Pharmaceuticals

17 pages, 2008 KiB

Open AccessArticle

Exploration of the Antioxidant and Anti-inflammatory Potential of Cassia sieberiana DC and Piliostigma thonningii (Schumach.) Milne-Redh, Traditionally Used in the Treatment of Hepatitis in the Hauts-Bassins Region of Burkina Faso

by Eliasse Zongo, Anna Busuioc, Roland Nâg-Tiero Meda, Andreea Veronica Botezatu, Maria Daniela Mihaila, Ana-Maria Mocanu, Sorin Marius Avramescu, Benjamin Kouliga Koama, Sami Eric Kam, Hadidiatou Belem, Franck Le Sage Somda, Clarisse Ouedraogo, Georges Anicet Ouedraogo and Rodica Mihaela Dinica

Pharmaceuticals 2023, 16(1), 133; https://doi.org/10.3390/ph16010133 - 16 Jan 2023

Cited by 2 | Viewed by 2850

Abstract

Inflammation is the supreme biological response to illness. In the Hauts-Bassins region, in traditional medicine, all parts of Cassia sieberiana and Piliostigma thonningii are used to treat hepatitis and inflammation. The aim of this study was to evaluate the in vitro antioxidant and [...] Read more.

Inflammation is the supreme biological response to illness. In the Hauts-Bassins region, in traditional medicine, all parts of Cassia sieberiana and Piliostigma thonningii are used to treat hepatitis and inflammation. The aim of this study was to evaluate the in vitro antioxidant and anti-inflammatory activities of their aqueous extracts. High performance liquid chromatography with photodiode array (HPLC-DAD) and ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC-MS/MS) analyses highlighted the presence of polyphenols and flavonoids. Antioxidant and anti-inflammatory activities were measured by various methods such as DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS 2,2’-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), TAC (total antioxidant capacity), anti-protease, anti-lipoxygenase, and membrane stabilization. The best antioxidant activity was observed in the bark (DPPH: IC50 = 13.45 ± 0.10 µg/mL) and roots (TAC = 29.68 ± 1.48 mg AAE/g DW) of Piliostigma thonningii and in the roots (ABTS: IC50 = 1.83 ± 0.34 µg/mL) of Cassia sieberiana. The best anti-inflammatory activity was observed in the bark (anti-lipoxygenase: IC50 = 13.04 ± 1.99 µg/mL) and leaves (anti-proteases: IC50 = 75.74 ± 1.07 µg/mL, membrane stabilization: IC50 = 48.32 ± 6.39 µg/mL) of Cassia sieberiana. Total polyphenols (ABTS: r = −0.679, TAC: r = 0.960) and condensed tannins (ABTS: r = −0.702, TAC: r = 0.701) were strongly correlated with antioxidant activity. Total flavonoids (anti-proteases: r = −0.729), condensed tannins (anti-proteases: r = 0.698), and vitamin C (anti-proteases: r = −0.953) were strongly correlated with anti-inflammatory activity. Total polyphenols, flavonoids, condensed tannins, and vitamin C could contribute to the antioxidant and anti-inflammatory activities of the two studied plants. These results could validate the traditional use of these plants to treat various inflammatory diseases. Full article

(This article belongs to the Special Issue Natural Pharmacons: Biologically Active Plant-Based Pharmaceuticals 2022)

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11 pages, 994 KiB

Open AccessArticle

Evaluation of Safety, Tolerability and Pharmacokinetic Characteristics of SA001 and Its Active Metabolite Rebamipide after Single and Multiple Oral Administration

by Sungyeun Bae, Ki Young Huh, Jaeseong Oh, Kyung-Sang Yu and Anhye Kim

Pharmaceuticals 2023, 16(1), 132; https://doi.org/10.3390/ph16010132 - 16 Jan 2023

Viewed by 2610

Abstract

Dry eye disease (DED) is one of the most common eye diseases caused by multiple factors. Rebamipide, which is currently used to treat peptic ulcer disease, was shown to enhance secretory function and modulate inflammation in animal disease models. Considering the pathophysiology of [...] Read more.

Dry eye disease (DED) is one of the most common eye diseases caused by multiple factors. Rebamipide, which is currently used to treat peptic ulcer disease, was shown to enhance secretory function and modulate inflammation in animal disease models. Considering the pathophysiology of DED, SA001 was developed expecting enhanced systemic exposure of rebamipide. Clinical trials to evaluate the safety, tolerability and pharmacokinetic (PK) characteristics of SA001 and its active metabolite rebamipide were conducted. After oral administration of SA001, blood and urine samples were collected for PK analysis of SA001 and rebamipide. PK parameters were compared between SA001 and conventional rebamipide (Bamedin^®) and also between fasted and fed. Safety and tolerability were evaluated throughout the study based on adverse events (AEs), physical examinations, vital signs, 12-lead electrocardiography and clinical laboratory tests. SA001 was rapidly absorbed and quickly converted to rebamipide. The systemic exposure of rebamipide was dose-proportional after single and multiple doses. The plasma concentration of rebamipide after administration of SA001 was higher with a dose adjusted AUC_last and C_max 2.20 and 5.45 times higher in the 240 mg dose group and 4.73 and 11.94 times higher in the 600 mg dose group compared to conventional rebamipide. The favorable PK and tolerability profiles support further clinical development. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets and Drug Candidates for the Treatment of Eye Diseases)

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23 pages, 3179 KiB

Open AccessEditor’s ChoiceArticle

N-Derivatives of (Z)-Methyl 3-(4-Oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylates as Antimicrobial Agents—In Silico and In Vitro Evaluation

by Anthi Petrou, Athina Geronikaki, Victor Kartsev, Antonios Kousaxidis, Aliki Papadimitriou-Tsantarliotou, Marina Kostic, Marija Ivanov, Marina Sokovic, Ioannis Nicolaou and Ioannis S. Vizirianakis

Pharmaceuticals 2023, 16(1), 131; https://doi.org/10.3390/ph16010131 - 16 Jan 2023

Cited by 4 | Viewed by 2074

Abstract

Herein, we report the experimental evaluation of the antimicrobial activity of seventeen new (Z)-methyl 3-(4-oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylate derivatives. All tested compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin as well as streptomycin by [...] Read more.

