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Pharmaceuticals, Volume 16, Issue 12 (December 2023) – 111 articles

Cover Story (view full-size image): Combining in silico and in vitro approaches allowed us to investigate the mechanism of action as CFTR correctors of three hybrid derivatives (2a, 7a and 7m) featuring the thiazole core tethered to the benzodioxole motif of VX809. Molecular modelling suggested that 2a, 7a and 7m interact with the MSD1/NBD1 interface. Biochemical analyses confirmed these data, showing that the three molecules affect the expression and stability of the F508del NBD1. We tested the ability of combinations of 2a, 7a and 7m with correctors already in clinical use to increase the activity of the F508del CFTR channel. We used VX661, a class I corrector binding to MSD1, and VX445, increasing the expression and stability of MSD2. A YFP assay was applied to confirm the additive influence of 2a, 7a and 7m on F508del CFTR function to that of VX661 and VX445. view this paper
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14 pages, 1307 KiB  
Case Report
Uncommon Septic Arthritis of the Hip Joint in an Immunocompetent Adult Patient Due to Bacillus pumilus and Paenibacillus barengoltzii Managed with Long-Term Treatment with Linezolid: A Case Report and Short Literature Review
Pharmaceuticals 2023, 16(12), 1743; https://doi.org/10.3390/ph16121743 - 18 Dec 2023
Cited by 1 | Viewed by 792
Abstract
The Bacillus and Paenibacillus genera are diverse soil-related bacterial pathogens. In this case report, we describe, to our knowledge, the first report of septic arthritis in a native hip joint in an immunocompetent adult patient caused by Bacillus pumilus and Paenibacillus barengoltzii. We describe [...] Read more.
The Bacillus and Paenibacillus genera are diverse soil-related bacterial pathogens. In this case report, we describe, to our knowledge, the first report of septic arthritis in a native hip joint in an immunocompetent adult patient caused by Bacillus pumilus and Paenibacillus barengoltzii. We describe the case of a 39-year-old Caucasian male patient who sought medical advice for chronic pain on the mobilization of the right hip, decreased range of motion, and physical asthenia. The patient underwent a surgical intervention (core decompression) for a right osteonecrosis of the femoral head, with a slightly favorable postoperative evolution after surgery for one month. Surgical treatment was planned on the basis of clinical and paraclinical investigations and the joint damage. The hip was explored using an anterior approach under spinal anesthesia and standard antibiotic prophylaxis. After resection of the femoral head, meticulous debridement of all inflammatory tissues was performed, and a preformed temporary spacer was inserted into the femoral canal. Bacteriological laboratory studies identified Bacillus pumilus and Paenibacillus barengoltzii via matrix-assisted laser desorption–ionization time-of-flight mass spectrometry analysis. The patient initially received nine days of empirical therapy with intravenous antibiotics (linezolid and meropenem). After the bacterial strains were identified, the patient received organism-specific antibiotic therapy with the same antibiotics and dose for eight days until discharge. After discharge, the patient was referred to another hospital, where he continued treatment with linezolid for seven weeks and, after that, four weeks of oral therapy with cotrimoxazole and rifampicin. During this period, no severe or potentially life-threatening adverse events were recorded during long-term treatment with linezolid or with the two oral antibiotics. In conclusion, our findings suggest that long-term treatment with linezolid may be a viable option for the management of bone and joint infections caused by Bacillus pumilus and Paenibacillus barengoltzii. Full article
(This article belongs to the Special Issue Infectious Disease Epidemiology and Pharmaceutical Development)
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19 pages, 5449 KiB  
Article
In Silico, In Vitro, and In Vivo Evaluation of Caffeine-Coated Nanoparticles as a Promising Therapeutic Avenue for AML through NF-Kappa B and TRAIL Pathways Modulation
Pharmaceuticals 2023, 16(12), 1742; https://doi.org/10.3390/ph16121742 - 18 Dec 2023
Cited by 1 | Viewed by 1093
Abstract
Background: Advancements in nanoscience have led to a profound paradigm shift in the therapeutic applications of medicinally important natural drugs. The goal of this research is to develop a nano-natural product for efficient cancer treatment. Methods and Results: For this purpose, mesoporous silica [...] Read more.
Background: Advancements in nanoscience have led to a profound paradigm shift in the therapeutic applications of medicinally important natural drugs. The goal of this research is to develop a nano-natural product for efficient cancer treatment. Methods and Results: For this purpose, mesoporous silica nanoparticles (MSNPs) were formulated, characterized, and loaded with caffeine to develop a targeted drug delivery system, i.e., caffeine-coated nanoparticles (CcNPs). In silico docking studies were conducted to examine the binding efficiency of the CcNPs with different apoptotic targets followed by in vitro and in vivo bioassays in respective animal models. Caffeine, administered both as a free drug and in nanomedicine form, along with doxorubicin, was delivered intravenously to a benzene-induced AML model. The anti-leukemic potential was assessed through hematological profiling, enzymatic biomarker analysis, and RT-PCR examination of genetic alterations in leukemia markers. Docking studies show strong inter-molecular interactions between CcNPs and apoptotic markers. In vitro analysis exhibits statistically significant antioxidant activity, whereas in vivo analysis exhibits normalization of the genetic expression of leukemia biomarkers STMN1 and S1009A, accompanied by the restoration of the hematological and morphological traits of leukemic blood cells in nanomedicine-treated rats. Likewise, a substantial improvement in hepatic and renal biomarkers is also observed. In addition to these findings, the nanomedicine successfully normalizes the elevated expression of GAPDH and mTOR induced by exposure to benzene. Further, the nanomedicine downregulates pro-survival components of the NF-kappa B pathway and upregulated P53 expression. Additionally, in the TRAIL pathway, it enhances the expression of pro-apoptotic players TRAIL and DR5 and downregulates the anti-apoptotic protein cFLIP. Conclusions: Our data suggest that MSNPs loaded with caffeine, i.e., CcNP/nanomedicine, can potentially inhibit transformed cell proliferation and induce pro-apoptotic TRAIL machinery to counter benzene-induced leukemia. These results render our nanomedicine as a potentially excellent therapeutic agent against AML. Full article
(This article belongs to the Special Issue Nano-Strategies in Fighting Cancer)
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14 pages, 308 KiB  
Article
At-Home Foscarnet Administration in Patients with Cytomegalovirus Infection Post-Allogeneic Stem Cell Transplantation: A Unicentric, Safe, and Feasible Program
Pharmaceuticals 2023, 16(12), 1741; https://doi.org/10.3390/ph16121741 - 18 Dec 2023
Viewed by 786
Abstract
Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our [...] Read more.
Cytomegalovirus (CMV) infection is a relevant cause of morbimortality in patients receiving allogeneic stem cell transplantation (allo-HCT). Foscarnet (FCN) is an effective drug against CMV administered intravenously and usually on an inpatient basis. The Home Care Unit (HCU) for hematologic patients at our hospital designed an at-home FCN administration model to avoid the hospitalization of patients requiring FCN treatment. This study analyzes whether the at-home administration of FCN is as safe and effective as its hospital administration. We collected and compared demographic, clinical, analytical, and economic data of patients with CMV infection post-allo-HCT who received FCN in the hospital (n = 16, 17 episodes) vs. at-home (n = 67, 88 episodes). The proportions of patients with cured CMV infections were comparable between the two groups (65.9% vs. 76.5%, p = 0.395). The median duration of FCN treatment was 15 (interquartile range [IQR] 9–23) and 14 (IQR 11–19) days in the HCU and inpatient cohorts, respectively (p = 0.692). There were no significant differences in the FCN toxicities between groups except for hypocalcemia (26.1% vs. 58.8%, p = 0.007), which was more prevalent in the inpatient cohort. A significant cost-effectiveness was found in the HCU cohort, with a median savings per episode of EUR 5270. It may be concluded that home administration of FCN is a safe, effective, and cost-efficient therapeutic option for patients with CMV infection and disease. Full article
(This article belongs to the Topic Research in Pharmacological Therapies)
12 pages, 2530 KiB  
Article
Beta Blockers Improve Prognosis When Used Early in Patients with Cardiogenic Shock: An Analysis of the FRENSHOCK Multicenter Prospective Registry
Pharmaceuticals 2023, 16(12), 1740; https://doi.org/10.3390/ph16121740 - 18 Dec 2023
Viewed by 745
Abstract
Background: Beta blockers (BBs) are a cornerstone for patients with heart failure (HF) and ventricular dysfunction. However, their use in patients recovering from a cardiogenic shock (CS) remains a bone of contention, especially regarding whether and when to reintroduce this class of drugs. [...] Read more.
