Pharmaceuticals

21 pages, 3036 KiB

Open AccessArticle

Polyphenols as Inhibitors of Antibiotic Resistant Bacteria—Mechanisms Underlying Rutin Interference with Bacterial Virulence

by Marija Ivanov, Katarina Novović, Milka Malešević, Miroslav Dinić, Dejan Stojković, Branko Jovčić and Marina Soković

Pharmaceuticals 2022, 15(3), 385; https://doi.org/10.3390/ph15030385 - 21 Mar 2022

Cited by 23 | Viewed by 3930

Abstract

The rising incidence of antibiotic resistant microorganisms urges novel antimicrobials development with polyphenols as appealing potential therapeutics. We aimed to reveal the most promising polyphenols among hesperetin, hesperidin, naringenin, naringin, taxifolin, rutin, isoquercitrin, morin, chlorogenic acid, ferulic acid, p-coumaric acid, and gallic [...] Read more.

The rising incidence of antibiotic resistant microorganisms urges novel antimicrobials development with polyphenols as appealing potential therapeutics. We aimed to reveal the most promising polyphenols among hesperetin, hesperidin, naringenin, naringin, taxifolin, rutin, isoquercitrin, morin, chlorogenic acid, ferulic acid, p-coumaric acid, and gallic acid based on antimicrobial capacity, antibiofilm potential, and lack of cytotoxicity towards HaCaT, and to further test its antivirulence mechanisms. Although the majority of studied polyphenols were able to inhibit bacterial growth and biofilm formation, the most promising activities were observed for rutin. Further investigation proved rutin’s ability to prevent/eradicate Pseudomonas aeruginosa and MRSA urinary catheter biofilms. Besides reduction of biofilm biomass, rutin antibiofilm mechanisms included reduction of cell viability, exopolysaccharide, and extracellular DNA levels. Moderate reduction of bacterial adhesion to human keratinocytes upon treatment was observed. Rutin antivirulence mechanisms included an impact on P. aeruginosa protease, pyocyanin, rhamnolipid, and elastase production and the downregulation of the lasI, lasR, rhlI, rhlR, pqsA and mvfR genes. Rutin also interfered with membrane permeability. Polyphenols could repress antibiotic resistant bacteria. Rutin has shown wide antimicrobial and antibiofilm capacity employing a range of mechanisms that might be used for the development of novel antimicrobials. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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50 pages, 9734 KiB

Open AccessReview

Recommendations to Synthetize Old and New β-Lactamases Inhibitors: A Review to Encourage Further Production

by Silvana Alfei and Guendalina Zuccari

Pharmaceuticals 2022, 15(3), 384; https://doi.org/10.3390/ph15030384 - 21 Mar 2022

Cited by 15 | Viewed by 4663 | Correction

Abstract

The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of [...] Read more.

The increasing emergence of bacteria producing β-lactamases enzymes (BLEs), able to inactivate the available β-lactam antibiotics (BLAs), causing the hydrolytic opening of their β-lactam ring, is one of the global major warnings. According to Ambler classification, BLEs are grouped in serine-BLEs (SBLEs) of class A, C, and D, and metal-BLEs (MBLEs) of class B. A current strategy to restore no longer functioning BLAs consists of associating them to β-lactamase enzymes inhibitors (BLEsIs), which, interacting with BLEs, prevent them hydrolyzing to the associated antibiotic. Worryingly, the inhibitors that are clinically approved are very few and inhibit only most of class A and C SBLEs, leaving several class D and all MBLEs of class B untouched. Numerous non-clinically approved new molecules are in development, which have shown broad and ultra-broad spectrum of action, some of them also being active on the New Delhi metal-β-lactamase-1 (NDM-1), which can hydrolyze all available BLAs except for aztreonam. To not duplicate the existing review concerning this topic, we have herein examined BLEsIs by a chemistry approach. To this end, we have reviewed both the long-established synthesis adopted to prepare the old BLEsIs, those proposed to achieve the BLEsIs that are newly approved, and those recently reported to prepare the most relevant molecules yet in development, which have shown high potency, providing for each synthesis the related reaction scheme. Full article

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

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14 pages, 4264 KiB

Open AccessArticle

Radiosynthesis and Preclinical Evaluation of Bispecific PSMA/FAP Heterodimers for Tumor Imaging

by Kongzhen Hu, Li Li, Yong Huang, Shimin Ye, Jiawei Zhong, Qingsong Yan, Yuhua Zhong, Lilan Fu, Pengju Feng and Hongsheng Li

Pharmaceuticals 2022, 15(3), 383; https://doi.org/10.3390/ph15030383 - 21 Mar 2022

Cited by 13 | Viewed by 3143

Abstract

Due to tumor heterogeneity and complex tumor–stromal interactions in multicellular systems, the efficiency of monospecific tracers for tumor diagnosis and therapy is currently limited. In light of the evidence of prostate-specific membrane antigen (PSMA) overexpression in tumor cells and fibroblast activation protein (FAP) [...] Read more.

Due to tumor heterogeneity and complex tumor–stromal interactions in multicellular systems, the efficiency of monospecific tracers for tumor diagnosis and therapy is currently limited. In light of the evidence of prostate-specific membrane antigen (PSMA) overexpression in tumor cells and fibroblast activation protein (FAP) upregulation in the tumor stroma, heterodimer dual targeting PSMA and FAP may have the potential to improve tumor diagnosis. Herein, we described the radiosynthesis, in vitro characterization, and micro-PET/CT imaging of two novel ¹⁸F-labeled bispecific PSMA/FAP heterodimers. ¹⁸F-labeled heterodimers showed high specificity and affinity targeting to PSMA and FAP in vitro and in vivo. Compared with the monospecific tracers [¹⁸F]AlF-PSMA-BCH and [¹⁸F]FAPI-42, both ¹⁸F-labeled heterodimers exhibited better tumor uptake in tumor-bearing mice. Their favorable characterizations such as convenient synthesis, high tumor uptake, and favorable pharmacokinetic profile could lead to their future applications as bispecific radiotracers for clinical cancer imaging. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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13 pages, 291 KiB

Open AccessArticle

Prevalence of Licit and Illicit Drugs Use during Pregnancy in Mexican Women

by Larissa-María Gómez-Ruiz, Emilia Marchei, Maria Concetta Rotolo, Pietro Brunetti, Giulio Mannocchi, Aracely Acosta-López, Ruth-Yesica Ramos-Gutiérrez, Mary-Buhya Varela-Busaka, Simona Pichini and Oscar Garcia-Algar

Pharmaceuticals 2022, 15(3), 382; https://doi.org/10.3390/ph15030382 - 21 Mar 2022

Cited by 6 | Viewed by 2794

Abstract

For the first time, the present study employed hair testing to investigate the prevalence of classical drugs of abuse and new psychoactive substances use during gestation in a cohort of 300 Mexican pregnant women. An interview was conducted to collect data on sociodemographic [...] Read more.