Herein, we report the experimental evaluation of the antimicrobial activity of seventeen new (Z)-methyl 3-(4-oxo-2-thioxothiazolidin-5-ylidene)methyl)-1H-indole-2-carboxylate derivatives. All tested compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin as well as streptomycin by 10–50 fold. The most sensitive bacterium was En. Cloacae, while E. coli was the most resistant one, followed by M. flavus. The most active compound appeared to be compound 8 with MIC at 0.004–0.03 mg/mL and MBC at 0.008–0.06 mg/mL. The antifungal activity of tested compounds was good to excellent with MIC in the range of 0.004–0.06 mg/mL, with compound 15 being the most potent. T. viride was the most sensitive fungal, while A. fumigatus was the most resistant one. Docking studies revealed that the inhibition of E. coli MurB is probably responsible for their antibacterial activity, while 14a–lanosterol demethylase of CYP51Ca is involved in the mechanism of antifungal activity. Furthermore, drug-likeness and ADMET profile prediction were performed. Finally, the cytotoxicity studies were performed for the most active compounds using MTT assay against normal MRC5 cells. Full article

(This article belongs to the Special Issue Novel Antibacterial Agents 2022)

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15 pages, 4393 KiB

Open AccessSystematic Review

Protective Effect of Vitamin D Supplementation on COVID-19-Related Intensive Care Hospitalization and Mortality: Definitive Evidence from Meta-Analysis and Trial Sequential Analysis

by Christiano Argano, Raffaella Mallaci Bocchio, Giuseppe Natoli, Salvatore Scibetta, Marika Lo Monaco and Salvatore Corrao

Pharmaceuticals 2023, 16(1), 130; https://doi.org/10.3390/ph16010130 - 16 Jan 2023

Cited by 23 | Viewed by 30955

Abstract

Background: The COVID-19 pandemic represents one of the world’s most important challenges for global public healthcare. Various studies have found an association between severe vitamin D deficiency and COVID-19-related outcomes. Vitamin D plays a crucial role in immune function and inflammation. Recent data [...] Read more.

Background: The COVID-19 pandemic represents one of the world’s most important challenges for global public healthcare. Various studies have found an association between severe vitamin D deficiency and COVID-19-related outcomes. Vitamin D plays a crucial role in immune function and inflammation. Recent data have suggested a protective role of vitamin D in COVID-19-related health outcomes. The purpose of this meta-analysis and trial sequential analysis (TSA) was to better explain the strength of the association between the protective role of vitamin D supplementation and the risk of mortality and admission to intensive care units (ICUs) in patients with COVID-19. Methods: We searched four databases on 20 September 2022. Two reviewers screened the randomized clinical trials (RCTs) and assessed the risk of bias, independently and in duplicate. The pre-specified outcomes of interest were mortality and ICU admission. Results: We identified 78 bibliographic citations. After the reviewers’ screening, only five RCTs were found to be suitable for our analysis. We performed meta-analyses and then TSAs. Vitamin D administration results in a decreased risk of death and ICU admission (standardized mean difference (95% CI): 0.49 (0.34–0.72) and 0.28 (0.20–0.39), respectively). The TSA of the protective role of vitamin D and ICU admission showed that, since the pooling of the studies reached a definite sample size, the positive association is conclusive. The TSA of the protective role of vitamin D in mortality risk showed that the z-curve was inside the alpha boundaries, indicating that the positive results need further studies. Discussion: The results of the meta-analyses and respective TSAs suggest a definitive association between the protective role of vitamin D and ICU hospitalization. Full article

(This article belongs to the Special Issue Drug Insight: Vitamin D and Its Analogs)

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25 pages, 4939 KiB

Open AccessArticle

Biological Evaluation of Valeriana Extracts from Argentina with Potent Cholinesterase Inhibition for the Treatment of Neurodegenerative Disorders and Their Comorbidities—The Case of Valeriana carnosa Sm. (Caprifoliaceae) Studied in Mice

by Carolina Marcucci, Marina Rademacher, Fabiola Kamecki, Valentina Pastore, Hernán Gerónimo Bach, Rafael Alejandro Ricco, Marcelo Luis Wagner, Damijan Knez, Stanislav Gobec, Natalia Colettis and Mariel Marder

Pharmaceuticals 2023, 16(1), 129; https://doi.org/10.3390/ph16010129 - 16 Jan 2023

Cited by 2 | Viewed by 2787

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder whose pathophysiology includes the abnormal accumulation of proteins (e.g., β-amyloid), oxidative stress, and alterations in neurotransmitter levels, mainly acetylcholine. Here we present a comparative study of the effect of extracts obtained from endemic Argentinian species of valerians, namely V. carnosa Sm., V. clarionifolia Phil. and V. macrorhiza Poepp. ex DC from Patagonia and V. ferax (Griseb.) Höck and V. effusa Griseb., on different AD-related biological targets. Of these anxiolytic, sedative and sleep-inducing valerians, V. carnosa proved the most promising and was assayed in vivo. All valerians inhibited acetylcholinesterase (IC₅₀ between 1.08–12.69 mg/mL) and butyrylcholinesterase (IC₅₀ between 0.0019–1.46 mg/mL). They also inhibited the aggregation of β-amyloid peptide, were able to chelate Fe²⁺ ions, and exhibited a direct relationship between antioxidant capacity and phenolic content. Moreover, V. carnosa was able to inhibit human monoamine oxidase A (IC₅₀: 0.286 mg/mL (0.213–0.384)). A daily intake of aqueous V. carnosa extract by male Swiss mice (50 and 150 mg/kg/day) resulted in anxiolytic and antidepressant-like behavior and improved spatial memory. In addition, decreased AChE activity and oxidative stress markers were observed in treated mouse brains. Our studies contribute to the development of indigenous herbal medicines as therapeutic agents for AD. Full article

(This article belongs to the Special Issue Advances in Acetylcholinesterase and Butyrylcholinesterase Inhibitors)

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17 pages, 2782 KiB

Open AccessArticle

Exploring the Synergistic Effect of Bergamot Essential Oil with Spironolactone Loaded Nano-Phytosomes for Treatment of Acne Vulgaris: In Vitro Optimization, In Silico Studies, and Clinical Evaluation

by Rofida Albash, Noha M. Badawi, Mohammed I. A. Hamed, Maha H. Ragaie, Sahar S. Mohammed, Rovan M. Elbesh, Khaled M. Darwish, Manar O. Lashkar, Sameh S. Elhady and Shaimaa Mosallam

Pharmaceuticals 2023, 16(1), 128; https://doi.org/10.3390/ph16010128 - 15 Jan 2023

Cited by 6 | Viewed by 2591

Abstract

The foremost target of the current work was to formulate and optimize a novel bergamot essential oil (BEO) loaded nano-phytosomes (NPs) and then combine it with spironolactone (SP) in order to clinically compare the efficiency of both formulations against acne vulgaris. The BEO-loaded [...] Read more.