Background: Beta blockers (BBs) are a cornerstone for patients with heart failure (HF) and ventricular dysfunction. However, their use in patients recovering from a cardiogenic shock (CS) remains a bone of contention, especially regarding whether and when to reintroduce this class of drugs. Methods: FRENSHOCK is a prospective multicenter registry including 772 CS patients from 49 centers. Our aim was to compare outcomes (1-month and 1-year all-cause mortality) between CS patients taking and those not taking BBs in three scenarios: (1) at 24 h after CS; (2) patients who did or did not discontinue BBs within 24 h; and (3) patients who did or did not undergo the early introduction of BBs. Results: Among the 693 CS included, at 24 h after the CS event, 95 patients (13.7%) were taking BB, while 598 (86.3%) were not. Between the groups, there were no differences in terms of major comorbidities or initial CS triggers. Patients receiving BBs at 24 h presented a trend toward reduced all-cause mortality both at 1 month (aHR = 0.61, 95% CI 0.34 to 1.1, p = 0.10) and 1 year, which was, in both cases, not significant. Compared with patients who discontinued BBs at 24 h, patients who did not discontinue BBs showed lower 1-month mortality (aHR = 0.43, 95% CI 0.2 to 0.92, p = 0.03) and a trend to lower 1-year mortality. No reduction in outcomes was observed in patients who underwent an early introduction of BB therapy. Conclusions: BBs are drugs of first choice in patients with HF and should also be considered early in patients with CS. In contrast, the discontinuation of BB therapy resulted in increased 1-month all-cause mortality and a trend toward increased 1-year all-cause mortality. Full article
(This article belongs to the Section Pharmacology)
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18 pages, 12894 KiB  
Article
Mitigating Scar Tissue Formation in Tendon Injuries: Targeting HMGB1, AMPK Activation, and Myofibroblast Migration All at Once
Pharmaceuticals 2023, 16(12), 1739; https://doi.org/10.3390/ph16121739 - 17 Dec 2023
Viewed by 779
Abstract
Tendon injuries, while prevalent, present significant challenges regarding their structural and functional restoration. Utilizing alpha-smooth muscle actin (α-SMA)-Ai9-scleraxis (Scx)-green fluorescent protein (GFP) transgenic mice, which exhibit both Scx (a tendon cell marker) and α-SMA (a myofibroblast marker), we explored the effects of metformin [...] Read more.
Tendon injuries, while prevalent, present significant challenges regarding their structural and functional restoration. Utilizing alpha-smooth muscle actin (α-SMA)-Ai9-scleraxis (Scx)-green fluorescent protein (GFP) transgenic mice, which exhibit both Scx (a tendon cell marker) and α-SMA (a myofibroblast marker), we explored the effects of metformin (Met) on tendon healing, repair, and its mechanisms of action. Our findings revealed that intraperitoneal (IP) injections of Met, administered before or after injury, as well as both, effectively prevented the release of HMGB1 into the tendon matrix and reduced circulating levels of HMGB1. Additionally, Met treatment increased and activated AMPK and suppressed TGF-β1 levels within the healing tendon. Tendon healing was also improved by blocking the migration of α-SMA+ myofibroblasts, reducing the prevalence of disorganized collagen fibers and collagen type III. It also enhanced the presence of collagen type I. These outcomes highlight Met’s anti-fibrotic properties in acutely injured tendons and suggest its potential for repurposing as a therapeutic agent to minimize scar tissue formation in tendon injuries, which could have profound implications in clinical practice. Full article
(This article belongs to the Section Biopharmaceuticals)
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17 pages, 9467 KiB  
Article
Promising Anti-Wrinkle Applications of Aromatic Extracts of Hedychium coronarium J. Koenig via Antioxidation and Collagenase Inhibition
Pharmaceuticals 2023, 16(12), 1738; https://doi.org/10.3390/ph16121738 - 17 Dec 2023
Viewed by 1183
Abstract
This study aimed to extract aromatic compounds from the rhizomes, leaf sheaths, and leaves of Hedychium coronarium and investigate their chemical compositions, cosmetic/cosmeceutical activities, and irritation potency. The chemical compositions were investigated via gas chromatography–mass spectrometry. The antioxidant activities were evaluated via spectrophotometry. [...] Read more.
This study aimed to extract aromatic compounds from the rhizomes, leaf sheaths, and leaves of Hedychium coronarium and investigate their chemical compositions, cosmetic/cosmeceutical activities, and irritation potency. The chemical compositions were investigated via gas chromatography–mass spectrometry. The antioxidant activities were evaluated via spectrophotometry. The anti-skin wrinkle properties were investigated via collagenase, elastase, and hyaluronidase inhibition. The irritation potency was observed via a hen’s egg–chorioallantoic membrane test. Eucalyptol was detected as a major component in the rhizomes and leaf sheaths, while β-caryophyllene was predominant in the leaves. The absolutes from the rhizomes were the strongest antioxidants, with ABTS scavenging properties similar to L-ascorbic acid. Interestingly, the equivalent concentration (EC1) of the absolute from the rhizome was 0.82 ± 0.01 µg FeSO4/g extract, which was significantly more potent than L-ascorbic acid (0.43 ± 0.03 µg FeSO4/g extract). The rhizome-derived absolute was the most effective against collagenase, while the concretes from the rhizomes and leaf sheaths showed promising anti-hyaluronidase activity with inhibitions of 90.5 ± 1.6% and 87.4 ± 5.1%, respectively. The irritability of the aromatic extracts was not different from that of the vehicle control, proving their safety. Therefore, the Hedychium coronarium rhizome-derived absolute was an attractive and potent antioxidant with anti-collagenase activities, indicating its potential for use in anti-aging formulations. Full article
(This article belongs to the Special Issue Antioxidants in the Processes of Retarding Ageing)
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18 pages, 18183 KiB  
Article
Biological Potential and Bioaccessibility of Encapsulated Curcumin into Cetyltrimethylammonium Bromide Modified Cellulose Nanocrystals
Pharmaceuticals 2023, 16(12), 1737; https://doi.org/10.3390/ph16121737 - 17 Dec 2023
Viewed by 825
Abstract
Curcumin is a natural phenolic compound with important biological functions. Despite its demonstrated efficacy in vitro, curcumin biological activities in vivo are dependent on its bioaccessibility and bioavailability, which have been highlighted as a crucial challenge. Cetyltrimethylammonium bromide-modified cellulose nanocrystals (CNC-CTAB) have been [...] Read more.