For the first time, the present study employed hair testing to investigate the prevalence of classical drugs of abuse and new psychoactive substances use during gestation in a cohort of 300 Mexican pregnant women. An interview was conducted to collect data on sociodemographic aspects of the patients, and a 9 cm-long hair strand was taken from the back of the head of each mother one month after delivery. A validated ultra-high-performance liquid chromatography–high-resolution mass spectrometry method was used for the screening of classic drugs, new psychoactive substances, and medications in maternal hair. Out of 300 examined hair samples from pregnant women, 127 (42.3%) resulted positive for psychoactive substances: 45 (35.4%) for cannabis only, 24 (18.9%) for methamphetamine only, 13 (10.2%) for cocaine only, 1 (0.3%) for heroin, 1 for N-N-dimethyltryptamine (0.3%), 1 for ketamine (0.8%), and 35 (16.3%) for more than one psychoactive substance. Furthermore, seven samples (2.3%) resulted positive for new psychoactive substances (NPS): two samples for synthetic cannabinoids, two for synthetic cathinones, and three for nor-fentanyl, and 3.3% of women hair resulted positive for anticonvulsant, antidepressant, and antipsychotic medications. Finally, 83 women hair samples (27.7%) tested positive for nicotine. Nonsteroidal anti-inflammatory drugs (NSAIDs) and other painkillers (60.0%), medications for the treatment of nausea and vomiting (12.3%), antihistamines (8.7%) and nasal/sinus decongestants (6.7%), cough suppressants (5.0%), and bronchodilator agents (5.0%) were also detected in pregnant women hair. The gestational use of psychoactive substances and exposure to tobacco smoke, assessed by hair testing, were associated with a significantly younger age and with a low education grade of the mothers (p < 0.005). This study provides a significant preliminary indication of the under-reported gestational consumption of licit and illicit psychoactive and pharmacologically active drugs in a Mexican environment, showing the value of toxicological and forensic analyses in the global effort to determine the health risks caused by classic drugs and new psychoactive substances during pregnancy. Full article

(This article belongs to the Special Issue Clinical and Forensic Toxicology: The Latest Updates)

19 pages, 3133 KiB

Open AccessArticle

Metformin Enhances TKI-Afatinib Cytotoxic Effect, Causing Downregulation of Glycolysis, Epithelial–Mesenchymal Transition, and EGFR-Signaling Pathway Activation in Lung Cancer Cells

by Pedro Barrios-Bernal, Norma Hernandez-Pedro, Mario Orozco-Morales, Rubí Viedma-Rodríguez, José Lucio-Lozada, Federico Avila-Moreno, Andrés F. Cardona, Rafael Rosell and Oscar Arrieta

Pharmaceuticals 2022, 15(3), 381; https://doi.org/10.3390/ph15030381 - 21 Mar 2022

Cited by 7 | Viewed by 3087

Abstract

The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or [...] Read more.

The combination of metformin and TKIs for non-small cell lung cancer has been proposed as a strategy to overcome resistance of neoplastic cells induced by several molecular mechanisms. This study sought to investigate the effects of a second generation TKI afatinib, metformin, or their combination on three adenocarcinoma lung cancer cell lines with different EGFRmutation status. A549, H1975, and HCC827 cell lines were treated with afatinib, metformin, and their combination for 72 h. Afterwards, several parameters were assessed including cytotoxicity, interactions, apoptosis, and EGFR protein levels at the cell membrane and several glycolytic, oxidative phosphorylation (OXPHOS), and EMT expression markers. All cell lines showed additive to synergic interactions for the induction of cytotoxicity caused by the tested combination, as well as an improved pro-apoptotic effect. This effect was accompanied by downregulation of glycolytic, EMT markers, a significant decrease in glucose uptake, extracellular lactate, and a tendency towards increased OXPHOS subunits expression. Interestingly, we observed a better response to the combined therapy in lung cancer cell lines A549 and H1975, which normally have low affinity for TKI treatment. Findings from this study suggest a sensitization to afatinib therapy by metformin in TKI-resistant lung cancer cells, as well as a reduction in cellular glycolytic phenotype. Full article

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

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10 pages, 281 KiB

Open AccessArticle

Association of Amlodipine with the Risk of In-Hospital Death in Patients with COVID-19 and Hypertension: A Reanalysis on 184 COVID-19 Patients with Hypertension

by Gwenolé Loas, Philippe Van de Borne, Gil Darquennes and Pascal Le Corre

Pharmaceuticals 2022, 15(3), 380; https://doi.org/10.3390/ph15030380 - 21 Mar 2022

Cited by 6 | Viewed by 2617

Abstract

Association between calcium channel blockers (CCBs) or functional inhibitors of acid sphingomyelinase (FIASMAs) use and decreased mortality in people with COVID-19 has been reported in recent studies. Since amlodipine is both a CCB and a FIASMA, the aim of this study was to [...] Read more.

Association between calcium channel blockers (CCBs) or functional inhibitors of acid sphingomyelinase (FIASMAs) use and decreased mortality in people with COVID-19 has been reported in recent studies. Since amlodipine is both a CCB and a FIASMA, the aim of this study was to investigate the association between chronic amlodipine use and the survival of people with hypertension infected with COVID-19. This retrospective cohort study used data extracted from the medical records of adult inpatients with hypertension and laboratory-confirmed COVID-19 between 1 March 2020 and 31 August 2020 with definite outcomes (discharged from hospital or deceased) from Erasme Hospital (Brussels, Belgium). We re-analyzed the data of the retrospective cohort study using only the 184 patients (103 males, 81 females) with a mean age of 69.54 years (SD = 14.6) with hypertension. The fifty-five participants (29.9%) receiving a chronic prescription of amlodipine were compared with the 129 patients who did not receive a chronic prescription of amlodipine. Univariate and multivariate logistic regressions were used to explore the relationships between mortality and sex, age, comorbidities, smoking, and amlodipine status. Out of the 184 participants, 132 (71.7%) survived and 52 (28.3%) died. The mortality rates were, respectively, 12.73% (n = 7) and 34.88% (n = 45) for the amlodipine and non-amlodipine groups. Multivariate logistic regression was significant (Chi square (5) = 29.11; p < 0.0001). Chronic kidney disease and malignant neoplasm were significant predictors as well as amlodipine status. For chronic kidney disease and malignant neoplasm, the odds ratio with 95% confidence interval (95% CI) were, respectively, 2.16 (95% CI: 1.04–4.5; p = 0.039) and 2.46 (95% CI: 1.01–6.01; p = 0.047). For amlodipine status the odds ratio was 0.29 (95% CI: 0.11–0.74; p = 0.009). The result of the present study suggests that amlodipine may be associated with reduced mortality in people with hypertension infected with COVID-19. Further research and randomized clinical trials are needed to confirm the potential protective effect of amlodipine in people with hypertension infected with COVID-19. Full article

(This article belongs to the Section Pharmacology)

15 pages, 2956 KiB

Open AccessArticle

Development and Performance Verification of the PBPK Model for Antazoline and Its Metabolite and Its Utilization for Pharmacological Hypotheses Formulating

by Barbara Wiśniowska, Joanna Giebułtowicz, Roman Piotrowski, Piotr Kułakowski and Sebastian Polak

Pharmaceuticals 2022, 15(3), 379; https://doi.org/10.3390/ph15030379 - 20 Mar 2022

Cited by 1 | Viewed by 2287

Abstract

Antazoline is an antihistaminic drug that is effective in the termination of paroxysmal atrial fibrillation. Despite its long presence in the market, antazoline’s ADME parameters and pharmacokinetic effects in humans are poorly characterized. The objective of this study was to fill this gap [...] Read more.

Antazoline is an antihistaminic drug that is effective in the termination of paroxysmal atrial fibrillation. Despite its long presence in the market, antazoline’s ADME parameters and pharmacokinetic effects in humans are poorly characterized. The objective of this study was to fill this gap by generation of in vitro and in vivo data and the development of a physiologically based pharmacokinetic model describing antazoline and its main metabolite disposition. A set of ADME parameters for the antazoline and its hydroxy metabolite is provided based on literature data, QSAR predictions, in vitro binding and metabolic stability assays. These can be used to feed PBPK models. In our current work, the developed PBPK model simulating simultaneously the pharmacokinetic profile of antazoline and its metabolite was successfully verified against the available clinical data and the presented capability to account for the clinically observed variability. When used to feed the PD model (e.g., simulating ECG), concentration-time profiles predicted by the model enable the assessment of antazoline’s effect in various clinical scenarios with the possibility to account for population differences or CP mediated drug-drug interactions. Full article

(This article belongs to the Special Issue The Prediction of Pharmacokinetics/Pharmacodynamics Using In-Silico Modeling)

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17 pages, 3922 KiB

Open AccessArticle

Targeting Wnt/Beta-Catenin Signaling in HPV-Positive Head and Neck Squamous Cell Carcinoma

by Faris F. Brkic, Stefan Stoiber, Tobias Maier, Elisabeth Gurnhofer, Lukas Kenner, Gregor Heiduschka and Lorenz Kadletz-Wanke

Pharmaceuticals 2022, 15(3), 378; https://doi.org/10.3390/ph15030378 - 20 Mar 2022

Cited by 8 | Viewed by 3442

Abstract

Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression [...] Read more.