The foremost target of the current work was to formulate and optimize a novel bergamot essential oil (BEO) loaded nano-phytosomes (NPs) and then combine it with spironolactone (SP) in order to clinically compare the efficiency of both formulations against acne vulgaris. The BEO-loaded NPs formulations were fabricated by the thin-film hydration and optimized by 3² factorial design. NPs’ assessments were conducted by measuring entrapment efficiency percent (EE%), particle size (PS), polydispersity index (PDI), and zeta potential (ZP). In addition, the selected BEO-NPs formulation was further combined with SP and then examined for morphology employing transmission electron microscopy and three months storage stability. Both BEO-loaded NPs selected formula and its combination with SP (BEO-NPs-SP) were investigated clinically for their effect against acne vulgaris after an appropriate in silico study. The optimum BEO-NPs-SP showed PS of 300.40 ± 22.56 nm, PDI of 0.571 ± 0.16, EE% of 87.89 ± 4.14%, and an acceptable ZP value of −29.7 ± 1.54 mV. Molecular modeling simulations showed the beneficial role of BEO constituents as supportive/connecting platforms for favored anchoring of SP on the Phosphatidylcholine (PC) interface. Clinical studies revealed significant improvement in the therapeutic response of BEO-loaded NPs that were combined with SP over BEO-NPs alone. In conclusion, the results proved the ability to utilize NPs as a successful nanovesicle for topical BEO delivery as well as the superior synergistic effect when combined with SP in combating acne vulgaris. Full article

(This article belongs to the Section Pharmaceutical Technology)

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24 pages, 5492 KiB

Open AccessArticle

SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors

by Nemanja Djokovic, Minna Rahnasto-Rilla, Nikolaos Lougiakis, Maija Lahtela-Kakkonen and Katarina Nikolic

Pharmaceuticals 2023, 16(1), 127; https://doi.org/10.3390/ph16010127 - 14 Jan 2023

Cited by 1 | Viewed by 1945

Abstract

A growing body of preclinical evidence recognized selective sirtuin 2 (SIRT2) inhibitors as novel therapeutics for treatment of age-related diseases. However, none of the SIRT2 inhibitors have reached clinical trials yet. Transformative potential of machine learning (ML) in early stages of drug discovery [...] Read more.

A growing body of preclinical evidence recognized selective sirtuin 2 (SIRT2) inhibitors as novel therapeutics for treatment of age-related diseases. However, none of the SIRT2 inhibitors have reached clinical trials yet. Transformative potential of machine learning (ML) in early stages of drug discovery has been witnessed by widespread adoption of these techniques in recent years. Despite great potential, there is a lack of robust and large-scale ML models for discovery of novel SIRT2 inhibitors. In order to support virtual screening (VS), lead optimization, or facilitate the selection of SIRT2 inhibitors for experimental evaluation, a machine-learning-based tool titled SIRT2i_Predictor was developed. The tool was built on a panel of high-quality ML regression and classification-based models for prediction of inhibitor potency and SIRT1-3 isoform selectivity. State-of-the-art ML algorithms were used to train the models on a large and diverse dataset containing 1797 compounds. Benchmarking against structure-based VS protocol indicated comparable coverage of chemical space with great gain in speed. The tool was applied to screen the in-house database of compounds, corroborating the utility in the prioritization of compounds for costly in vitro screening campaigns. The easy-to-use web-based interface makes SIRT2i_Predictor a convenient tool for the wider community. The SIRT2i_Predictor’s source code is made available online. Full article

(This article belongs to the Special Issue The Age of In-Silico Methods in Drug Discovery, Development, Manufacture and Quality Control)

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24 pages, 3551 KiB

Open AccessReview

Terminalia arjuna, a Cardioprotective Herbal Medicine–Relevancy in the Modern Era of Pharmaceuticals and Green Nanomedicine—A Review

by Purnimajayasree Ramesh and Arunkumar Palaniappan

Pharmaceuticals 2023, 16(1), 126; https://doi.org/10.3390/ph16010126 - 13 Jan 2023

Cited by 6 | Viewed by 5553

Abstract

Herbal medicines were the main source of therapeutic agents in the ancestral era. Terminalia arjuna (TA) is one such medicinal plant widely known for its several medicinal properties, especially its cardiovascular properties. They have several phytochemicals, such as flavonoids, polyphenols, triterpenoids, tannins, glycosides, [...] Read more.

Herbal medicines were the main source of therapeutic agents in the ancestral era. Terminalia arjuna (TA) is one such medicinal plant widely known for its several medicinal properties, especially its cardiovascular properties. They have several phytochemicals, such as flavonoids, polyphenols, triterpenoids, tannins, glycosides, and several minerals, proteins, and others that are responsible for the above-mentioned medicinal properties. In this review, we have first elaborated on the various processes and their parameters for the efficient extraction of relevant phytochemicals from TA extracts. Secondly, the mechanisms behind the various medicinal properties of TA extracts are explained. We have also highlighted the role of TA extracts on the green synthesis of metallic nanoparticles, especially silver and gold nanoparticles, with an elucidation on the mechanisms behind the synthesis of nanoparticles. Finally, TA extracts-based polymeric formulations are discussed with limitations and future perspectives. We believe that this review could help researchers understand the importance of a well-known cardioprotective medicinal plant, TA, and its biomedical properties, as well as their role in green nanotechnology and various formulations explored for encapsulating them. This review will help researchers design better and greener nanomedicines as well as better formulations to improve the stability and bioavailability of TA extracts. Full article

(This article belongs to the Special Issue Herbal Products: Development and Innovation)

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22 pages, 5590 KiB

Open AccessArticle

Novel Benzimidazole Derived Imine Ligand and Its Co(III) and Cu(II) Complexes as Anticancer Agents: Chemical Synthesis, DFT Studies, In Vitro and In Vivo Biological Investigations

by Prakasha G, H. D. Revanasiddappa, Jayalakshmi B, Prabhakar B. T, Chandan Shivamallu, Prashant M. Viswanath, Raghu Ram Achar, Ekaterina Silina, Victor Stupin, Natalia Manturova, Ali A. Shati, Mohammad Y. Alfaifi, Serag Eldin I. Elbehairi, Sanja J. Armaković, Stevan Armaković and Shiva Prasad Kollur

Pharmaceuticals 2023, 16(1), 125; https://doi.org/10.3390/ph16010125 - 13 Jan 2023

Cited by 4 | Viewed by 2195

Abstract

The emerging interest in the field of coordination chemistry and their biological applications has created a novel impact in the field of chemical biology. With this motivation, in this work we have synthesized a novel benzimidazole derived imine ligand, 2-((E)-((1H-benzo[d]-2-yl)methylimino)methyl)-4-fluorophenol (HBMF) [...] Read more.