Curcumin is a natural phenolic compound with important biological functions. Despite its demonstrated efficacy in vitro, curcumin biological activities in vivo are dependent on its bioaccessibility and bioavailability, which have been highlighted as a crucial challenge. Cetyltrimethylammonium bromide-modified cellulose nanocrystals (CNC-CTAB) have been shown to be effective in curcumin encapsulation, as they have the potential to enhance biological outcomes. This study evaluated the biological effects of curcumin encapsulated within CNC-CTAB structures, namely its antioxidant, anti-inflammatory and antimicrobial properties, as well as the release profile under digestion conditions and intestinal permeability. Encapsulated curcumin demonstrated antioxidant and anti-inflammatory properties, effectively reducing reactive oxygen species and cytokine production by intestinal cells. The delivery system exhibited antimicrobial properties against Campylobacter jejuni bacteria, further suggesting its potential in mitigating intestinal inflammation. The system showed the ability to protect curcumin from degradation and facilitate its interaction with the intestinal epithelium, highlighting the potential of CNC-CTAB as carrier to enhance curcumin intestinal biological functions. Full article
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14 pages, 558 KiB  
Article
Validation of an HPLC-DAD Method for Quercetin Quantification in Nanoparticles
Pharmaceuticals 2023, 16(12), 1736; https://doi.org/10.3390/ph16121736 - 17 Dec 2023
Viewed by 1008
Abstract
The evaluation of the efficacy of incorporation of quercetin in nanoparticles is crucial, both for the development and quality control of pharmaceutical formulations. The validation of analytical methods for the precise quantification of quercetin is useful for the evaluation of various potential quercetin [...] Read more.
The evaluation of the efficacy of incorporation of quercetin in nanoparticles is crucial, both for the development and quality control of pharmaceutical formulations. The validation of analytical methods for the precise quantification of quercetin is useful for the evaluation of various potential quercetin delivery systems and quercetin pharmacokinetics. This work aimed to validate a high-performance liquid chromatography with diode array detection (HPLC-DAD) method for quercetin detection and quantification in nanoparticles. Different mobile phase conditions and detection wavelengths (254 and 368 nm) were tested, and the major validation parameters were assessed (precision, accuracy, linearity, sensitivity, stability, and selectivity). The best peak resolution was obtained when quercetin was analyzed at 368 nm with a mobile phase of 1.5% acetic acid and a water/acetonitrile/methanol ratio of 55:40:5. Under these conditions, quercetin also eluted rapidly (retention time of 3.6 min). The method proved to be linear (R2 > 0.995), specific, and repeatable (variation coefficient between 2.4% and 6.7%) and presented intermediate precision (variation coefficient between 7.2% and 9.4%). The accuracy of the analysis ranged between 88.6% and 110.7%, and detection and quantification limits were 0.046 and 0.14 µg/mL, respectively. Quercetin solutions were more stable when stored at 4 °C than at room temperature or −20 °C. This validated method satisfied more parameters of bias assessment than most recent methods for quercetin determination and presented itself as more sensitive and efficient than general spectrophotometric methods. The method was successfully used for the analysis of quercetin incorporation in nanoparticles and will be evaluated in the future for its adequacy for the determination of quercetin in more complex matrices. Full article
(This article belongs to the Section Natural Products)
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25 pages, 6316 KiB  
Review
Sialic Acid Mimetic Microglial Sialic Acid-Binding Immunoglobulin-like Lectin Agonism: Potential to Restore Retinal Homeostasis and Regain Visual Function in Age-Related Macular Degeneration
Pharmaceuticals 2023, 16(12), 1735; https://doi.org/10.3390/ph16121735 - 16 Dec 2023
Viewed by 917
Abstract
Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis [...] Read more.
Age-related macular degeneration (AMD), a leading cause of visual loss and dysfunction worldwide, is a disease initiated by genetic polymorphisms that impair the negative regulation of complement. Proteomic investigation points to altered glycosylation and loss of Siglec-mediated glyco-immune checkpoint parainflammatory and inflammatory homeostasis as the main determinant for the vision impairing complications of macular degeneration. The effect of altered glycosylation on microglial maintained retinal para-inflammatory homeostasis and eventual recruitment and polarization of peripheral blood monocyte-derived macrophages (PBMDMs) into the retina can explain the phenotypic variability seen in this clinically heterogenous disease. Restoring glyco-immune checkpoint control with a sialic acid mimetic agonist targeting microglial/macrophage Siglecs to regain retinal para-inflammatory and inflammatory homeostasis is a promising therapeutic that could halt the progression of and improve visual function in all stages of macular degeneration. Full article
(This article belongs to the Special Issue Microglia and Astrocytes as Drug Targets)
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17 pages, 1969 KiB  
Review
Research Progress on the Synergistic Anti-Tumor Effect of Natural Anti-Tumor Components of Chinese Herbal Medicine Combined with Chemotherapy Drugs
Pharmaceuticals 2023, 16(12), 1734; https://doi.org/10.3390/ph16121734 - 15 Dec 2023
Viewed by 728
Abstract
The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their [...] Read more.
The application of chemotherapy drugs in tumor treatment has a long history, but the lack of selectivity of drugs often leads to serious side effects during chemotherapy. The natural anti-tumor ingredients derived from Chinese herbal medicine are attracting increased attention due to their diverse anti-tumor effects, abundant resources, and minimal side effects. An effective anti-tumor strategy may lie in the combination of these naturally derived anti-tumor ingredients with conventional chemotherapy drugs. This approach could potentially inhibit tumor growth and the development of drug resistance in tumor cells while reducing the adverse effects of chemotherapy drugs. This review provides a comprehensive overview of the combined therapy strategies integrating natural anti-tumor components from Chinese herbal medicine with chemotherapy drugs in current research. We primarily summarize various compounds in Chinese herbal medicine exhibiting natural anti-tumor activities and the relevant mechanisms in synergistic anti-tumor combination therapy. The focus of this paper is on underlining that this integrative approach, combining natural anti-tumor components of Chinese herbal medicine with chemotherapy drugs, presents a novel cancer treatment methodology, thereby providing new insights for future oncological research. Full article
18 pages, 3155 KiB  
Article
Adenosine A1 Receptors Participate in Excitability Changes after Cortical Epileptic Afterdischarges in Immature Rats
Pharmaceuticals 2023, 16(12), 1733; https://doi.org/10.3390/ph16121733 - 15 Dec 2023
Viewed by 666
Abstract
Background: Postictal refractoriness, i.e., the inability to elicit a new epileptic seizure immediately after the first one, is present in mature animals. Immature rats did not exhibit this refractoriness, and it is replaced by postictal potentiation. In addition to the immediate postictal [...] Read more.