Wnt/Beta-Catenin signaling is involved in the carcinogenesis of different solid malignant tumors. The interaction of Creb-binding protein (CBP) with Beta-Catenin is a pivotal component of the Wnt/Beta-Catenin signaling pathway. The first aim of this study was to evaluate the association of CBP expression with survival in patients with human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC). Second, the in vitro effects of the inhibition of CBP/Beta-Catenin interaction were analyzed. In particular, the effects of ICG-001, an inhibitor of CBP/Beta-Catenin interaction, on proliferation, cell death, modulation of Wnt/Beta-Catenin target expression, and cell migration were examined in vitro. High CBP expression is significantly associated with better survival on mRNA and protein levels. Furthermore, we observed cytotoxic as well as anti-migratory effects of ICG-001. These effects were particularly more potent in the HPV-positive than in the -negative cell line. Mechanistically, ICG-001 treatment induced apoptosis and led to a downregulation of CBP, c-MYC, and Cyclin D1 in HPV-positive cells, indicating inhibition of Wnt/Beta-Catenin signaling. In conclusion, high CBP expression is observed in HPV-positive HNSCC patients with a good prognosis, and ICG-001 showed a promising antineoplastic potential, particularly in HPV-positive HNSCC cells. Therefore, ICG-001 may potentially become an essential component of treatment de-escalation regimens for HPV-positive HNSCC. Further studies are warranted for additional assessment of the mechanistic background of our in vitro findings. Full article

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

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14 pages, 1384 KiB

Open AccessArticle

Inhibition of Respiratory RNA Viruses by a Composition of Ionophoric Polyphenols with Metal Ions

by Topaz Kreiser, Dor Zaguri, Shreya Sachdeva, Rachel Zamostiano, Josef Mograbi, Daniel Segal, Eran Bacharach and Ehud Gazit

Pharmaceuticals 2022, 15(3), 377; https://doi.org/10.3390/ph15030377 - 20 Mar 2022

Cited by 7 | Viewed by 9015

Abstract

Controlling the infectivity of respiratory RNA viruses is critical, especially during the current SARS-CoV-2 pandemic. There is an unmet need for therapeutic agents that can reduce viral replication, preferably independent of the accumulation of viral mutations. Zinc ions have an apparent activity as [...] Read more.

Controlling the infectivity of respiratory RNA viruses is critical, especially during the current SARS-CoV-2 pandemic. There is an unmet need for therapeutic agents that can reduce viral replication, preferably independent of the accumulation of viral mutations. Zinc ions have an apparent activity as modulators of intracellular viral RNA replication and thus, appear attractive in reducing viral RNA load and infectivity. However, the intracellular concentration of zinc is usually too low for achieving an optimal inhibitory effect. Various herbal polyphenols serve as excellent zinc ionophores with known antiviral properties. Here, we combined zinc picolinate with a collection of flavonoids, representing commonly used polyphenols. Copper was added to avoid ionic imbalance during treatment and to improve efficacy. Each component separately, as well as their combinations, did not interfere with the viability of cultured A549, H1299, or Vero cells in vitro as determined by MTT assay. The safe combinations were further evaluated to determine antiviral activity. Fluorescence-activated cell sorting and quantitative polymerase chain reaction were used to evaluate antiviral activity of the combinations. They revealed a remarkable (50–95%) decrease, in genome replication levels of a diverse group of respiratory RNA viruses, including the human coronavirus OC43 (HCoV-OC43; a betacoronavirus that causes the common cold), influenza A virus (IAV, strain A/Puerto Rico/8/34 H1N1), and human metapneumovirus (hMPV). Collectively, our results offer an orally bioavailable therapeutic approach that is non-toxic, naturally sourced, applicable to numerous RNA viruses, and potentially insensitive to new mutations and variants. Full article

(This article belongs to the Section Biopharmaceuticals)

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27 pages, 24015 KiB

Open AccessArticle

One-Pot Synthesis and Molecular Modeling Studies of New Bioactive Spiro-Oxindoles Based on Uracil Derivatives as SARS-CoV-2 Inhibitors Targeting RNA Polymerase and Spike Glycoprotein

by Samar A. El-Kalyoubi, Ahmed Ragab, Ola A. Abu Ali, Yousry A. Ammar, Mohamed G. Seadawy, Aya Ahmed and Eman A. Fayed

Pharmaceuticals 2022, 15(3), 376; https://doi.org/10.3390/ph15030376 - 20 Mar 2022

Cited by 40 | Viewed by 2977

Abstract

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for [...] Read more.

The first outbreak in Wuhan, China, in December 2019 was reported about severe acute coronaviral syndrome 2 (SARS-CoV-2). The global coronavirus disease 2019 (COVID-19) pandemic in 2020 resulted in an extremely high potential for dissemination. No drugs are validated in large-scale studies for significant effectiveness in the clinical treatment of COVID-19 patients, despite the worsening trends of COVID-19. This study aims to design a simple and efficient cyclo-condensation reaction of 6-aminouracil derivatives 2a–e and isatin derivatives 1a–c to synthesize spiro-oxindoles 3a–d, 4a–e, and 5a–e. All compounds were tested in vitro against the SARS-CoV-2. Four spiro[indoline-3,5′-pyrido[2,3-d:6,5-d’]dipyrimidine derivatives 3a, 4b, 4d, and 4e showed high activities against the SARS-CoV-2 in plaque reduction assay and were subjected to further RNA-dependent-RNA-polymerase (RdRp) and spike glycoprotein inhibition assay investigations. The four compounds exhibited potent inhibitory activity ranging from 40.23 ± 0.09 to 44.90 ± 0.08 nM and 40.27 ± 0.17 to 44.83 ± 0.16 nM, respectively, when compared with chloroquine as a reference standard, which showed 45 ± 0.02 and 45 ± 0.06 nM against RdRp and spike glycoprotein, respectively. The computational study involving the docking studies of the binding mode inside two proteins ((RdRp) (PDB: 6m71), and (SGp) (PDB: 6VXX)) and geometrical optimization used to generate some molecular parameters were performed for the most active hybrids. Full article

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

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8 pages, 239 KiB

Open AccessCommunication

Isavuconazole Treatment for Invasive Fungal Infections in Pediatric Patients

by Philippe Zimmermann, Benoit Brethon, Julie Roupret-Serzec, Marion Caseris, Lauriane Goldwirt, André Baruchel and Marie de Tersant

Pharmaceuticals 2022, 15(3), 375; https://doi.org/10.3390/ph15030375 - 19 Mar 2022

Cited by 7 | Viewed by 2527

Abstract

This work’s objective was to evaluate the safety of isavuconazole (ISA) as a treatment or prophylaxis for invasive fungal infections (IFIs) in immunocompromised children. IFI was reported as proven or probable according to international definitions. Therapeutic drug monitoring was performed using mass tandem [...] Read more.