The emerging interest in the field of coordination chemistry and their biological applications has created a novel impact in the field of chemical biology. With this motivation, in this work we have synthesized a novel benzimidazole derived imine ligand, 2-((E)-((1H-benzo[d]-2-yl)methylimino)methyl)-4-fluorophenol (HBMF) and its Co(III) and Cu(II) complexes. The metal complexes (C1–C4) were synthesized in 2:1 (HBMF: metal ion) and 1:1:1 (HBMF: metal ion: 1,10-phen) ratios. Structural elucidations of all the synthesized compounds were performed using FT-IR, UV-Visible, NMR, Mass spectroscopy and elemental analysis techniques. A combination of first principles calculations and molecular dynamics simulations was applied to computationally investigate the structural, reactive, and spectroscopic properties of the newly synthesized HBMF ligand and its complexes with copper and cobalt metal ions. Quantum-mechanical calculations in this study were based on the density functional theory (DFT), while molecular dynamics (MD) simulations were based on the OPLS4 force field. The DFT calculations were used to obtain the reactive and spectroscopic properties of the ligand and its complexes, while molecular dynamics (MD) simulations were used to address the ligand’s reactivity with water. Further, the in vitro anti-proliferative activity of the compounds was tested against the A549, Ehrlich–Lettre ascites carcinoma (EAC), SIHA and NIH3T3 cell lines. The biological results depicted that the compound C4, with molecular formula C₂₇H₂₃Cl₂CoFN₅O₃ exhibited profound anti-proliferative activity against the EAC cell line with a significant IC₅₀ value of 10 µm when compared to its parent ligand and other remaining metal complexes under study. Various assays of hematological parameters (alkaline phosphate, creatinine, urea, RBC and WBC) were performed, and significant results were obtained from the experiments. Furthermore, the effect of C4 on neovascularization was evaluated by stimulating the angiogenesis with rVEGF₁₆₅, which was compared with non-tumor models. The EAC cells were cultured in vivo and administrated with 50 and 75 mg/kg of two doses and tumor parameters were evaluated. Full article

(This article belongs to the Special Issue Pharmacological Activities of Schiff Bases and/or Their Metal Complexes)

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11 pages, 2330 KiB

Open AccessArticle

MAPK Cascade Signaling Is Involved in α-MMC Induced Growth Inhibition of Multiple Myeloma MM.1S Cells via G2 Arrest and Mitochondrial-Pathway-Dependent Apoptosis In Vitro

by Zi-Wei Cai, Ting Ye, Pei-Wen Jiang, Yu-Jiao Liao, Lin Wang, Qing-Liang Zhang, Wen-Qian Du, Min Huang, Ping Yang and Min-Hui Li

Pharmaceuticals 2023, 16(1), 124; https://doi.org/10.3390/ph16010124 - 13 Jan 2023

Cited by 1 | Viewed by 1792

Abstract

Multiple myeloma is a hematological malignancy characterized by the unrestricted proliferation of plasma cells that secrete monoclonal immunoglobulins in the bone marrow. Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein extracted from the seeds of the edible plant Momordica charantia L., which has [...] Read more.

Multiple myeloma is a hematological malignancy characterized by the unrestricted proliferation of plasma cells that secrete monoclonal immunoglobulins in the bone marrow. Alpha-momorcharin (α-MMC) is a type I ribosome-inactivating protein extracted from the seeds of the edible plant Momordica charantia L., which has a variety of biological activities. This study aimed to investigate the inhibitory effect of α-MMC on the proliferation of multiple myeloma MM.1S cells and the molecular mechanism of MM.1S cell death induced through the activation of cell signal transduction pathways. The cell counting kit-8 (CCK-8) assay was used to determine the inhibitory effect of α-MMC on the proliferation of MM.1S cells and its toxic effect on normal human peripheral blood mononuclear cells (PBMCs). The effect of α-MMC on the MM.1S cells’ morphology was observed via inverted microscope imaging. The effects of α-MMC on the MM.1S cell cycle, mitochondrial membrane potential (MMP), and apoptosis were explored using propidium iodide, JC-1, annexin V- fluorescein isothiocyanate/propidium iodide fluorescence staining, and flow cytometry (FCM) analysis. Western blot was used to detect the expressions levels of apoptosis-related proteins and MAPK-signaling-pathway-related proteins in MM.1S cells induced by α-MMC. The results of the CCK-8 showed that in the concentration range of no significant toxicity to PBMCs, α-MMC inhibited the proliferation of MM.1S cells in a time-dependent and concentration-dependent manner, and the IC₅₀ value was 13.04 and 7.518 μg/mL for 24 and 48 h, respectively. Through inverted microscope imaging, it was observed that α-MMC induced a typical apoptotic morphology in MM.1S cells. The results of the FCM detection and analysis showed that α-MMC could arrest the MM.1S cells cycle at the G2 phase, decrease the MMP, and induce cell apoptosis. Western blot analysis found that α-MMC upregulated the expression levels of Bax, Bid, cleaved caspase-3, and cleaved PARP, and downregulated the expression levels of Mcl-1. At the same time, α-MMC decreased the expression levels of p-c-Raf, p-MEK1/2, p-ERK1/2, p-MSK1, and p-P90RSK, and increased the expression levels of p-p38, p-SPAK/JNK, p-c-Jun, and p-ATF2. The above results suggest that α-MMC can inhibit the proliferation of multiple myeloma MM.1S cells. MAPK cascade signaling is involved in the growth inhibition effect of α-MMC on MM.1S cells via cycle arrest and mitochondrial-pathway-dependent apoptosis. Full article

(This article belongs to the Special Issue Anticancer Compounds in Medicinal Plants 2023)

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12 pages, 2834 KiB

Open AccessArticle

Established Immortalized Cavernous Endothelial Cells Improve Erectile Dysfunction in Rats with Cavernous Nerve Injury

by Sang Hong Bak, Jae Heon Kim, Seung U. Kim, Dong-Seok Lee, Yun Seob Song and Hong J. Lee

Pharmaceuticals 2023, 16(1), 123; https://doi.org/10.3390/ph16010123 - 13 Jan 2023

Viewed by 2175

Abstract

The main cause of erectile dysfunction (ED) is the damage in penile cavernous endothelial cells (EC). Murine primary ECs have a limited growth potential, and the easy availability of murine ECs will facilitate the study of cavernous endothelial dysfunction in rats. This study [...] Read more.

The main cause of erectile dysfunction (ED) is the damage in penile cavernous endothelial cells (EC). Murine primary ECs have a limited growth potential, and the easy availability of murine ECs will facilitate the study of cavernous endothelial dysfunction in rats. This study was performed to establish immortalized rat penile cavernous ECs (rEC) and investigate how they could repair erectile dysfunction in rats with cavernous nerve injury (CNI). rEC was isolated enzymatically by collagenase digestion and were cultured. An amphotropic replication-incompetent retroviral vector encoding v-myc oncogene was used to transfect rEC for immortalization (vREC). Morphological and immunohistochemical properties of vREC were examined. Eight-week-old male Sprague-Dawley rats were divided into three groups of five rats each, including group 1 = sham operation, group 2 = bilateral CN injury, group 3 = vREC (1 × 10⁶ cells) treatment after CNI. Erectile response was assessed at 2, 4 weeks after transplantation of vREC., Penile tissue were harvested at 4 weeks after transplantation and immune–histochemical examination was performed. vREC showed the expression of CD31, vWF, cell type-specific markers for EC by RT-PCR and flowcytometry. At 2, 4 weeks after transplantation, rats with CNI had significantly lower erectile function than control group (p < 0.05). The group transplanted with vREC showed higher erectile function than the group without vRECs (p < 0.05). vREC was established and repaired erectile dysfunction in rats with CNI. This cell line may be useful for studying mechanisms and drug screening of erectile dysfunction of rats. Full article

(This article belongs to the Special Issue Diagnostics and Pharmacology of Male Reproduction)

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17 pages, 1181 KiB

Open AccessEditor’s ChoiceReview

Prolactin Relationship with Fertility and In Vitro Fertilization Outcomes—A Review of the Literature

by Mirela E. Iancu, Alice I. Albu and Dragoș N. Albu

Pharmaceuticals 2023, 16(1), 122; https://doi.org/10.3390/ph16010122 - 13 Jan 2023

Cited by 1 | Viewed by 8096

Abstract

Hyperprolactinemia is a known cause of amenorrhea and infertility. However, there is an increasing body of evidence suggesting that prolactin is involved in multiple physiological aspects of normal reproduction. Thus, the present paper aims to review the current literature regarding the relationship between [...] Read more.