Background: Postictal refractoriness, i.e., the inability to elicit a new epileptic seizure immediately after the first one, is present in mature animals. Immature rats did not exhibit this refractoriness, and it is replaced by postictal potentiation. In addition to the immediate postictal potentiation, there is a delayed potentiation present at both ages. These phenomena were studied using cortical epileptic afterdischarges as a model. Objective: We aimed to analyze participation of adenosine A1 receptors in postictal potentiation and depression. Methods: Adenosine A1 receptors were studied by means of Western blotting in the cerebral cortex with a focus on the age groups studied electrophysiologically. Stimulation and recording electrodes were implanted epidurally in 12- and 25-day-old rats. The first stimulation always induced conditioning epileptic afterdischarge (AD), and 1 min after its end, the stimulation was repeated to elicit the second, testing AD. Then, the drugs were administered and paired stimulations were repeated 10 min later. A selective agonist CCPA (0.5 and 1 mg/kg i.p.) and a selective antagonist DPCPX (0.1, 0.5 and 1 mg/kg i.p.) were used to examine the possible participation of adenosine A1 receptors. Results: Control younger animals exhibited potentiation of the testing AD and a moderate increase in both conditioning and testing ADs after an injection of saline. The A1 receptor agonist CCPA shortened both post-drug ADs, and neither potentiation was present. The administration of an antagonist DPCPX resulted in marked prolongation of the conditioning AD (delayed potentiation), and the second testing AD was shorter than the post-drug conditioning AD, i.e., there was no longer immediate potentiation of ADs. To eliminate effects of the solvent dimethylsulfoxide, we added experiments with DPCPX suspended with the help of Tween 80. The results were similar, only the prolongation of ADs was not as large, and the testing ADs were significantly depressed. The older control group exhibited a nearly complete suppression of the first testing AD. There was no significant change in the conditioning and testing ADs after CCPA (delayed potentiation was blocked). Both groups of DPCPX-treated rats (with DMSO or Tween) exhibited significant augmentation of delayed potentiation but no significant difference in the immediate depression. Adenosine A1 receptors were present in the cerebral cortex of both age groups, and their quantity was higher in 12- than in 25-day-old animals. Conclusions: An agonist of the A1 receptor CCPA suppressed both types of postictal potentiation in 12-day-old rats, whereas the A1 antagonist DPCPX suppressed immediate potentiation but markedly augmented the delayed one. Immediate postictal refractoriness in 25-day-old rats was only moderately (non-significantly) affected; meanwhile, the delayed potentiation was strongly augmented. Full article
(This article belongs to the Section Pharmacology)
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61 pages, 30929 KiB  
Review
Umbelliferone and Its Synthetic Derivatives as Suitable Molecules for the Development of Agents with Biological Activities: A Review of Their Pharmacological and Therapeutic Potential
Pharmaceuticals 2023, 16(12), 1732; https://doi.org/10.3390/ph16121732 - 15 Dec 2023
Viewed by 1108
Abstract
Umbelliferone (UMB), known as 7-hydroxycoumarin, hydrangine, or skimmetine, is a naturally occurring coumarin in the plant kingdom, mainly from the Umbelliferae family that possesses a wide variety of pharmacological properties. In addition, the use of nanoparticles containing umbelliferone may improve anti-inflammatory or anticancer [...] Read more.
Umbelliferone (UMB), known as 7-hydroxycoumarin, hydrangine, or skimmetine, is a naturally occurring coumarin in the plant kingdom, mainly from the Umbelliferae family that possesses a wide variety of pharmacological properties. In addition, the use of nanoparticles containing umbelliferone may improve anti-inflammatory or anticancer therapy. Also, its derivatives are endowed with great potential for therapeutic applications due to their broad spectrum of biological activities such as anti-inflammatory, antioxidant, neuroprotective, antipsychotic, antiepileptic, antidiabetic, antimicrobial, antiviral, and antiproliferative effects. Moreover, 7-hydroxycoumarin ligands have been implemented to develop 7-hydroxycoumarin-based metal complexes with improved pharmacological activity. Besides therapeutic applications, umbelliferone analogues have been designed as fluorescent probes for the detection of biologically important species, such as enzymes, lysosomes, and endosomes, or for monitoring cell processes and protein functions as well various diseases caused by an excess of hydrogen peroxide. Furthermore, 7-hydroxy-based chemosensors may serve as a highly selective tool for Al3+ and Hg2+ detection in biological systems. This review is devoted to a summary of the research on umbelliferone and its synthetic derivatives in terms of biological and pharmaceutical properties, especially those reported in the literature during the period of 2017–2023. Future potential applications of umbelliferone and its synthetic derivatives are presented. Full article
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15 pages, 2460 KiB  
Article
Antimicrobial, Anticancer, and Antioxidant Activities of Maize and Clover Pollen Grains Extracts: A Comparative Study with Phytochemical Characterizations
Pharmaceuticals 2023, 16(12), 1731; https://doi.org/10.3390/ph16121731 - 15 Dec 2023
Cited by 1 | Viewed by 921
Abstract
The failure to treat infectious diseases due to the continual emergence of drug-resistant microbes poses a huge and serious challenge for human health globally. Currently, the discovery and development of natural therapeutic compounds are attracting considerable attention from researchers worldwide. In this project, [...] Read more.
The failure to treat infectious diseases due to the continual emergence of drug-resistant microbes poses a huge and serious challenge for human health globally. Currently, the discovery and development of natural therapeutic compounds are attracting considerable attention from researchers worldwide. In this project, two types of pollen grains (maize and clover) were evaluated for potential antimicrobial activities. Extracts of both pollen grains were purified using HPLC, which has been shown to have numerous phenolic and flavonoid compounds. Pyro catechol and methyl gallate were detected in high concentrations (1145.56 and 1056.57 µg/mL, respectively) in the maize extract, while caffeic acid, quercetin, and kaempferol (464.73, 393.05, and 390.93 µg/mL, respectively) were among the compounds observed at high concentrations in the clover pollen grains extract. Staphylococcus aureus, Escherichia coli, Salmonella typhi, and Candida albicans were more sensitive to the clover pollen grains extract with inhibition zones of 22 ± 0.2, 18 ± 0.1, 29 ± 0.3, and 42 ± 0.4 mm compared to the size of the inhibitory zones caused by the maize pollen grains extract (19 ± 0.3, 15 ± 0.4, 27 ± 0.1, and 22 ± 0.4 mm, respectively). Moreover, lower MIC values for the clover pollen grains extract were recorded against C. albicans (1.97 ± 0.04 µg/mL), S. aureus (62.5 ± 1.00 µg/mL), and E. coli (62.5 ± 0.07 µg/mL) than the MICs caused by the maize pollen grains extract. The use of a transmission electron microscope revealed that the E. coli that had been treated with the clover pollen grains extract showed changes in its cell walls compared to that treated with the maize pollen grains extract. The clover pollen grains extract exhibited a stronger antioxidant potential, with an IC50 value of 22.18 µg/mL, compared to an IC50 value of 54.85 µg/mL for the maize pollen grains extract, via a DPPH scavenging assay. Regarding anticancer activity, the maize pollen grains extract was revealed to be more effective in terms of inhibiting the human colon cancer cell line HCT-116, with an IC50 value of 67.02 ± 1.37 µg/mL, compared with the observed toxicity caused by the clover extract, with an IC50 value of 75.03 ± 1.02 µg/mL. Overall, the clover pollen grains extract demonstrated potent antibacterial and antioxidant activities, but not anticancer activity, when compared to the maize grains extract. Thus, the current findings related to both types of pollen grains (clover and maize) highlight their potential therapeutic applications for the treatment of certain infectious diseases and malignancies. Full article
(This article belongs to the Topic Challenges and Future Prospects of Antibacterial Therapy)
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16 pages, 1634 KiB  
Article
Development of a Novel Bronchodilator Vaping Drug Delivery System Based on Thermal Degradation Properties
Pharmaceuticals 2023, 16(12), 1730; https://doi.org/10.3390/ph16121730 - 15 Dec 2023
Viewed by 747
Abstract
This work aims to investigate bronchodilator delivery with the use of different vaping drug delivery systems (VDDS) by determining the dose equivalence delivered in relation to different references: a clinical jet nebulizer, a pMDI (pressurized metered dose inhaler) and a DPI (dry powder [...] Read more.
