴,-tetraacetic acid-[Tyr3,Thr8]-octreotide (177Lu-DOTA-TOC) and, more recently, by a lead specific chelator (PSC) containing 203/212Pb-PSC-PEG2-TOC (PSC-TOC). The molar activity (AM) can play a crucial role in tumor uptake, especially in receptor-mediated uptake, such as in NETs. Therefore, an investigation of the influence of different molar activities of 203/212Pb-PSC-TOC on cell uptake was investigated. (2) Methods: Optimized radiolabeling of 203/212Pb-PSC-TOC was performed with 50 µg of precursor in a NaAc/AcOH buffer at pH 5.3–5.5 within 15–45 min at 95° C. Cell uptake was studied in AR42 J, HEK293 sst2, and ZR75-1 cells. (3) Results: 203/212Pb-PSC-TOC was radiolabeled with high radiochemical purity >95% and high radiochemical yield >95%, with AM ranging from 0.2 to 61.6 MBq/nmol. The cell uptake of 203Pb-PSC-TOC (AM = 38 MBq/nmol) was highest in AR42 J (17.9%), moderate in HEK293 sstr (9.1%) and lowest in ZR75-1 (0.6%). Cell uptake increased with the level of AM. (4) Conclusions: A moderate AM of 15–40 MBq/nmol showed the highest cell uptake. No uptake limitation was found in the first 24–48 h. Further escalation experiments with even higher AM should be performed in the future. It was shown that AM plays an important role because of its direct dependence on the cellular uptake levels, possibly due to less receptor saturation with non-radioactive ligands at higher AM. Full article
(This article belongs to the Special Issue Therapeutic Radionuclides in Nuclear Medicine)
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16 pages, 3132 KiB  
Article
In Vitro Antibiofilm Effect of N-Acetyl-L-cysteine/Dry Propolis Extract Combination on Bacterial Pathogens Isolated from Upper Respiratory Tract Infections
Pharmaceuticals 2023, 16(11), 1604; https://doi.org/10.3390/ph16111604 - 14 Nov 2023
Viewed by 741
Abstract
Bacterial biofilms play an important role in the pathogenesis of chronic upper respiratory tract infections. In addition to conventional antimicrobial therapy, N-acetyl-L-cysteine (NAC) and propolis are dietary supplements that are often recommended as supportive therapy for upper respiratory tract infections. However, no data [...] Read more.
Bacterial biofilms play an important role in the pathogenesis of chronic upper respiratory tract infections. In addition to conventional antimicrobial therapy, N-acetyl-L-cysteine (NAC) and propolis are dietary supplements that are often recommended as supportive therapy for upper respiratory tract infections. However, no data on the beneficial effect of their combination against bacterial biofilms can be found in the scientific literature. Therefore, the aim of our study was to investigate the in vitro effect of N-acetyl-L-cysteine (NAC) and dry propolis extract in fixed combinations (NAC/dry propolis extract fixed combination) on biofilm formation by bacterial species isolated from patients with chronic rhinosinusitis, chronic otitis media, and chronic adenoiditis. The prospective study included 48 adults with chronic rhinosinusitis, 29 adults with chronic otitis media, and 33 children with chronic adenoiditis. Bacteria were isolated from tissue samples obtained intraoperatively and identified using the MALDI-TOF Vitek MS System. The antimicrobial activity, synergism, and antibiofilm effect of NAC/dry propolis extract fixed combination were studied in vitro. A total of 116 different strains were isolated from the tissue samples, with staphylococci being the most frequently isolated in all patients (57.8%). MICs of the NAC/dry propolis extract fixed combination ranged from 1.25/0.125 to 20/2 mg NAC/mg propolis. A synergistic effect (FICI ≤ 0.5) was observed in 51.7% of strains. The majority of isolates from patients with chronic otitis media were moderate biofilm producers and in chronic adenoiditis they were weak biofilm producers, while the same number of isolates in patients with chronic rhinosinusitis were weak and moderate biofilm producers. Subinhibitory concentrations of the NAC/propolis combination ranging from 0.625–0.156 mg/mL to 10–2.5 mg/mL of NAC combined with 0.062–0.016 mg/mL to 1–0.25 mg/mL of propolis inhibited biofilm formation in all bacterial strains. Suprainhibitory concentrations ranging from 2.5–10 mg/mL to 40–160 mg/mL of NAC in combination with 0.25–1 mg/mL to 4–16 mg/mL of propolis completely eradicated the biofilm. In conclusion, the fixed combination of NAC and dry propolis extract has a synergistic effect on all stages of biofilm formation and eradication of the formed biofilm in bacteria isolated from upper respiratory tract infections. Full article
(This article belongs to the Section Pharmacology)
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12 pages, 1046 KiB  
Review
Entecavir: A Review and Considerations for Its Application in Oncology
Pharmaceuticals 2023, 16(11), 1603; https://doi.org/10.3390/ph16111603 - 14 Nov 2023
Viewed by 1158
Abstract
Entecavir (ETV) is a drug used as a first-line treatment for chronic hepatitis B (CHB) virus infection because it is a guanosine nucleoside analogue with activity against the hepatitis B virus polymerase. The ETV dosage can range from 0.5 mg to 1 mg [...] Read more.
Entecavir (ETV) is a drug used as a first-line treatment for chronic hepatitis B (CHB) virus infection because it is a guanosine nucleoside analogue with activity against the hepatitis B virus polymerase. The ETV dosage can range from 0.5 mg to 1 mg once a day and the most common side effects include headache, insomnia, fatigue, dizziness, somnolence, vomiting, diarrhea, nausea, dyspepsia, and increased liver enzyme levels. In addition to its conventional use, ETV acts as an inhibitor of lysine-specific demethylase 5B (KDM5B), an enzyme that is overexpressed in breast, lung, skin, liver, and prostate tumors and is involved in the hormonal response, stem cell regeneration, genomic stability, cell proliferation, and differentiation. The KDM5B enzyme acts as a transcriptional repressor in tumor suppressor genes, silencing them, and its overexpression leads to drug resistance in certain tumor types. Furthermore, the literature suggests that KDM5B activates the PI3K/AKT signaling pathway, while reducing KDM5B expression decreases AKT signaling, resulting in decreased tumor cell proliferation. In silico studies have demonstrated that ETV can inhibit tumor cell proliferation and induce apoptosis by reducing KDM5B expression. ETV also appears to inhibit PARP-1, has a high genetic barrier, reducing the chance of resistance development, and can also prevent the reactivation of the hepatitis B virus in cancer patients, which have proven to be significant advantages regarding its use as a repurposed drug in oncology. Therefore, ETV holds promise beyond its original therapeutic indication. Full article
(This article belongs to the Special Issue Small Molecules in Targeted Cancer Therapy and Diagnosis)
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