Hyperprolactinemia is a known cause of amenorrhea and infertility. However, there is an increasing body of evidence suggesting that prolactin is involved in multiple physiological aspects of normal reproduction. Thus, the present paper aims to review the current literature regarding the relationship between serum prolactin level and in vitro fertilization (IVF)/intracytoplasmic sperm injection outcome and the role of dopamine agonists treatment in IVF success. Moreover, the mechanisms by which prolactin may exert its role in fertility and infertility were summarized. Although not all studies agree, the available evidence suggests that higher prolactin levels in follicular fluid are associated with increased oocytes competence, but also with positive effects on corpus luteum formation and survival, endometrial receptivity, blastocyst implantation potential and survival of low-motile sperm. Transient hyperprolactinemia found in IVF cycles was reported in most of the studies not to be related to IVF outcome, although a few reports suggested that it may be associated with higher implantation and pregnancy rates, and better-cumulated pregnancy outcomes. Administration of dopamine agonists for hyperprolactinemia preceding IVF treatment does not seem to negatively impact the IVF results, while treatment of transient hyperprolactinemia during IVF might be beneficial in terms of fertilization rates and conception rates. Due to limited available evidence, future studies are necessary to clarify the optimal level of circulating prolactin in patients performing IVF and the role of dopamine agonist treatment. Full article

(This article belongs to the Section Pharmacology)

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16 pages, 2793 KiB

Open AccessArticle

Design of Novel Tricaprylin-Incorporated Multi-Layered Liposomal System for Skin Delivery of Ascorbic Acid with Improved Chemical Stability

by Myoung Jin Ho, Dong Woo Park and Myung Joo Kang

Pharmaceuticals 2023, 16(1), 121; https://doi.org/10.3390/ph16010121 - 13 Jan 2023

Cited by 3 | Viewed by 2133

Abstract

L-ascorbic acid (Vit C) possesses a variety of dermatological functions in maintaining skin health and anti-aging properties. However, its topical application is challenging owing to its liability to light, oxygen, or heat. Therefore, in this study, a novel liposomal system, including a lipophilic [...] Read more.

L-ascorbic acid (Vit C) possesses a variety of dermatological functions in maintaining skin health and anti-aging properties. However, its topical application is challenging owing to its liability to light, oxygen, or heat. Therefore, in this study, a novel liposomal system, including a lipophilic neutral oil named a lipo-oil-some (LOS), was designed to improve the chemical stability and aid the skin absorption of Vit C. The vesicular systems were prepared using the ethanol injection method, employing phosphatidylcholine, cholesterol, dipalmitoyl-sn-glycerol-3-phosphoglycerol, and tricaprylin as neutral oil. The optimized LOS was characterized as follows: shape, multi-layered sphere; size, 981 nm; zeta potential, −58 mV; and Vit C encapsulation efficiency, 35%. The encapsulation of the labile compound into the novel system markedly enhanced photostability, providing over 10% higher Vit C remaining compared to Vit C solution or Vit C-loaded conventional liposome under a light intensity of 20,000 lx. On the other hand, the ex vivo skin permeation and accumulation of Vit C with the LOS system were comparable to those of smaller conventional liposomes (198 nm) in a Franz diffusion cell model mounted with porcine skin. Based on these findings, we concluded that the novel liposomal system could be utilized for skin delivery of Vit C with enhanced chemical stability. Full article

(This article belongs to the Special Issue Pharmaceutical Excipients in Formulation Design and Drug Delivery)

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20 pages, 4068 KiB

Open AccessArticle

Integrative Ligand-Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Simulation Approaches Identified Potential Lead Compounds against Pancreatic Cancer by Targeting FAK1

by Mohammad Habibur Rahman Molla, Mohammed Othman Aljahdali, Md Afsar Ahmed Sumon, Amer H. Asseri, Hisham N. Altayb, Md. Shafiqul Islam, Ahad Amer Alsaiari, F. A. Dain Md Opo, Nushrat Jahan, Foysal Ahammad and Farhan Mohammad

Pharmaceuticals 2023, 16(1), 120; https://doi.org/10.3390/ph16010120 - 13 Jan 2023

Cited by 7 | Viewed by 4027

Abstract

Pancreatic cancer is a very deadly disease with a 5-year survival rate, making it one of the leading causes of cancer-related deaths globally. Focal adhesion kinase 1 (FAK1) is a ubiquitously expressed protein in pancreatic cancer. FAK, a tyrosine kinase that is overexpressed [...] Read more.

Pancreatic cancer is a very deadly disease with a 5-year survival rate, making it one of the leading causes of cancer-related deaths globally. Focal adhesion kinase 1 (FAK1) is a ubiquitously expressed protein in pancreatic cancer. FAK, a tyrosine kinase that is overexpressed in cancer cells, is crucial for the development of tumors into malignant phenotypes. FAK functions in response to extracellular signals by triggering transmembrane receptor signaling, which enhances focal adhesion turnover, cell adhesion, cell migration, and gene expression. The ligand-based drug design approach was used to identify potential compounds against the target protein, which included molecular docking: ADME (absorption, distribution, metabolism, and excretion), toxicity, molecular dynamics (MD) simulation, and molecular mechanics generalized born surface area (MM-GBSA). Following the retrieval of twenty hits, four compounds were selected for further evaluation based on a molecular docking approach. Three newly discovered compounds, including PubChem CID24601203, CID1893370, and CID16355541, with binding scores of −10.4, −10.1, and −9.7 kcal/mol, respectively, may serve as lead compounds for the treatment of pancreatic cancer associated with FAK1. The ADME (absorption, distribution, metabolism, and excretion) and toxicity analyses demonstrated that the compounds were effective and nontoxic. However, further wet laboratory investigations are required to evaluate the activity of the drugs against the cancer. Full article

(This article belongs to the Special Issue Structure and Ligand Based Drug Design)

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17 pages, 12502 KiB

Open AccessArticle

Sorafenib/2800Z Co-Loaded into Cholesterol and PEG Grafted Polylysine NPs for Liver Cancer Treatment

by Chen Zhang, Wu Zhong, Ying Cao, Bohao Liu, Xiaojun Tao and Zhuan Li

Pharmaceuticals 2023, 16(1), 119; https://doi.org/10.3390/ph16010119 - 13 Jan 2023

Cited by 4 | Viewed by 2139

Abstract

The treatment of liver cancer remains challenging due to the low responsiveness of advanced cancer to therapeutic options. Sorafenib is the first line chemotherapeutic drug for advanced liver cancer but is frequently associated with severe side effects lead to discontinuation of chemotherapy. We [...] Read more.