This work aims to investigate bronchodilator delivery with the use of different vaping drug delivery systems (VDDS) by determining the dose equivalence delivered in relation to different references: a clinical jet nebulizer, a pMDI (pressurized metered dose inhaler) and a DPI (dry powder inhaler). Three different bronchodilators were used (terbutaline, salbutamol hemisulfate, ipratropium bromide). The e-liquids contained the active pharmaceutical ingredient (API) in powder form. Two different VDDS were tested (JUUL and a GS AIR 2 atomizer paired with a variable lithium-ion battery (i-stick TC 40 W), 1.5 ohm resistance, and 15 W power). Samples were collected using a glass twin impinger (GTI). High-performance liquid chromatography (HPLC) was used to quantify the drugs. A next-generation impactor (NGI) was used to measure the particle size distribution. Terbutaline emerged as the optimal API for bronchodilator delivery in both VDDS devices. It achieved the delivery of a respirable dose of 20.05 ± 4.2 µg/puff for GS AIR 2 and 2.98 ± 0.52 µg/puff for JUUL. With these delivered doses, it is possible to achieve a dose equivalence similar to that of a jet nebulizer and DPI, all while maintaining a reasonable duration, particularly with the GS AIR 2. This study is the first to provide evidence that vaping bronchodilators work only with appropriate formulation, vaping technology, and specific drugs, depending on their thermal degradation properties. Full article
(This article belongs to the Section Pharmaceutical Technology)
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32 pages, 10134 KiB  
Review
Complexes of Ruthenium(II) as Promising Dual-Active Agents against Cancer and Viral Infections
Pharmaceuticals 2023, 16(12), 1729; https://doi.org/10.3390/ph16121729 - 15 Dec 2023
Viewed by 1252
Abstract
Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer and viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, and ruthenium complexes, are under study [...] Read more.
Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer and viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, and ruthenium complexes, are under study as possible anticancer and antiviral agents. The two Ru(III) and Ru(II) complexes, namely, BOLD-100 and RAPTA-C, are presently being studied in a clinical trial and preclinical studies evaluation, respectively, as anticancer agents. Interestingly, BOLD-100 has also recently demonstrated antiviral activity against SARS-CoV-2, which is the virus responsible for the COVID-19 pandemic. Over the last years, much effort has been dedicated to discovering new dual anticancer–antiviral agents. Ru-based complexes could be very suitable in this respect. Thus, this review focuses on the most recent studies regarding newly synthesized Ru(II) complexes for use as anticancer and/or antiviral agents. Full article
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20 pages, 1941 KiB  
Review
Chenopodium quinoa Willd. and Amaranthus hybridus L.: Ancestral Andean Food Security and Modern Anticancer and Antimicrobial Activity
Pharmaceuticals 2023, 16(12), 1728; https://doi.org/10.3390/ph16121728 - 15 Dec 2023
Cited by 1 | Viewed by 1263
Abstract
The species Chenopodium quinoa Willd. and Amaranthus hybridus L. are Andean staples, part of the traditional diet and gastronomy of the people of the highlands of Colombia, Ecuador, Peru, Bolivia, northern Argentina and Chile, with several ethnopharmacological uses, among them anticancer applications. This [...] Read more.
The species Chenopodium quinoa Willd. and Amaranthus hybridus L. are Andean staples, part of the traditional diet and gastronomy of the people of the highlands of Colombia, Ecuador, Peru, Bolivia, northern Argentina and Chile, with several ethnopharmacological uses, among them anticancer applications. This review aims to present updated information on the nutritional composition, phytochemistry, and antimicrobial and anticancer activity of Quinoa and Amaranth. Both species contribute to food security due to their essential amino acid contents, which are higher than those of most staples. It is highlighted that the biological activity, especially the antimicrobial activity in C. quinoa, and the anticancer activity in both species is related to the presence of phytochemicals present mostly in leaves and seeds. The biological activity of both species is consistent with their phytochemical composition, with phenolic acids, flavonoids, carotenoids, alkaloids, terpenoids, saponins and peptides being the main compound families of interest. Extracts of different plant organs of both species and peptide fractions have shown in vitro and, to a lesser degree, in vivo activity against a variety of bacteria and cancer cell lines. These findings confirm the antimicrobial and anticancer activity of both species, C. quinoa having more reported activity than A. hybridus through different compounds and mechanisms. Full article
(This article belongs to the Special Issue Plant Products as Antimicrobial and Anticancer Agents)
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13 pages, 3642 KiB  
Article
Betanin from Beetroot (Beta vulgaris L.) Regulates Lipid Metabolism and Promotes Fat Browning in 3T3-L1 Adipocytes
Pharmaceuticals 2023, 16(12), 1727; https://doi.org/10.3390/ph16121727 - 14 Dec 2023
Viewed by 847
Abstract
Fat browning, which converts white adipose tissue to brown, has attracted attention as a promising strategy for the treatment of obesity. Betanin (BT) has been reported to have potential anti-obesity activity. 3T3-L1 cells were differentiated for 7 days during BT treatment. The BT [...] Read more.
Fat browning, which converts white adipose tissue to brown, has attracted attention as a promising strategy for the treatment of obesity. Betanin (BT) has been reported to have potential anti-obesity activity. 3T3-L1 cells were differentiated for 7 days during BT treatment. The BT concentration range for the study was determined using an MTT assay, and lipid accumulation was evaluated by Oil-Red-O staining. The expression of protein level was analyzed by Western blot. Immunofluorescence images were performed with confocal microscopy to visually show the amount and location of thermogenesis factor uncoupling protein1 (UCP1) and mitochondria. qRT-PCR was performed to evaluate mRNA expression. BT inhibited lipid accumulation and increased the expression of UCP1, peroxisome-proliferator-activated receptor gamma (PPARγ), and PPARγ coactivator-1 alpha (PGC-1α). In addition, the increases in beige adipocyte-specific markers were observed, supporting BT-mediated browning of the fat tissue. The UCP1 was localized in the inner membrane of the mitochondria, and its expression was associated with mitochondrial activation. Consistent with this, the mRNA expression of mitochondrial biogenesis markers increased in 3T3-L1 cells after BT treatment. Immunofluorescence staining also indicated an increased number of mitochondria and UCP1, respectively. Moreover, BT inhibited lipogenesis and enhanced lipolysis and fatty acid oxidation. This mechanism has been suggested to be mediated by an adenosine monophosphate-activated protein kinase (AMPK) pathway. BT induces fat browning and regulates lipid metabolism via the AMPK-mediated pathway in 3T3-L1 cells, suggesting that BT can be a promising candidate for controlling obesity. Full article
(This article belongs to the Special Issue Natural Products for the Treatment of Obesity)
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15 pages, 1865 KiB  
Article
HPLC-DAD Analysis and Investigation of Biological Properties of the Leaves of Globularia alypum (L.), Infusion Extract
Pharmaceuticals 2023, 16(12), 1726; https://doi.org/10.3390/ph16121726 - 14 Dec 2023
Viewed by 850
Abstract
Globularia alypum L. (GA) belonging to the Globulariaceae family is a Mediterranean plant which is widely used in traditional Tunisian medicine. The aim of this study was to investigate the phytochemical composition, antioxidant, anti-arthritic, antiproliferative, antibacterial and antibiofilm potential of aqueous GA leaf [...] Read more.