This work’s objective was to evaluate the safety of isavuconazole (ISA) as a treatment or prophylaxis for invasive fungal infections (IFIs) in immunocompromised children. IFI was reported as proven or probable according to international definitions. Therapeutic drug monitoring was performed using mass tandem spectrometry to quantify trough plasma concentrations. Targeted ISA levels were 2–4 mg/L, as reported in adult series. Nine patients received ISA as a curative treatment, and six received ISA as prophylaxis. IFIs were proven in four cases and probable in five. The median ISA trough plasma concentration in curative use was 3.19 mg/L [0.88;5.00], and it was 2.94 mg/L [2.77;3.29] in the prophylactic use. The median durations of treatment were 81 days [15;276] and 95 days [15;253], respectively. Three patients had elevated aspartate aminotransferase and alanine aminotransferase, and three patients had elevated creatinine serum. The IFI response was satisfactory in all cases at day 90. No side effects were reported. No patients developed an IFI. Our data underline the safety of an ISA 100 mg dosing regimen in children of <30 kg, which we recommend in this fragile population. We suggest that ISA plasma levels are monitored 10 days after ISA initiation and then every two weeks, alongside guided therapeutic drug monitoring (TDM) administration. Full article

(This article belongs to the Section Pharmacology)

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14 pages, 1384 KiB

Open AccessReview

New Applications of JAK/STAT Inhibitors in Pediatrics: Current Use of Ruxolitinib

by Annalisa Marcuzzi, Erika Rimondi, Elisabetta Melloni, Arianna Gonelli, Antonio Giacomo Grasso, Egidio Barbi and Natalia Maximova

Pharmaceuticals 2022, 15(3), 374; https://doi.org/10.3390/ph15030374 - 19 Mar 2022

Cited by 7 | Viewed by 4873

Abstract

Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK–STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. [...] Read more.

Janus kinases (JAK) are a family of tyrosine kinases (JAK1, JAK2, JAK3, and TYK2) that transduce cytokine-mediated signals through the JAK–STAT metabolic pathway. These kinases act by regulating the transcription of specific genes capable of inducing biological responses in several immune cell subsets. Inhibition of Janus kinases interferes with the JAK–STAT signaling pathway. Besides being used in the treatment of cancer and inflammatory diseases, in recent years, they have also been used to treat inflammatory conditions, such as graft-versus-host disease (GVHD) and cytokine release syndrome as complications of allogeneic hematopoietic stem cell transplantation and cell therapy. Recently, the FDA approved the use of ruxolitinib, a JAK1/2 inhibitor, in the treatment of acute steroid-refractory GVHD (SR-aGVHD), highlighting the role of JAK inhibition in this immune deregulation. Ruxolitinib was initially used to treat myelofibrosis and true polycythemia in a high-dose treatment and caused hematological toxicity. Since a lower dosage often could not be effective, the use of ruxolitinib was suspended. Subsequently, ruxolitinib was evaluated in adult patients with SR-aGVHD and was found to achieve a rapid and effective response. In addition, its early low-dose use in pediatric patients affected by GVHD has proved effective, safe, and reasonably preventive. The review aims to describe the potential properties of ruxolitinib to identify new therapeutic strategies. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Immune Disease)

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13 pages, 1810 KiB

Open AccessPerspective

Polymorphic and Higher-Order G-Quadruplexes as Possible Transcription Regulators: Novel Perspectives for Future Anticancer Therapeutic Applications

by Riccardo Rigo, Elisabetta Groaz and Claudia Sissi

Pharmaceuticals 2022, 15(3), 373; https://doi.org/10.3390/ph15030373 - 19 Mar 2022

Cited by 5 | Viewed by 2402

Abstract

In the past two decades, significant efforts have been put into designing small molecules to target selected genomic sites where DNA conformational rearrangements control gene expression. G-rich sequences at oncogene promoters are considered good points of intervention since, under specific environmental conditions, they [...] Read more.

In the past two decades, significant efforts have been put into designing small molecules to target selected genomic sites where DNA conformational rearrangements control gene expression. G-rich sequences at oncogene promoters are considered good points of intervention since, under specific environmental conditions, they can fold into non-canonical tetrahelical structures known as G-quadruplexes. However, emerging evidence points to a frequent lack of correlation between small molecule targeting of G-quadruplexes at gene promoters and the expression of the associated protein, which hampers pharmaceutical applications. The wide genomic localization of G-quadruplexes along with their highly polymorphic behavior may account for this scenario, suggesting the need for more focused drug design strategies. Here, we will summarize the G4 structural features that can be considered to fulfill this goal. In particular, by comparing a telomeric sequence with the well-characterized G-rich domain of the KIT promoter, we will address how multiple secondary structures might cooperate to control genome architecture at a higher level. If this holds true, the link between drug–DNA complex formation and the associated cellular effects will need to be revisited. Full article

(This article belongs to the Special Issue Quadruplex Nucleic Acid Ligands in Drug Discovery)

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29 pages, 3178 KiB

Open AccessArticle

Up-to-Date Overview of the Use of Natural Ingredients in Sunscreens

by Diana I. S. P. Resende, Ana Jesus, José M. Sousa Lobo, Emília Sousa, Maria T. Cruz, Honorina Cidade and Isabel F. Almeida

Pharmaceuticals 2022, 15(3), 372; https://doi.org/10.3390/ph15030372 - 18 Mar 2022

Cited by 9 | Viewed by 5369

Abstract

The photoprotective skincare segment is in high demand to meet consumer concerns on UV-induced skin damage, with a recent trend towards sunscreen alternatives with a natural origin. In this study, the use of natural ingredients, either from terrestrial or marine origin, in a [...] Read more.

The photoprotective skincare segment is in high demand to meet consumer concerns on UV-induced skin damage, with a recent trend towards sunscreen alternatives with a natural origin. In this study, the use of natural ingredients, either from terrestrial or marine origin, in a panel of 444 sunscreen commercial formulations (2021) was analyzed. Ingredients from terrestrial organisms represent the large majority found in the analyzed sunscreen formulations (48%), whereas marine ingredients are present only in 13% of the analyzed products. A deeper analysis regarding the most prevalent families of ingredients from terrestrial and marine organisms used as top ingredients is also presented, as well as their mechanisms of action. This study provides an up-to-date overview of the sunscreen market regarding the use of natural ingredients, which is of relevance for scientists involved in the development of new sunscreens to identify opportunities for innovation. Full article

(This article belongs to the Section Natural Products)

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44 pages, 18162 KiB

Open AccessReview

Current and Future Prospective of Injectable Hydrogels—Design Challenges and Limitations

by Saud Almawash, Shaaban K. Osman, Gulam Mustafa and Mohamed A. El Hamd

Pharmaceuticals 2022, 15(3), 371; https://doi.org/10.3390/ph15030371 - 18 Mar 2022

Cited by 31 | Viewed by 7795

Abstract

Injectable hydrogels (IHs) are smart biomaterials and are the most widely investigated and versatile technologies, which can be either implanted or inserted into living bodies with minimal invasion. Their unique features, tunable structure and stimuli-responsive biodegradation properties make these IHs promising in many [...] Read more.

Injectable hydrogels (IHs) are smart biomaterials and are the most widely investigated and versatile technologies, which can be either implanted or inserted into living bodies with minimal invasion. Their unique features, tunable structure and stimuli-responsive biodegradation properties make these IHs promising in many biomedical applications, including tissue engineering, regenerative medicines, implants, drug/protein/gene delivery, cancer treatment, aesthetic corrections and spinal fusions. In this review, we comprehensively analyze the current development of several important types of IHs, including all those that have received FDA approval, are under clinical trials or are available commercially on the market. We also analyze the structural chemistry, synthesis, bonding, chemical/physical crosslinking and responsive release in association with current prospective research. Finally, we also review IHs’ associated future prospects, hurdles, limitations and challenges in their development, fabrication, synthesis, in situ applications and regulatory affairs. Full article

(This article belongs to the Special Issue Hydrogels in Biomedical Applications)

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19 pages, 2531 KiB

Open AccessArticle

Design and Development of Levodopa Loaded Polymeric Nanoparticles for Intranasal Delivery

by Mohd Zulhelmy Ahmad, Akmal Hidyat Bin Sabri, Qonita Kurnia Anjani, Juan Domínguez-Robles, Normala Abdul Latip and Khuriah Abdul Hamid

Pharmaceuticals 2022, 15(3), 370; https://doi.org/10.3390/ph15030370 - 18 Mar 2022

Cited by 14 | Viewed by 4068

Abstract

Intranasal delivery is an alternative administration route to deliver levodopa (L-Dopa) to the brain. This drug delivery route offers high drug permeability across the nasal epithelium and rapid absorption into the central nervous system (CNS) while bypassing first-pass metabolism. In this study, we [...] Read more.