The treatment of liver cancer remains challenging due to the low responsiveness of advanced cancer to therapeutic options. Sorafenib is the first line chemotherapeutic drug for advanced liver cancer but is frequently associated with severe side effects lead to discontinuation of chemotherapy. We previously developed a specific SIRT7 inhibitor 2800Z, which suppressed tumor growth and enhanced the chemosensitivity of sorafenib. In this study, we constructed polylysine polymer nanoparticles modified with cholesterol and GSH-sensitive PEG (mPssPC) to load sorafenib (SOR) and the SIRT7 inhibitor 2800Z to form dual-loaded NPs (S2@PsPCs) to reduce the toxicity and increase efficacy of sorafenib in liver cancer. The average size of S2@PsPC NPs was approximately 370 nm and the zeta potential was approximately 50–53 mV. We found that the release of the drugs exhibited pH sensitivity and was significantly accelerated in an acid release medium simulating the tumor environment. In addition, S2@PsPC NPs inhibited the proliferation and induced apoptosis of liver cancer cells in vitro. An in vivo study further revealed that S2@PsPCs showed high specificity to the liver cancer but low affinity and toxicity to the main organs including the heart, kidneys, lungs, and liver. Our data thus further approved the combination of a SIRT7 inhibitor and sorafenib for the treatment of liver cancer and provided new drug delivery system for targeted therapy. Full article

(This article belongs to the Section Pharmacology)

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0 pages, 1434 KiB

Open AccessArticle

The Effects of Different Doses of Sildenafil on Coronary Blood Flow and Oxidative Stress in Isolated Rat Hearts

by Nada Banjac, Velibor Vasović, Nebojša Stilinović, Ana Tomas, Lucija Vasović, Nikola Martić, Dušan Prodanović and Vladimir Jakovljević

Pharmaceuticals 2023, 16(1), 118; https://doi.org/10.3390/ph16010118 - 13 Jan 2023

Cited by 2 | Viewed by 2146 | Correction

Abstract

The dose-response relationship of sildenafil effects on cardiac function is not completely elucidated. The aim of this study was to assess the effects of different doses of sildenafil on coronary flow and oxidative stress in isolated rat hearts. Coronary flow and markers of [...] Read more.

The dose-response relationship of sildenafil effects on cardiac function is not completely elucidated. The aim of this study was to assess the effects of different doses of sildenafil on coronary flow and oxidative stress in isolated rat hearts. Coronary flow and markers of oxidative stress, including nitrite outflow, and superoxide anion production in coronary effluent, were determined for isolated rat hearts. The experiments were performed during control conditions and in the presence of sildenafil (10, 20, 50, 200 nM) alone or with Nω-nitro-L-arginine monomethyl ester (L-NAME) (30 μM). Sildenafil was shown to result in a significant increase in coronary flow at lower coronary perfusion pressure (CPP) values at all administered doses, whereas, with an increase in CPP, a reduction in coronary flow was observed. An increase in nitric oxide (NO) was most pronounced in the group treated with the lowest dose of sildenafil at the highest CPP value. After the inhibition of the NO-cyclic guanosine monophosphate (cGMP) signaling (NOS) system by L-NAME, only a dose of 200 nM sildenafil was high enough to overcome the inhibition and to boost release of O₂⁻. That effect was CPP-dependent, with statistical significance reached at 80, 100 and 120 mmHg. Our findings indicate that sildenafil causes changes in heart vasculature in a dose-dependent manner, with a shift from a vasodilatation effect to vasoconstriction with a pressure increase. The highest dose administered is capable of producing superoxide anion radicals in terms of NOS system inhibition. Full article

(This article belongs to the Special Issue Phosphodiesterases as Drug Targets: Development and Challenges)

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21 pages, 3258 KiB

Open AccessArticle

Combined Gamma Conglutin and Lupanine Treatment Exhibits In Vivo an Enhanced Antidiabetic Effect by Modulating the Liver Gene Expression Profile

by Paloma Lucía Guerra-Ávila, Tereso J. Guzmán, José Alfredo Domínguez-Rosales, Pedro Macedonio García-López, Alejandra Beatriz Cervantes-Garduño, Michael Wink and Carmen Magdalena Gurrola-Díaz

Pharmaceuticals 2023, 16(1), 117; https://doi.org/10.3390/ph16010117 - 13 Jan 2023

Cited by 4 | Viewed by 2368

Abstract

Previous studies have individually shown the antidiabetic potential of gamma conglutin (Cγ) and lupanine from lupins. Until now, the influence of combining both compounds and the effective dose of the combination have not been assessed. Moreover, the resulting gene expression profile from this [...] Read more.

Previous studies have individually shown the antidiabetic potential of gamma conglutin (Cγ) and lupanine from lupins. Until now, the influence of combining both compounds and the effective dose of the combination have not been assessed. Moreover, the resulting gene expression profile from this novel combination remains to be explored. Therefore, we aimed to evaluate different dose combinations of Cγ and lupanine by the oral glucose tolerance test (OGTT) to identify the higher antidiabetic effect on a T2D rat model. Later, we administered the selected dose combination during a week. Lastly, we evaluated biochemical parameters and liver gene expression profile using DNA microarrays and bioinformatic analysis. We found that the combination of 28 mg/kg BW Cγ + 20 mg/kg BW lupanine significantly reduced glycemia and lipid levels. Moreover, this treatment positively influenced the expression of Pdk4, G6pc, Foxo1, Foxo3, Ppargc1a, Serpine1, Myc, Slc37a4, Irs2, and Igfbp1 genes. The biological processes associated with these genes are oxidative stress, apoptosis regulation, and glucose and fatty-acid homeostasis. For the first time, we report the beneficial in vivo effect of the combination of two functional lupin compounds. Nevertheless, further studies are needed to investigate the pharmacokinetics and pharmacodynamics of the Cγ + lupanine combined treatment. Full article

(This article belongs to the Special Issue Natural Products in Diabetes Mellitus)

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13 pages, 2800 KiB

Open AccessArticle

BIreactive: Expanding the Scope of Reactivity Predictions to Propynamides

by Markus R. Hermann, Christofer S. Tautermann, Peter Sieger, Marc A. Grundl and Alexander Weber

Pharmaceuticals 2023, 16(1), 116; https://doi.org/10.3390/ph16010116 - 12 Jan 2023

Cited by 2 | Viewed by 1918

Abstract

We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity [...] Read more.