Globularia alypum L. (GA) belonging to the Globulariaceae family is a Mediterranean plant which is widely used in traditional Tunisian medicine. The aim of this study was to investigate the phytochemical composition, antioxidant, anti-arthritic, antiproliferative, antibacterial and antibiofilm potential of aqueous GA leaf extracts (AGAL). Quantitative analyses of the different constituents of extracts were evaluated by high-performance liquid chromatography with photodiode-array detection (HPLC-DAD). Spectrophotometric methods and chemical tests were used for antioxidant and anti-arthritic activities. The antiproliferative study was evaluated using colorectal cancer SW620 cells, while the antibacterial assessment and analysis of the antibiofilm effects were determined by the microdilution method and the crystal violet assay, respectively. AGAL extracts presented several components, mainly Nepetin-7-Glucoside and trans-ferrulic acid. The results showed that they had an important antioxidant (IC50 = 0.34; 0.38 and 1.20 mg/mL) and anti-arthritic (IC50 = 2.94 mg/mL) properties, and these effects are displayed in a dose-dependent manner. In addition, this extract demonstrated significant antiproliferative (IC50 = 50 µg/mL), antibacterial (MIC = 6.25 mg/mL and MBC = 6.25 mg/mL), and antibiofilm (59.70% at 25 mg/mL) properties especially against S. aureus. The results achieved confirm the important role of this plant as a source of therapeutic activities. Full article
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14 pages, 2353 KiB  
Article
Glibenclamide-Loaded Engineered Nanovectors (GNVs) Modulate Autophagy and NLRP3-Inflammasome Activation
Pharmaceuticals 2023, 16(12), 1725; https://doi.org/10.3390/ph16121725 - 13 Dec 2023
Viewed by 922
Abstract
Activation of the NLRP3 inflammasome in response to either exogenous (PAMPs) or endogenous (DAMPs) stimuli results in the production of IL-18, caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent [...] Read more.
Activation of the NLRP3 inflammasome in response to either exogenous (PAMPs) or endogenous (DAMPs) stimuli results in the production of IL-18, caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status plays a role in human pathologies, including Alzheimer’s disease (AD). Autophagic removal of NLRP3 inflammasome activators can reduce inflammasome activation and inflammation. Likewise, inflammasome signaling pathways regulate autophagy, allowing the development of inflammatory responses but preventing excessive and detrimental inflammation. Nanotechnology led to the development of liposome engineered nanovectors (NVs) that can load and carry drugs. We verified in an in vitro model of AD-associated inflammation the ability of Glibenclamide-loaded NVs (GNVs) to modulate the balance between inflammasome activation and autophagy. Human THP1dM cells were LPS-primed and oligomeric Aß-stimulated in the presence/absence of GNVs. IL-1β, IL-18 and activated caspase-1 production was evaluated by the Automated Immunoassay System (ELLA); ASC speck formation (a marker of NLRP3 activation) was analyzed by FlowSight Imaging flow-cytometer (AMNIS); the expression of autophagy targets was investigated by RT-PCR and Western blot (WB); and the modulation of autophagy-related up-stream signaling pathways and Tau phosphorylation were WB-quantified. Results showed that GNVs reduce activation of the NLRP3 inflammasome and prevent the Aß-induced phosphorylation of ERK, AKT, and p70S6 kinases, potentiating autophagic flux and counteracting Tau phosphorylation. These preliminary results support the investigation of GNVs as a possible novel strategy in disease and rehabilitation to reduce inflammasome-associated inflammation. Full article
(This article belongs to the Section Biopharmaceuticals)
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16 pages, 3490 KiB  
Article
Discovery of Potent Indolyl-Hydrazones as Kinase Inhibitors for Breast Cancer: Synthesis, X-ray Single-Crystal Analysis, and In Vitro and In Vivo Anti-Cancer Activity Evaluation
Pharmaceuticals 2023, 16(12), 1724; https://doi.org/10.3390/ph16121724 - 13 Dec 2023
Viewed by 825
Abstract
According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer [...] Read more.
According to data provided by the World Health Organization (WHO), a total of 2.3 million women across the globe received a diagnosis of breast cancer in the year 2020, and among these cases, 685,000 resulted in fatalities. As the incidence of breast cancer statistics continues to rise, it is imperative to explore new avenues in the ongoing battle against this disease. Therefore, a number of new indolyl-hydrazones were synthesized by reacting the ethyl 3-formyl-1H-indole-2-carboxylate 1 with thiosemicarbazide, semicarbazide.HCl, 4-nitrophenyl hydrazine, 2,4-dinitrophenyl hydrazine, and 4-amino-5-(1H-indol-2-yl)-1,2,4-triazole-3-thione to afford the new hit compounds, which were assigned chemical structures as thiosemicarbazone 3, bis(hydrazine derivative) 5, semicarbzone 6, Schiff base 8, and the corresponding hydrazones 10 and 12 by NMR, elemental analysis, and X-ray single-crystal analysis. The MTT assay was employed to investigate the compounds’ cytotoxicity against breast cancer cells (MCF-7). Cytotoxicity results disclosed potent IC50 values against MCF-7, especially compounds 5, 8, and 12, with IC50 values of 2.73 ± 0.14, 4.38 ± 0.23, and 7.03 ± 0.37 μM, respectively, compared to staurosproine (IC50 = 8.32 ± 0.43 μM). Consequently, the activities of compounds 5, 8, and 12 in relation to cell migration were investigated using the wound-healing test. The findings revealed notable wound-healing efficacy, with respective percentages of wound closure measured at 48.8%, 60.7%, and 51.8%. The impact of the hit compounds on cell proliferation was assessed by examining their apoptosis-inducing properties. Intriguingly, compound 5 exhibited a significant enhancement in cell death within MCF-7 cells, registering a notable increase of 39.26% in comparison to the untreated control group, which demonstrated only 1.27% cell death. Furthermore, the mechanism of action of compound 5 was scrutinized through testing against kinase receptors. The results revealed significant kinase inhibition, particularly against PI3K-α, PI3K-β, PI3K-δ, CDK2, AKT-1, and EGFR, showcasing promising activity, compared to standard drugs targeting these receptors. In the conclusive phase, through in vivo assay, compound 5 demonstrated a substantial reduction in tumor volume, decreasing from 106 mm³ in the untreated control to 56.4 mm³. Moreover, it significantly attenuated tumor proliferation by 46.9%. In view of these findings, the identified leads exhibit promises for potential development into future medications for the treatment of breast cancer, as they effectively hinder both cell migration and proliferation. Full article
(This article belongs to the Special Issue Heterocyclic Compounds in Medicinal Chemistry)
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14 pages, 2489 KiB  
Article
Regulatory Effect of Ficus carica Latex on Cell Cycle Progression in Human Papillomavirus-Positive Cervical Cancer Cell Lines: Insights from Gene Expression Analysis
Pharmaceuticals 2023, 16(12), 1723; https://doi.org/10.3390/ph16121723 - 12 Dec 2023
Viewed by 877
Abstract
Cervical cancer presents a significant global health concern with high-risk human papillomaviruses (HPVs) identified as the main cause of this cancer. Although current treatment methods for cervical cancer can eliminate lesions, preventing metastatic spread and minimizing tissue damage remain a major challenge. Therefore, [...] Read more.
Cervical cancer presents a significant global health concern with high-risk human papillomaviruses (HPVs) identified as the main cause of this cancer. Although current treatment methods for cervical cancer can eliminate lesions, preventing metastatic spread and minimizing tissue damage remain a major challenge. Therefore, the development of a safer and innovative therapeutic approach is of the utmost importance. Natural products like fig latex, derived from the Ficus carica tree, have demonstrated promising anti-cancer properties when tested on cervical cancer cell lines. However, the specific mechanisms by which fig latex exerts its effects are still unknown. In this study, we conducted RNA-Seq analysis to explore how fig latex may counteract carcinogenesis in HPV-positive cervical cancer cell lines, namely, CaSki (HPV type 16-positive) and HeLa (HPV type 18-positive). Our results from this investigation indicate that fig latex influences the expression of genes associated with the development and progression of cervical cancer, including pathways related to “Nonsense-Mediated Decay (NMD)”, “Cell Cycle regulation”, “Transcriptional Regulation by TP53”, and “Apoptotic Process”. This selective impact of fig latex on cancer-related pathways suggests a potential novel therapeutic approach for HPV-related cervical cancer. Full article
(This article belongs to the Special Issue Exploring Natural Products with Antioxidant and Anticancer Properties)
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14 pages, 1355 KiB  
Review
The Impact of Sex on the Response to Proton Pump Inhibitor Treatment
Pharmaceuticals 2023, 16(12), 1722; https://doi.org/10.3390/ph16121722 - 12 Dec 2023
Viewed by 1373
Abstract
Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. [...] Read more.
Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment. Full article
(This article belongs to the Special Issue Sex Differences in Pharmaceutical Practice)
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42 pages, 1592 KiB  
Review
Single and Multitarget Systems for Drug Delivery and Detection: Up-to-Date Strategies for Brain Disorders
Pharmaceuticals 2023, 16(12), 1721; https://doi.org/10.3390/ph16121721 - 12 Dec 2023
Viewed by 1154
Abstract
This review summarizes the recent findings on the development of different types of single and multitarget nanoparticles for disease detection and drug delivery to the brain, focusing on promising active principles encapsulated and nanoparticle surface modification and functionalization. Functionalized nanoparticles have emerged as [...] Read more.
This review summarizes the recent findings on the development of different types of single and multitarget nanoparticles for disease detection and drug delivery to the brain, focusing on promising active principles encapsulated and nanoparticle surface modification and functionalization. Functionalized nanoparticles have emerged as promising tools for the diagnosis and treatment of brain disorders, offering a novel approach to addressing complex neurological challenges. They can act as drug delivery vehicles, transporting one or multiple therapeutic agents across the blood–brain barrier and precisely releasing them at the site of action. In diagnostics, functionalized nanoparticles can serve as highly sensitive contrast agents for imaging techniques such as magnetic resonance imaging and computed tomography scans. By attaching targeting ligands to the nanoparticles, they can selectively accumulate in the affected areas of the brain, enhancing the accuracy of disease detection. This enables early diagnosis and monitoring of conditions like Alzheimer’s or Parkinson’s diseases. While the field is still evolving, functionalized nanoparticles represent a promising path for advancing our ability to diagnose and treat brain disorders with greater precision, reduced invasiveness, and improved therapeutic outcomes. Full article
(This article belongs to the Special Issue Molecular Systems for the Delivery of Drugs and Contrast Agents)
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12 pages, 1567 KiB  
Article
Combining Cisplatin with Different Radiation Qualities—Interpretation of Cytotoxic Effects In Vitro by Isobolographic Analysis
Pharmaceuticals 2023, 16(12), 1720; https://doi.org/10.3390/ph16121720 - 12 Dec 2023
Viewed by 758
Abstract
Background: The combination of platinum-containing cytostatic drugs with different radiation qualities has been studied for years. Despite their massive side effects, these drugs still belong to the therapeutic portfolio in cancer treatment. To overcome the disadvantages of cisplatin, our study investigated the cytotoxic [...] Read more.
Background: The combination of platinum-containing cytostatic drugs with different radiation qualities has been studied for years. Despite their massive side effects, these drugs still belong to the therapeutic portfolio in cancer treatment. To overcome the disadvantages of cisplatin, our study investigated the cytotoxic effects of combining radionuclides with cisplatin. Methods: FaDu cells were treated with cisplatin (concentration ≈ 2 µM) and additionally irradiated after two hours with the alpha-emitter 223Ra, the beta-emitter 188Re as well as external X-rays using dose ranges of 2–6 Gy. Cell survival was followed by colony formation assays and plotted against cisplatin concentration and radiation dose. The results were interpreted by isobolograms. Results: Isobolographic analyses revealed a supra-additive cytotoxic effect for the combination of cisplatin and 223Ra. A sub-additive effect was observed for the combination of cisplatin and 188Re, whereas a protective effect was found for the combination with X-rays. Conclusions: The combination of cisplatin and 223Ra may have the potential to create a successfully working therapy scheme for various therapy approaches, whereas the combination with 188Re as well as single-dose X-ray treatment did not lead to a detectable radiosensitizing effect. Thus, the combination with alpha-emitters might be advantageous and, therefore, should be followed in future studies when combined with cytostatic drugs. Full article
(This article belongs to the Special Issue Therapeutic Radionuclides in Nuclear Medicine)
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12 pages, 1007 KiB  
Review
Optimal Agents for Visualizing Collagen Tissue Microarchitecture Using Contrast-Enhanced MicroCT
Pharmaceuticals 2023, 16(12), 1719; https://doi.org/10.3390/ph16121719 - 12 Dec 2023
Viewed by 724
Abstract
Micro-computed tomography (microCT) is a common tool for the visualization of the internal composition of organic tissues. Collagen comprises approximately 25–35% of the whole-body protein content in mammals, and the structure and arrangement of collagen fibers contribute significantly to the integrity of tissues. [...] Read more.
Micro-computed tomography (microCT) is a common tool for the visualization of the internal composition of organic tissues. Collagen comprises approximately 25–35% of the whole-body protein content in mammals, and the structure and arrangement of collagen fibers contribute significantly to the integrity of tissues. Collagen type I is also frequently used as a key structural component in tissue-engineered and bioprinted tissues. However, the imaging of collagenous tissues is limited by their inherently low X-ray attenuation, which makes them indistinguishable from most other soft tissues. An imaging contrast agent that selectively alters X-ray attenuation is thus essential to properly visualize collagenous tissue using a standard X-ray tube microCT scanner. This review compares various contrast-enhanced techniques reported in the literature for MicroCT visualization of collagen-based tissues. An ideal microCT contrast agent would meet the following criteria: (1) it diffuses through the tissue quickly; (2) it does not deform or impair the object being imaged; and (3) it provides sufficient image contrast for reliable visualization of the orientation of individual fibers within the collagen network. The relative benefits and disadvantages of each method are discussed. Lugol’s solution (I3K), phosphotungstic acid (H3PW12O40), mercury(II) chloride (HgCl2), and Wells–Dawson polyoxometalates came closest to fitting the criteria. While none of the contrast agents discussed in the literature met all criteria, each one has advantages to consider in the context of specific lab capabilities and imaging priorities. Full article
(This article belongs to the Special Issue Next-Generation Contrast Agents for Medical Imaging)
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22 pages, 411 KiB  
Review
Pathophysiology and Therapeutic Management of Bone Loss in Patients with Critical Illness
Pharmaceuticals 2023, 16(12), 1718; https://doi.org/10.3390/ph16121718 - 11 Dec 2023
Viewed by 1035
Abstract
Patients with critical illnesses are at higher risk of comorbidities, which can include bone mineral density loss, bone turnover marker increase, and fragility fractures. Patients admitted to intensive care units (ICUs) have a higher risk of bone fractures. Since hypermetabolism is a characteristic [...] Read more.