Intranasal delivery is an alternative administration route to deliver levodopa (L-Dopa) to the brain. This drug delivery route offers high drug permeability across the nasal epithelium and rapid absorption into the central nervous system (CNS) while bypassing first-pass metabolism. In this study, we developed a library of polymeric nanocarrier systems for L-Dopa utilising poly(lactic-co-glycolic acid) (PLGA) and chitosan. A total of three PLGA nanoparticles formulations (P1, P2 and P3) were prepared using a modified water-in-oil-in-water (W/O/W) solvent evaporation technique, while four formulations of chitosan nanoparticles (C1, C2, C3 and C4) were prepared by ionic gelation method with sodium tripolyphosphate (TPP) as a cross-linking agent. Upon characterising nanocarriers developed, it was discovered that C2 demonstrated the best results with regard to droplet size (553 ± 52 nm), polydispersity index (0.522), zeta potential (+46.2 ± 2.3 mV), and encapsulation efficiency (82.38% ± 1.63). Transmission electron microscopy (TEM) and scanning electron microscopy (SEM) further corroborated the particle size analysis highlighting that C2 displayed uniform particle size with spherical morphology. Additionally, X-ray diffraction analysis (XRD) revealed that C2 was in an amorphous state while Fourier transform infrared (FTIR) analysis showed that there were no chemical interactions that might change the chemical structure of L-Dopa within the polymeric nanoparticle matrix. Lastly, an in-vivo intranasal study in male Wistar rats showed that the absorption of L-Dopa when formulated as chitosan nanoparticles was significantly enhanced (p < 0.05) by approximately two-fold compared to unmodified L-Dopa. Therefore, this work illustrates that formulating L-Dopa into chitosan nanoparticles for intranasal delivery is a potentially viable formulation strategy to improve the bioavailability of the drug for the treatment of Parkinson’s disease. Full article

(This article belongs to the Section Pharmaceutical Technology)

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17 pages, 4748 KiB

Open AccessArticle

Lycorine Ameliorates Thioacetamide-Induced Hepatic Fibrosis in Rats: Emphasis on Antioxidant, Anti-Inflammatory, and STAT3 Inhibition Effects

by Huda Mohammed Alkreathy and Ahmed Esmat

Pharmaceuticals 2022, 15(3), 369; https://doi.org/10.3390/ph15030369 - 18 Mar 2022

Cited by 15 | Viewed by 2683

Abstract

Liver fibrosis is a foremost medical concern worldwide. In Saudi Arabia, numerous risk factors contribute to its high rates. Lycorine—a natural alkaloid—has antioxidant, anti-inflammatory, and antitumor activates. It has been reported to inhibit STAT3 in cancer. Therefore, this study aimed at investigating the [...] Read more.

Liver fibrosis is a foremost medical concern worldwide. In Saudi Arabia, numerous risk factors contribute to its high rates. Lycorine—a natural alkaloid—has antioxidant, anti-inflammatory, and antitumor activates. It has been reported to inhibit STAT3 in cancer. Therefore, this study aimed at investigating the possible antifibrotic effect of lycorine against thioacetamide (TAA)-induced liver fibrosis in rats and at elucidating the possible mechanisms. Liver fibrosis was induced by TAA (200 mg/kg i.p.), three per week for four weeks. Treatment with lycorine (0.5 and 1 mg/kg/d) amended TAA-induced rise of serum transaminases that was confirmed histopathologically. Moreover, it ameliorated liver fibrosis in a dose-dependent manner, as indicated by hindering the TAA-induced increase of hepatic hydroxyproline content, α-smooth muscle actin (α-SMA) and transforming growth factor (TGF-β1) expressions. TAA-induced oxidative stress was amended by lycorine treatment via restoring reduced glutathione and diminishing lipid peroxidation. Moreover, lycorine ameliorated hepatic inflammation by preventing the rise of inflammatory cytokines. Notably, lycorine inhibited STAT3 activity, as evidenced by the decreased phospho-STAT3 expression, accompanied by the elevation of the hepatic Bax/Bcl-2 ratio. In conclusion, lycorine hinders TAA-induced liver fibrosis in rats, due to—at least partly—its antioxidative and anti-inflammatory properties, along with its ability to inhibit STAT3 signaling. Full article

(This article belongs to the Section Pharmacology)

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17 pages, 3844 KiB

Open AccessArticle

Enantioselectivity of Pentedrone and Methylone on Metabolic Profiling in 2D and 3D Human Hepatocyte-like Cells

by Bárbara Silva, Joana Saraiva Rodrigues, Ana Sofia Almeida, Ana Rita Lima, Carla Fernandes, Paula Guedes de Pinho, Joana Paiva Miranda and Fernando Remião

Pharmaceuticals 2022, 15(3), 368; https://doi.org/10.3390/ph15030368 - 17 Mar 2022

Cited by 5 | Viewed by 2398

Abstract

Pentedrone and methylone can express stereoselectivity in toxicokinetic and toxicodynamic processes. Similarly, their chiral discrimination in metabolism, which was not yet evaluated, can result in different metabolic profiles and subsequent hepatotoxic effects. Therefore, the aim of this work was to assess, for the [...] Read more.

Pentedrone and methylone can express stereoselectivity in toxicokinetic and toxicodynamic processes. Similarly, their chiral discrimination in metabolism, which was not yet evaluated, can result in different metabolic profiles and subsequent hepatotoxic effects. Therefore, the aim of this work was to assess, for the first time, both the hepatic cytotoxic and metabolic profile of pentedrone and methylone enantiomers using physiologically relevant in vitro models. The hepatotoxicity of these compounds was observed in a concentration-dependent manner in human stem-cell-derived hepatocyte-like cells (HLCs) cultured under 3D (3D-HLCs) and 2D (2D-HLCs) conditions. Enantioselectivity, on the other hand, was only shown for pentedrone (1 mM) in 3D-HLCs, being R-(−)-pentedrone the most cytotoxic. Furthermore, the metabolic profile was initially evaluated in human liver microsomes (HLM) and further demonstrated in 3D-HLCs and 2D-HLCs applying a gas chromatography coupled to a mass spectrometer (GC–MS) technique. Methylone and pentedrone showed distinct and preferential metabolic routes for their enantiomers, resulting in the production of differentiated metabolites; R-(+)-methylone and R-(−)-pentedrone are the most metabolized enantiomers. In conclusion, the results demonstrated enantioselectivity for pentedrone and methylone in the metabolic processes, with enantioselectivity in cytotoxicity for pentedrone. Full article

(This article belongs to the Special Issue Psychoactive Substances: Pharmacology and Toxicology)

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18 pages, 3909 KiB

Open AccessArticle

E-Cigarette Aerosol Deposition and Disposition of [¹¹C]Nicotine Using Positron Emission Tomography: A Comparison of Nicotine Uptake in Lungs and Brain Using Two Different Nicotine Formulations

by Anders Wall, Sara Roslin, Beatrice Borg, Simon McDermott, Tanvir Walele, Thomas Nahde, Grant O’Connell, Joseph Thompson, Mark Lubberink and Gunnar Antoni

Pharmaceuticals 2022, 15(3), 367; https://doi.org/10.3390/ph15030367 - 17 Mar 2022

Cited by 12 | Viewed by 3464

Abstract

Smoking is a cause of serious disease in smokers. Electronic cigarettes, delivering aerosolized nicotine, offer adult smokers a potentially less harmful alternative to combustible cigarettes. This explorative PET/CT study investigated the distribution and deposition of inhaled [¹¹C]nicotine using the myblu [...] Read more.