We present the first comprehensive study on the prediction of reactivity for propynamides. Covalent inhibitors like propynamides often show improved potency, selectivity, and unique pharmacologic properties compared to their non-covalent counterparts. In order to achieve this, it is essential to tune the reactivity of the warhead. This study shows how three different in silico methods can predict the in vitro properties of propynamides, a covalent warhead class integrated into approved drugs on the market. Whereas the electrophilicity index is only applicable to individual subclasses of substitutions, adduct formation and transition state energies have a good predictability for the in vitro reactivity with glutathione (GSH). In summary, the reported methods are well suited to estimate the reactivity of propynamides. With this knowledge, the fine tuning of the reactivity is possible which leads to a speed up of the design process of covalent drugs. Full article

(This article belongs to the Special Issue Targeted Covalent Inhibitors in Drug Discovery, Chemical Biology and Beyond)

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25 pages, 2642 KiB

Open AccessArticle

Metformin Induces Apoptosis in Human Pancreatic Cancer (PC) Cells Accompanied by Changes in the Levels of Histone Acetyltransferases (Particularly, p300/CBP-Associated Factor (PCAF) Protein Levels)

by Izabela Szymczak-Pajor, Józef Drzewoski, Ewa Świderska, Justyna Strycharz, Anna Gabryanczyk, Jacek Kasznicki, Marta Bogdańska and Agnieszka Śliwińska

Pharmaceuticals 2023, 16(1), 115; https://doi.org/10.3390/ph16010115 - 12 Jan 2023

Cited by 4 | Viewed by 3213

Abstract

Accumulating evidence (mainly from experimental research) suggests that metformin possesses anticancer properties through the induction of apoptosis and inhibition of the growth and proliferation of cancer cells. However, its effect on the enzymes responsible for histone acetylation status, which plays a key role [...] Read more.

Accumulating evidence (mainly from experimental research) suggests that metformin possesses anticancer properties through the induction of apoptosis and inhibition of the growth and proliferation of cancer cells. However, its effect on the enzymes responsible for histone acetylation status, which plays a key role in carcinogenesis, remains unclear. Therefore, the aim of our study was to evaluate the impact of metformin on histone acetyltransferases (HATs) (i.e., p300/CBP-associated factor (PCAF), p300, and CBP) and on histone deacetylases (HDACs) (i.e., SIRT-1 in human pancreatic cancer (PC) cell lines, 1.2B4, and PANC-1). The cells were exposed to metformin, an HAT inhibitor (HATi), or a combination of an HATi with metformin for 24, 48, or 72 h. Cell viability was determined using an MTT assay, and the percentage of early apoptotic cells was determined with an Annexin V-Cy3 Apoptosis Detection Assay Kit. Caspase-9 activity was also assessed. SIRT-1, PCAF, p300, and CBP expression were determined at the mRNA and protein levels using RT-PCR and Western blotting methods, respectively. Our results reveal an increase in caspase-9 in response to the metformin, indicating that it induced the apoptotic death of both 1.2B4 and PANC-1 cells. The number of cells in early apoptosis and the activity of caspase-9 decreased when treated with an HATi alone or a combination of an HATi with metformin, as compared to metformin alone. Moreover, metformin, an HATi, and a combination of an HATi with metformin also modified the mRNA expression of SIRT-1, PCAF, CBP, and p300. However, metformin did not change the expression of the studied genes in 1.2B4 cells. The results of the Western blot analysis showed that metformin diminished the protein expression of PCAF in both the 1.2B4 and PANC-1 cells. Hence, it appears possible that PCAF may be involved in the metformin-mediated apoptosis of PC cells. Full article

(This article belongs to the Special Issue Metformin: Mechanism and Application 2022)

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18 pages, 3134 KiB

Open AccessArticle

Oxy210, a Semi-Synthetic Oxysterol, Inhibits Profibrotic Signaling in Cellular Models of Lung and Kidney Fibrosis

by Feng Wang, Frank Stappenbeck and Farhad Parhami

Pharmaceuticals 2023, 16(1), 114; https://doi.org/10.3390/ph16010114 - 12 Jan 2023

Viewed by 2165

Abstract

Oxy210, a semi-synthetic oxysterol derivative, displays cell-selective inhibition of Hedgehog (Hh) and transforming growth factor beta (TGF-β) signaling in epithelial cells, fibroblasts, and macrophages as well as antifibrotic and anti-inflammatory efficacy in models of liver fibrosis. In the present report, we examine the [...] Read more.

Oxy210, a semi-synthetic oxysterol derivative, displays cell-selective inhibition of Hedgehog (Hh) and transforming growth factor beta (TGF-β) signaling in epithelial cells, fibroblasts, and macrophages as well as antifibrotic and anti-inflammatory efficacy in models of liver fibrosis. In the present report, we examine the effects of Oxy210 in cellular models of lung and kidney fibrosis, such as human lung fibroblast cell lines IMR-90, derived from healthy lung tissue, and LL97A, derived from an idiopathic pulmonary fibrosis (IPF) patient. In addition, we examine the effects of Oxy210 in primary human renal fibroblasts, pericytes, mesangial cells, and renal tubular epithelial cells, known for their involvement in chronic kidney disease (CKD) and kidney fibrosis. We demonstrate in fibroblasts that the expression of several profibrotic TGF-β target genes, including fibronectin (FN), collagen 1A1 (COL1A1), and connective tissue growth factor (CTGF) are inhibited by Oxy210, both at the basal level and following TGF-β stimulation in a statistically significant manner. The inhibition of COL1A1 gene expression translated directly to significantly reduced COL1A1 protein expression. In human primary small airway epithelial cells (HSAECs) and renal tubular epithelial cells, Oxy210 significantly inhibited TGF-β target gene expression associated with epithelial–mesenchymal transition (EMT). Oxy210 also inhibited the proliferation of fibroblasts, pericytes, and mesangial cells in a dose-dependent and statistically significant manner. Full article

(This article belongs to the Special Issue Recent Advances in TGF-β Inhibitors for the Therapeutic Management of Cancer and Fibrosis)

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14 pages, 6669 KiB

Open AccessArticle

Ciclopirox Olamine Induces Proliferation Inhibition and Protective Autophagy in Hepatocellular Carcinoma

by Xinyan Wan, Junqi Xiang, Hui Fan, Ying Jiang, Yiting Lu, Chundong Zhang, Ying Zhang, Quanmei Chen and Yunlong Lei

Pharmaceuticals 2023, 16(1), 113; https://doi.org/10.3390/ph16010113 - 12 Jan 2023

Cited by 4 | Viewed by 2311

Abstract

Hepatocellular carcinoma is one of the most common fatal malignancies worldwide. Thus far, the hepatocellular carcinoma prognosis has been bleak due to deficiencies in the identification and diagnosis of early hepatocellular carcinoma. Ciclopirox olamine (CPX) is a synthetic antifungal agent and has been [...] Read more.