Patients with critical illnesses are at higher risk of comorbidities, which can include bone mineral density loss, bone turnover marker increase, and fragility fractures. Patients admitted to intensive care units (ICUs) have a higher risk of bone fractures. Since hypermetabolism is a characteristic of ICU patients, such patients are often rapidly affected by systemic deterioration, which often results in systemic wasting disease. Major risk factors for ICU-related bone loss include physical restraint, inflammation, neuroendocrine stress, malnutrition, and medications. A medical history of critical illness should be acknowledged as a risk factor for impaired bone metabolism. Bone loss associated with ICU admission should be recognized as a key component of post-intensive care syndrome, and further research that focuses on treatment protocols and prevention strategies is required. Studies aimed at maintaining gut integrity have emphasized protein administration and nutrition, while research is ongoing to evaluate the therapeutic benefits of anti-resorptive agents and physical therapy. This review examines both current and innovative clinical strategies that are used for identifying risk factors of bone loss. It provides an overview of perioperative outcomes and discusses the emerging novel treatment modalities. Furthermore, the review presents future directions in the treatment of ICU-related bone loss. Full article
(This article belongs to the Special Issue Pharmacotherapy of Bone Diseases)
20 pages, 3505 KiB  
Article
Lipidomics Profiling of Metformin-Induced Changes in Obesity and Type 2 Diabetes Mellitus: Insights and Biomarker Potential
Pharmaceuticals 2023, 16(12), 1717; https://doi.org/10.3390/ph16121717 - 11 Dec 2023
Cited by 1 | Viewed by 947
Abstract
Metformin is the first-line oral medication for treating type 2 diabetes mellitus (T2DM). In the current study, an untargeted lipidomic analytical approach was used to investigate the alterations in the serum lipidome of a cohort of 89 participants, including healthy lean controls and [...] Read more.
Metformin is the first-line oral medication for treating type 2 diabetes mellitus (T2DM). In the current study, an untargeted lipidomic analytical approach was used to investigate the alterations in the serum lipidome of a cohort of 89 participants, including healthy lean controls and obese diabetic patients, and to examine the alterations associated with metformin administration. A total of 115 lipid molecules were significantly dysregulated (64 up-regulated and 51 down-regulated) in the obese compared to lean controls. However, the levels of 224 lipid molecules were significantly dysregulated (125 up-regulated and 99 down-regulated) in obese diabetic patients compared to the obese group. Metformin administration in obese diabetic patients was associated with significant dysregulation of 54 lipid molecule levels (20 up-regulated and 34 down-regulated). Levels of six molecules belonging to five lipid subclasses were simultaneously dysregulated by the effects of obesity, T2DM, and metformin. These include two putatively annotated triacylglycerols (TGs), one plasmenyl phosphatidylcholine (PC), one phosphatidylglycerol (PGs), one sterol lipid (ST), and one Mannosyl-phosphoinositol ceramide (MIPC). This study provides new insights into our understanding of the lipidomics alterations associated with obesity, T2DM, and metformin and offers a new platform for potential biomarkers for the progression of diabetes and treatment response in obese patients. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)
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29 pages, 20132 KiB  
Article
A Systematic Study of Yiqi Qubai Standard Decoction for Treating Vitiligo Based on UPLC-Q-TOF/MS Combined with Chemometrics, Molecular Docking, and Cellular and Zebrafish Assays
Pharmaceuticals 2023, 16(12), 1716; https://doi.org/10.3390/ph16121716 - 11 Dec 2023
Viewed by 832
Abstract
The Yiqi Qubai (YQ) formula is a hospital preparation for treating vitiligo in China that has had reliable efficacy for decades. The formula consists of four herbs; however, the extraction process to produce the formula is obsolete and the active ingredients and mechanisms [...] Read more.
The Yiqi Qubai (YQ) formula is a hospital preparation for treating vitiligo in China that has had reliable efficacy for decades. The formula consists of four herbs; however, the extraction process to produce the formula is obsolete and the active ingredients and mechanisms remain unknown. Therefore, in this paper, fingerprints were combined with the chemometrics method to screen high-quality herbs for the preparation of the YQ standard decoction (YQD). Then, the YQD preparation procedure was optimized using response surface methodology. A total of 44 chemical constituents, as well as 36 absorption components (in rat plasma) of YQD, were identified via UPLC-Q-TOF/MS. Based on the ingredients, the quality control system of YQD was optimized by establishing the SPE-UPLC-Q-TOF/MS identification method and the HPLC quantification method. Network pharmacological analysis and molecular docking showed that carasinaurone, calycosin-7-O-β-d-glucoside, methylnissolin-3-O-glucoside, genkwanin, akebia saponin D, formononetin, akebia saponin B, and apigenin may be the key active components for treating vitiligo; the core targets associated with them were AKT1, MAPK1, and mTOR, whereas the related pathways were the PI3K-Akt, MAPK, and FoxO signaling pathways. Cellular assays showed that YQD could promote melanogenesis and tyrosinase activity, as well as the transcription and expression of tyrosinase-associated proteins (i.e., TRP-1) in B16F10 cells. In addition, YQD also increased extracellular tyrosinase activity. Further efficacy validation showed that YQD significantly promotes melanin production in zebrafish. These may be the mechanisms by which YQD improves the symptoms of vitiligo. This is the first systematic study of the YQ formula that has optimized the standard decoction preparation method and investigated the active ingredients, quality control, efficacy, and mechanisms of YQD. The results of this study lay the foundations for the clinical application and further development of the YQ formula. Full article
(This article belongs to the Special Issue Chemometrics in Pharmaceutical Research)
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21 pages, 2681 KiB  
Review
Cardiac PET Imaging of ATP Binding Cassette (ABC) Transporters: Opportunities and Challenges
Pharmaceuticals 2023, 16(12), 1715; https://doi.org/10.3390/ph16121715 - 11 Dec 2023
Viewed by 735
Abstract
Adenosine triphosphate binding cassette (ABC) transporters are a broad family of membrane protein complexes that use energy to transport molecules across cells and/or intracellular organelle lipid membranes. Many drugs used to treat cardiac diseases have an affinity for these transporters. Among others, P-glycoprotein [...] Read more.
Adenosine triphosphate binding cassette (ABC) transporters are a broad family of membrane protein complexes that use energy to transport molecules across cells and/or intracellular organelle lipid membranes. Many drugs used to treat cardiac diseases have an affinity for these transporters. Among others, P-glycoprotein (P-gp) plays an essential role in regulating drug concentrations that reach cardiac tissue and therefore contribute to cardiotoxicity. As a molecular imaging modality, positron emission tomography (PET) has emerged as a viable technique to investigate the function of P-gp in organs and tissues. Using PET imaging to evaluate cardiac P-gp function provides new insights for drug development and improves the precise use of medications. Nevertheless, information in this field is limited. In this review, we aim to examine the current applications of ABC transporter PET imaging and its tracers in the heart, with a specific emphasis on P-gp. Furthermore, the opportunities and challenges in this novel field will be discussed. Full article
36 pages, 2464 KiB  
Review
Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders
Pharmaceuticals 2023, 16(12), 1714; https://doi.org/10.3390/ph16121714 - 11 Dec 2023
Viewed by 1643
Abstract
Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of [...] Read more.
Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention for its potential neuroprotective properties due to the growing demand for treatments for Alzheimer’s, Parkinson’s, and motor neuron diseases. This review synthesizes experimental and clinical studies on metformin’s mechanisms of action and potential therapeutic benefits for neurodegenerative disorders. A comprehensive search of electronic databases, including PubMed, MEDLINE, Embase, and Cochrane library, focused on key phrases such as “metformin”, “neuroprotection”, and “neurodegenerative diseases”, with data up to September 2023. Recent research on metformin’s glucoregulatory mechanisms reveals new molecular targets, including the activation of the LKB1–AMPK signaling pathway, which is crucial for chronic administration of metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. The precise role of respiratory chain complexes (I and IV), of the mitochondrial targets, or of the lysosomes in metformin effects remains to be established by further research. Research on extrahepatic targets like the gut and microbiota, as well as its antioxidant and immunomodulatory properties, is crucial for understanding neurodegenerative disorders. Experimental data on animal models shows promising results, but clinical studies are inconclusive. Understanding the molecular targets and mechanisms of its effects could help design clinical trials to explore and, hopefully, prove its therapeutic effects in neurodegenerative conditions. Full article
(This article belongs to the Special Issue Metformin: Mechanism and Application 2023)
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