Smoking is a cause of serious disease in smokers. Electronic cigarettes, delivering aerosolized nicotine, offer adult smokers a potentially less harmful alternative to combustible cigarettes. This explorative PET/CT study investigated the distribution and deposition of inhaled [¹¹C]nicotine using the myblu^TM e-cigarette with two nicotine formulations, freebase and lactate salt. Fifteen healthy adult smokers participated in the two-part study to assess the distribution and accumulation of [¹¹C]nicotine in the respiratory pathways and brain. Time-activity data for the respiratory pathways, lungs, oesophagus and brain were derived. 31–36% of both inhaled tracer formulations accumulated in the lung within 15–35 s. [¹¹C]Nicotine_freebase exhibited higher uptake and deposition in the upper respiratory pathways. For [¹¹C]nicotine_lactate, brain deposition peaked at 4–5%, with an earlier peak and a steeper decline. A different kinetic profile was obtained for [¹¹C]nicotine_lactate with lower tracer uptake and accumulation in the upper respiratory pathways and an earlier peak and a steeper decline in lung and brain. Using nicotine lactate formulations in e-cigarettes may thus contribute to greater adult smoker acceptance and satisfaction compared to freebase formulations, potentially aiding a transition from combustible cigarettes and an acceleration of tobacco harm reduction initiatives. Full article

(This article belongs to the Section Radiopharmaceutical Sciences)

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42 pages, 1696 KiB

Open AccessReview

Cannabidiol on the Path from the Lab to the Cancer Patient: Opportunities and Challenges

by Miguel Olivas-Aguirre, Liliana Torres-López, Kathya Villatoro-Gómez, Sonia Mayra Perez-Tapia, Igor Pottosin and Oxana Dobrovinskaya

Pharmaceuticals 2022, 15(3), 366; https://doi.org/10.3390/ph15030366 - 17 Mar 2022

Cited by 10 | Viewed by 5367

Abstract

Cannabidiol (CBD), a major non-psychotropic component of cannabis, is receiving growing attention as a potential anticancer agent. CBD suppresses the development of cancer in both in vitro (cancer cell culture) and in vivo (xenografts in immunodeficient mice) models. For critical evaluation of the [...] Read more.

Cannabidiol (CBD), a major non-psychotropic component of cannabis, is receiving growing attention as a potential anticancer agent. CBD suppresses the development of cancer in both in vitro (cancer cell culture) and in vivo (xenografts in immunodeficient mice) models. For critical evaluation of the advances of CBD on its path from laboratory research to practical application, in this review, we wish to call the attention of scientists and clinicians to the following issues: (a) the biological effects of CBD in cancer and healthy cells; (b) the anticancer effects of CBD in animal models and clinical case reports; (c) CBD’s interaction with conventional anticancer drugs; (d) CBD’s potential in palliative care for cancer patients; (e) CBD’s tolerability and reported side effects; (f) CBD delivery for anticancer treatment. Full article

(This article belongs to the Special Issue Cannabidiol: Advances in Therapeutic Applications and Future Perspectives)

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22 pages, 5112 KiB

Open AccessArticle

Use of Early Donated COVID-19 Convalescent Plasma Is Optimal to Preserve the Integrity of Lymphatic Endothelial Cells

by Nada Amri, Rémi Bégin, Nolwenn Tessier, Laurent Vachon, Louis Villeneuve, Philippe Bégin, Renée Bazin, Lionel Loubaki and Catherine Martel

Pharmaceuticals 2022, 15(3), 365; https://doi.org/10.3390/ph15030365 - 17 Mar 2022

Cited by 3 | Viewed by 2808

Abstract

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune [...] Read more.

Convalescent plasma therapy (CPT) has gained significant attention since the onset of the coronavirus disease 2019 (COVID-19) pandemic. However, clinical trials designed to study the efficacy of CPT based on antibody concentrations were inconclusive. Lymphatic transport is at the interplay between the immune response and the resolution of inflammation from peripheral tissues, including the artery wall. As vascular complications are a key pathogenic mechanism in COVID-19, leading to inflammation and multiple organ failure, we believe that sustaining lymphatic vessel function should be considered to define optimal CPT. We herein sought to determine what specific COVID-19 convalescent plasma (CCP) characteristics should be considered to limit inflammation-driven lymphatic endothelial cells (LEC) dysfunction. CCP donated 16 to 100 days after the last day of symptoms was characterized and incubated on inflammation-elicited adult human dermal LEC (aHDLEC). Plasma analysis revealed that late donation correlates with higher concentration of circulating pro-inflammatory cytokines. Conversely, extracellular vesicles (EVs) derived from LEC are more abundant in early donated plasma (r = −0.413, p = 0.004). Thus, secretion of LEC-EVs by an impaired endothelium could be an alarm signal that instigate the self-defense of peripheral lymphatic vessels against an excessive inflammation. Indeed, in vitro experiments suggest that CCP obtained rapidly following the onset of symptoms does not damage the aHDLEC junctions as much as late-donated plasma. We identified a particular signature of CCP that would counteract the effects of an excessive inflammation on the lymphatic endothelium. Accordingly, an easy and efficient selection of convalescent plasma based on time of donation would be essential to promote the preservation of the lymphatic and immune system of infected patients. Full article

(This article belongs to the Special Issue COVID-19 in Pharmaceuticals)

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13 pages, 7422 KiB

Open AccessArticle

Quercetin and Quercitrin from Agrimonia pilosa Ledeb Inhibit the Migration and Invasion of Colon Cancer Cells through the JNK Signaling Pathway

by Nguyet-Tran Trinh, Thi Minh Ngoc Nguyen, Jong-In Yook, Sang-Gun Ahn and Soo-A Kim

Pharmaceuticals 2022, 15(3), 364; https://doi.org/10.3390/ph15030364 - 17 Mar 2022

Cited by 11 | Viewed by 2492

Abstract

Considering the high metastatic potential of colorectal cancer (CRC), the inhibition of metastasis is important for anti-CRC therapy. Agrimonia pilosa Ledeb (A. pilosa) is a perennial herbaceous plant that is widely distributed in Asia. The extracts of A. pilosa have shown [...] Read more.

Considering the high metastatic potential of colorectal cancer (CRC), the inhibition of metastasis is important for anti-CRC therapy. Agrimonia pilosa Ledeb (A. pilosa) is a perennial herbaceous plant that is widely distributed in Asia. The extracts of A. pilosa have shown diverse pharmacological properties, such as antimicrobial, anti-inflammatory, and antitumor activities. In the present study, the antimetastatic activity of A. pilosa was evaluated. Methanol extraction from the roots of A. pilosa was performed by high-performance liquid chromatography (HPLC) and 12 fractions were obtained. Among these, fraction 4 showed the most potent inhibitory effect on the migration of colon cancer cells. Using LC-HR MS analysis, quercetin and quercitrin were identified as flavonoids contained in fraction 4. Like fraction 4, quercetin and quercitrin effectively inhibited the migration and invasion of RKO cells. While the level of E-cadherin was increased, the levels of N-cadherin and vimentin were decreased by the same agents. Although they all activate the p38, JNK, and ERK signaling pathways, only SP600125, an inhibitor of the JNK pathway, specifically inhibited the effect of fraction 4, quercetin, and quercitrin on cell migration. An in vivo experiment also confirmed the antitumor activity of quercetin and quercitrin. Collectively, these results suggest that A. pilosa and its two flavonoids, quercetin and quercitrin, are candidates for the antimetastatic treatment of CRC. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant Based Pharmaceuticals)

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21 pages, 3554 KiB

Open AccessArticle

Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

by Attila Vámos, Abhirup Shaw, Klára Varga, István Csomós, Gábor Mocsár, Zoltán Balajthy, Cecília Lányi, Zsolt Bacso, Mária Szatmári-Tóth and Endre Kristóf

Pharmaceuticals 2022, 15(3), 363; https://doi.org/10.3390/ph15030363 - 17 Mar 2022

Cited by 6 | Viewed by 2983

Abstract

Brown and beige adipocytes have multilocular lipid droplets, express uncoupling protein (UCP) 1, and promote energy expenditure. In rodents, when the stimulus of browning subsides, parkin-dependent mitophagy is activated and dormant beige adipocytes persist. In humans, however, the molecular events during the beige [...] Read more.

Brown and beige adipocytes have multilocular lipid droplets, express uncoupling protein (UCP) 1, and promote energy expenditure. In rodents, when the stimulus of browning subsides, parkin-dependent mitophagy is activated and dormant beige adipocytes persist. In humans, however, the molecular events during the beige to white transition have not been studied in detail. In this study, human primary subcutaneous abdominal preadipocytes were differentiated to beige for 14 days, then either the beige culture conditions were applied for an additional 14 days or it was replaced by a white medium. Control white adipocytes were differentiated by their specific cocktail for 28 days. Peroxisome proliferator-activated receptor γ-driven beige differentiation resulted in increased mitochondrial biogenesis, UCP1 expression, fragmentation, and respiration as compared to white. Morphology, UCP1 content, mitochondrial fragmentation, and basal respiration of the adipocytes that underwent transition, along with the induction of mitophagy, were similar to control white adipocytes. However, white converted beige adipocytes had a stronger responsiveness to dibutyril-cAMP, which mimics adrenergic stimulus, than the control white ones. Gene expression patterns showed that the removal of mitochondria in transitioning adipocytes may involve both parkin-dependent and -independent pathways. Preventing the entry of beige adipocytes into white transition can be a feasible way to maintain elevated thermogenesis and energy expenditure. Full article

(This article belongs to the Section Pharmacology)

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19 pages, 7034 KiB

Open AccessArticle

Tumor Suppressive Role of miR-342-5p and miR-491-5p in Human Osteosarcoma Cells

by Clément Veys, Manon Jammes, Françoise Rédini, Laurent Poulain, Christophe Denoyelle, Florence Legendre and Philippe Galera

Pharmaceuticals 2022, 15(3), 362; https://doi.org/10.3390/ph15030362 - 16 Mar 2022

Cited by 8 | Viewed by 2264

Abstract

Osteosarcomas are the most common type of malignant bone tumor. These tumors are characterized by the synthesis of an osteoid matrix. Current treatments are based on surgery and combination chemotherapy. However, for metastatic or recurrent tumors, chemotherapy is generally ineffective, and osteosarcomas are [...] Read more.

Osteosarcomas are the most common type of malignant bone tumor. These tumors are characterized by the synthesis of an osteoid matrix. Current treatments are based on surgery and combination chemotherapy. However, for metastatic or recurrent tumors, chemotherapy is generally ineffective, and osteosarcomas are sometimes unresectable. Thus, the use of microRNAs (miRNAs) may represent an attractive alternative for the development of new therapies. Using high-throughput functional screening based on impedancemetry, we previously selected five miRNAs with potential chemosensitizing or antiproliferative effects on chondrosarcoma cells. We validated the tumor-suppressive activity of miR-491-5p and miR-342-5p in three chondrosarcoma cell lines. Here, we carried out individual functional validation of these five miRNAs in three osteosarcoma cell lines used as controls to evaluate their specificity of action on another type of bone sarcoma. The cytotoxic effects of miR-491-5p and miR-342-5p were also confirmed in osteosarcoma cells. Both miRNAs induced apoptosis. They increased Bcl-2 homologous antagonist killer (Bak) protein expression and directly targeted Bcl-2 lymphoma-extra large (Bcl-xL). MiR-342-5p also decreased B-cell lymphoma-2 (Bcl-2) protein expression, and miR-491-5p decreased that of Epidermal Growth Factor Receptor (EGFR). MiR-342-5p and miR-491-5p show tumor-suppressive activity in osteosarcomas. This study also confirms the potential of Bcl-xL as a therapeutic target in osteosarcomas. Full article

(This article belongs to the Special Issue siRNA Therapeutics: From Bench Lab to Clinics)

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19 pages, 6683 KiB

Open AccessArticle

Identifying HSV-1 Inhibitors from Natural Compounds via Virtual Screening Targeting Surface Glycoprotein D

by Jiadai Wu, Helen Power, Monica Miranda-Saksena, Peter Valtchev, Aaron Schindeler, Anthony L. Cunningham and Fariba Dehghani

Pharmaceuticals 2022, 15(3), 361; https://doi.org/10.3390/ph15030361 - 16 Mar 2022

Cited by 4 | Viewed by 2581

Abstract

Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents [...] Read more.

Herpes simplex virus (HSV) infections are a worldwide health problem in need of new effective treatments. Of particular interest is the identification of antiviral agents that act via different mechanisms compared to current drugs, as these could interact synergistically with first-line antiherpetic agents to accelerate the resolution of HSV-1-associated lesions. For this study, we applied a structure-based molecular docking approach targeting the nectin-1 and herpesvirus entry mediator (HVEM) binding interfaces of the viral glycoprotein D (gD). More than 527,000 natural compounds were virtually screened using Autodock Vina and then filtered for favorable ADMET profiles. Eight top hits were evaluated experimentally in African green monkey kidney cell line (VERO) cells, which yielded two compounds with potential antiherpetic activity. One active compound (1-(1-benzofuran-2-yl)-2-[(5Z)-2H,6H,7H,8H-[1,3] dioxolo[4,5-g]isoquinoline-5-ylidene]ethenone) showed weak but significant antiviral activity. Although less potent than antiherpetic agents, such as acyclovir, it acted at the viral inactivation stage in a dose-dependent manner, suggesting a novel mode of action. These results highlight the feasibility of in silico approaches for identifying new antiviral compounds, which may be further optimized by medicinal chemistry approaches. Full article

(This article belongs to the Special Issue Recent Advances in the Discovery and Development of Biomolecules as Antiviral Drugs)

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18 pages, 4458 KiB

Open AccessArticle

Biological Evaluation in Resistant Cancer Cells and Study of Mechanism of Action of Arylvinyl-1,2,4-Trioxanes

by Jerome P. L. Ng, Mohit K. Tiwari, Ali Adnan Nasim, Rui Long Zhang, Yuanqing Qu, Richa Sharma, Betty Yuen Kwan Law, Dharmendra K. Yadav, Sandeep Chaudhary, Paolo Coghi and Vincent Kam Wai Wong

Pharmaceuticals 2022, 15(3), 360; https://doi.org/10.3390/ph15030360 - 16 Mar 2022

Cited by 6 | Viewed by 2684

Abstract

1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, [...] Read more.

1,2,4-trioxane is a pharmacophore, which possesses a wide spectrum of biological activities, including anticancer effects. In this study, the cytotoxic effect and anticancer mechanism of action of a set of 10 selected peroxides were investigated on five phenotypically different cancer cell lines (A549, A2780, HCT8, MCF7, and SGC7901) and their corresponding drug-resistant cancer cell lines. Among all peroxides, only 7 and 8 showed a better P-glycoprotein (P-gp) inhibitory effect at a concentration of 100 nM. These in vitro results were further validated by in silico docking and molecular dynamic (MD) studies, where compounds 7 and 8 exhibited docking scores of −7.089 and −8.196 kcal/mol, respectively, and remained generally stable in 100 ns during MD simulation. Further experiments revealed that peroxides 7 and 8 showed no significant effect on ROS accumulations and caspase-3 activity in A549 cells. Peroxides 7 and 8 were also found to decrease cell membrane potential. In addition, peroxides 7 and 8 were demonstrated to oxidize a flavin cofactor, possibly elucidating its mechanism of action. In conclusion, apoptosis induced by 1,2,4-trioxane was shown to undergo via a ROS- and caspase-3-independent pathway with hyperpolarization of cell membrane potential. Full article

(This article belongs to the Special Issue Recent Advances in Antiviral, Anticancer and Antimalarial Therapy Using Artemisinins and Synthetic Mimics)

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28 pages, 702 KiB

Open AccessReview

Medical Cannabis in Pediatric Oncology: Friend or Foe?

by Megan Malach, Igor Kovalchuk and Olga Kovalchuk

Pharmaceuticals 2022, 15(3), 359; https://doi.org/10.3390/ph15030359 - 16 Mar 2022

Cited by 5 | Viewed by 4000

Abstract

The antineoplastic effects of cannabis have been known since 1975. Since the identification of the components of the endogenous cannabinoid system (ECS) in the 1990s, research into the potential of cannabinoids as medicine has exploded, including in anti-cancer research. However, nearly all of [...] Read more.

The antineoplastic effects of cannabis have been known since 1975. Since the identification of the components of the endogenous cannabinoid system (ECS) in the 1990s, research into the potential of cannabinoids as medicine has exploded, including in anti-cancer research. However, nearly all of this research has been on adults. Physicians and governing bodies remain cautious in recommending the use of cannabis in children, since the ECS develops early in life and data about cannabis exposure in utero show negative outcomes. However, there exist many published cases of use of cannabis in children to treat pediatric epilepsy and chemotherapy-induced nausea and vomiting (CINV) that show both the safety and efficacy of cannabis in pediatric populations. Additionally, promising preclinical evidence showing that cannabis has anti-cancer effects on pediatric cancer warrants further investigation of cannabis’ use in pediatric cancer patients, as well as other populations of pediatric patients. This review aims to examine the evidence regarding the potential clinical utility of cannabis as an anti-cancer treatment in children by summarizing what is currently known about uses of medical cannabis in children, particularly regarding its anti-cancer potential. Full article

(This article belongs to the Special Issue Cannabidiol: Advances in Therapeutic Applications and Future Perspectives)

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22 pages, 8202 KiB

Open AccessEditor’s ChoiceReview

Targeted Drug Delivery to the Central Nervous System Using Extracellular Vesicles

by Lina Zhou, Sunitha Kodidela, Sandip Godse, Stacey Thomas-Gooch, Asit Kumar, Babatunde Raji, Kaining Zhi, Harry Kochat and Santosh Kumar

Pharmaceuticals 2022, 15(3), 358; https://doi.org/10.3390/ph15030358 - 15 Mar 2022

Cited by 17 | Viewed by 4223

Abstract

The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders [...] Read more.

The blood brain barrier (BBB) maintains the homeostasis of the central nervous system (CNS) and protects the brain from toxic substances present in the circulating blood. However, the impermeability of the BBB to drugs is a hurdle for CNS drug development, which hinders the distribution of the most therapeutic molecules into the brain. Therefore, scientists have been striving to develop safe and effective technologies to advance drug penetration into the CNS with higher targeting properties and lower off-targeting side effects. This review will discuss the limitation of artificial nanomedicine in CNS drug delivery and the use of natural extracellular vesicles (EVs), as therapeutic vehicles to achieve targeted delivery to the CNS. Information on clinical trials regarding CNS targeted drug delivery using EVs is very limited. Thus, this review will also briefly highlight the recent clinical studies on targeted drug delivery in the peripheral nervous system to shed light on potential strategies for CNS drug delivery. Different technologies engaged in pre- and post-isolation have been implemented to further utilize and optimize the natural property of EVs. EVs from various sources have also been applied in the engineering of EVs for CNS targeted drug delivery in vitro and in vivo. Here, the future feasibility of those studies in clinic will be discussed. Full article

(This article belongs to the Special Issue Targeted and Stimulus-Responsive Nanomedicines for the Treatment of Central Nervous System (CNS) Disorders)

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18 pages, 3366 KiB

Open AccessArticle

Novel In Vivo Assessment of Antimicrobial Efficacy of Ciprofloxacin Loaded Mesoporous Silica Nanoparticles against Salmonella typhimurium Infection

by Maher N. Alandiyjany, Ahmed S. Abdelaziz, Ahmed Abdelfattah-Hassan, Wael A. H. Hegazy, Arwa A. Hassan, Sara T. Elazab, Eman A. A. Mohamed, Eman S. El-Shetry, Ayman A. Saleh, Naser A. ElSawy and Doaa Ibrahim

Pharmaceuticals 2022, 15(3), 357; https://doi.org/10.3390/ph15030357 - 15 Mar 2022

Cited by 34 | Viewed by 3494

Abstract

Salmonella enterica serovar Typhimurium (S. typhimurium) is known for its intracellular survival, evading the robust inflammation and adaptive immune response of the host. The emergence of decreased ciprofloxacin (CIP) susceptibility (DCS) requires a prolonged antibiotic course with increased dosage, leading to [...] Read more.

Salmonella enterica serovar Typhimurium (S. typhimurium) is known for its intracellular survival, evading the robust inflammation and adaptive immune response of the host. The emergence of decreased ciprofloxacin (CIP) susceptibility (DCS) requires a prolonged antibiotic course with increased dosage, leading to threatening, adverse effects. Moreover, antibiotic-resistant bacteria can persist in biofilms, causing serious diseases. Hence, we validated the in vitro and in vivo efficacy of ciprofloxacin-loaded mesoporous silica nanoparticles (CIP–MSN) using a rat model of salmonella infection to compare the oral efficacy of 5 mg/kg body weight CIP–MSN and a traditional treatment regimen with 10 mg/kg CIP postinfection. Our results revealed that mesoporous silica particles can regulate the release rate of CIP with an MIC of 0.03125 mg/L against DCS S. typhimurium with a greater than 50% reduction of biofilm formation without significantly affecting the viable cells residing within the biofilm, and a sub-inhibitory concentration of CIP–MSN significantly reduced invA and FimA gene expressions. Furthermore, oral supplementation of CIP–MSN had an insignificant effect on all blood parameter values as well as on liver and kidney function parameters. MPO and NO activities that are key mediators of oxidative stress were abolished by CIP–MSN supplementation. Additionally, CIP–MSN supplementation has a promising role in attenuating the elevated secretion of pro-inflammatory cytokines and chemokines in serum from S. typhimurium-infected rats with a reduction in pro-apoptotic gene expression, resulting in reduced S. typhimurium-induced hepatic apoptosis. This counteracted the negative effects of the S. typhimurium challenge, as seen in a corrected histopathological picture of both the intestine and liver, along with increased bacterial clearance. We concluded that, compared with a normal ciprofloxacin treatment regime, MSN particles loaded with a half-dose of ciprofloxacin exhibited controlled release of the antibiotic, which can prolong the antibacterial effect. Full article

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

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19 pages, 4369 KiB

Open AccessArticle

Phytol and Heptacosane Are Possible Tools to Overcome Multidrug Resistance in an In Vitro Model of Acute Myeloid Leukemia

by Manuela Labbozzetta, Paola Poma, Marco Tutone, James A. McCubrey, Maurizio Sajeva and Monica Notarbartolo

Pharmaceuticals 2022, 15(3), 356; https://doi.org/10.3390/ph15030356 - 15 Mar 2022

Cited by 9 | Viewed by 2744

Abstract

Drug resistance is the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, and remains a major problem in cancer therapy. Resistance mechanisms are multifactorial and involve more strictly pharmacological factors, such as P-glycoprotein (P-gp) and biological factors [...] Read more.

Drug resistance is the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, and remains a major problem in cancer therapy. Resistance mechanisms are multifactorial and involve more strictly pharmacological factors, such as P-glycoprotein (P-gp) and biological factors such as inhibitor of apoptosis proteins (IAPs) and the nuclear factor-kappa B (NF-κB) pathway. Possible therapeutic strategies for the treatment of acute myeloid leukemia (AML) have increased in recent years; however, drug resistance remains a problem for most pa-tients. Phytol and heptacosane are the major compounds of Euphorbia intisy essential oil (EO) which were demonstrated to inhibit P-gp in a multidrug resistant in vitro model of AML. This study investigated the mechanism by which phytol and heptacosane improve P-gp-mediated drug transport. Phytol suppresses the P-gp expression via NF-κB inhibition and does not seem to act on the efflux system. Heptacosane acts as a substrate and potent P-gp inhibitor, demonstrating the ability to retain the substrate doxorubicin inside the cell and enhancing its cytotoxic effects. Our results suggest that these compounds act as non-toxic modulators of P-gp through different mechanisms and are able to revert P-gp-mediated drug resistance in tumor cells. Full article

(This article belongs to the Section Pharmacology)

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Pharmaceuticals, Volume 15, Issue 3 (March 2022) – 124 articles

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