Hepatocellular carcinoma is one of the most common fatal malignancies worldwide. Thus far, the hepatocellular carcinoma prognosis has been bleak due to deficiencies in the identification and diagnosis of early hepatocellular carcinoma. Ciclopirox olamine (CPX) is a synthetic antifungal agent and has been considered as an anti-cancer candidate drug recently, though the detailed mechanisms related to its anti-cancer effect in hepatocellular carcinoma have not yet been revealed. Here, we found that CPX could inhibit proliferation in HCC cells but not in intrahepatic cholangiocarcinoma cells by arresting the cell cycle. Moreover, the anti-cancer effects of CPX in HCC cells were also attributed to CPX-triggered ROS accumulation and DJ-1 downregulation. Additionally, CPX could promote complete autophagic flux, which alleviated the anti-cancer effect of CPX in HCC cells, whereas the ROS scavenger (NAC) would attenuate CPX-induced protective autophagy. Interestingly, CPX could also induce glycogen clustering in HCC cells. Altogether, this study provides a new insight into the detailed molecular mechanisms of CPX as an anti-cancer therapy and a strategy for treating hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Natural Products as Drug Candidates for Redox-Related Human Disease)

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17 pages, 1849 KiB

Open AccessArticle

Antihyperglycemic Effects of Annona cherimola Miller and the Flavonoid Rutin in Combination with Oral Antidiabetic Drugs on Streptozocin-Induced Diabetic Mice

by Miguel Valdes, Fernando Calzada, Jesús Martínez-Solís and Julita Martínez-Rodríguez

Pharmaceuticals 2023, 16(1), 112; https://doi.org/10.3390/ph16010112 - 12 Jan 2023

Cited by 5 | Viewed by 1975

Abstract

Ethanolic extract obtained from Annona cherimola Miller (EEAc) and the flavonoid rutin (Rut) were evaluated in this study to determine their antihyperglycemic content, % HbA1c reduction, and antihyperlipidemic activities. Both treatments were evaluated separately and in combination with the oral antidiabetic drugs (OADs) [...] Read more.

Ethanolic extract obtained from Annona cherimola Miller (EEAc) and the flavonoid rutin (Rut) were evaluated in this study to determine their antihyperglycemic content, % HbA1c reduction, and antihyperlipidemic activities. Both treatments were evaluated separately and in combination with the oral antidiabetic drugs (OADs) acarbose (Aca), metformin (Met), glibenclamide (Gli), and canagliflozin (Cana) in acute and subchronic assays. The evaluation of the acute assay showed that EEAc and Rut administered separately significantly reduce hyperglycemia in a manner similar to OADs and help to reduce % HbA1c and hyperlipidemia in the subchronic assay. The combination of EEAc + Met showed the best activity by reducing the hyperglycemia content, % HbA1c, Chol, HDL-c, and LDL-c. Rutin in combination with OADs used in all treatments significantly reduced the hyperglycemia content that is reflected in the reduction in % HbA1c. In relation to the lipid profiles, all combinate treatments helped to avoid an increase in the measured parameters. The results show the importance of evaluating the activity of herbal remedies in combination with drugs to determine their activities and possible side effects. Moreover, the combination of rutin with antidiabetic drugs presented considerable activity, and this is the first step for the development of novel DM treatments. Full article

(This article belongs to the Special Issue Pharmacological Activities of Flavonoids and Its Analogues)

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22 pages, 2185 KiB

Open AccessReview

Review on Bortezomib Resistance in Multiple Myeloma and Potential Role of Emerging Technologies

by Gül Kozalak, İsmail Bütün, Erçil Toyran and Ali Koşar

Pharmaceuticals 2023, 16(1), 111; https://doi.org/10.3390/ph16010111 - 12 Jan 2023

Cited by 8 | Viewed by 4051

Abstract

Multiple myeloma is a hematological cancer type. For its treatment, Bortezomib has been widely used. However, drug resistance to this effective chemotherapeutic has been developed for various reasons. 2D cell cultures and animal models have failed to understand the MM disease and Bortezomib [...] Read more.

Multiple myeloma is a hematological cancer type. For its treatment, Bortezomib has been widely used. However, drug resistance to this effective chemotherapeutic has been developed for various reasons. 2D cell cultures and animal models have failed to understand the MM disease and Bortezomib resistance. It is therefore essential to utilize new technologies to reveal a complete molecular profile of the disease. In this review, we in-depth examined the possible molecular mechanisms that cause Bortezomib resistance and specifically addressed MM and Bortezomib resistance. Moreover, we also included the use of nanoparticles, 3D culture methods, microfluidics, and organ-on-chip devices in multiple myeloma. We also discussed whether the emerging technology offers the necessary tools to understand and prevent Bortezomib resistance in multiple myeloma. Despite the ongoing research activities on MM, the related studies cannot provide a complete summary of MM. Nanoparticle and 3D culturing have been frequently used to understand MM disease and Bortezomib resistance. However, the number of microfluidic devices for this application is insufficient. By combining siRNA/miRNA technologies with microfluidic devices, a complete molecular genetic profile of MM disease could be revealed. Microfluidic chips should be used clinically in personal therapy and point-of-care applications. At least with Bortezomib microneedles, it could be ensured that MM patients can go through the treatment process more painlessly. This way, MM can be switched to the curable cancer type list, and Bortezomib can be targeted for its treatment with fewer side effects. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Multiple Myeloma)

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27 pages, 24548 KiB

Open AccessReview

Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance

by Nur Syafiqah Rahim, Yuan Seng Wu, Maw Shin Sim, Appalaraju Velaga, Srinivasa Reddy Bonam, Subash C. B. Gopinath, Vetriselvan Subramaniyan, Ker Woon Choy, Sin-Yeang Teow, Ismail M. Fareez, Chandramathi Samudi, Shamala Devi Sekaran, Mahendran Sekar and Rhanye Mac Guad

Pharmaceuticals 2023, 16(1), 110; https://doi.org/10.3390/ph16010110 - 11 Jan 2023

Cited by 3 | Viewed by 3266

Abstract

There are six members of the transmembrane 4 superfamily (TM4SF) that have similar topology and sequence homology. Physiologically, they regulate tissue differentiation, signal transduction pathways, cellular activation, proliferation, motility, adhesion, and angiogenesis. Accumulating evidence has demonstrated, among six TM4SF members, the regulatory roles [...] Read more.

There are six members of the transmembrane 4 superfamily (TM4SF) that have similar topology and sequence homology. Physiologically, they regulate tissue differentiation, signal transduction pathways, cellular activation, proliferation, motility, adhesion, and angiogenesis. Accumulating evidence has demonstrated, among six TM4SF members, the regulatory roles of transmembrane 4 L6 domain family members, particularly TM4SF1, TM4SF4, and TM4SF5, in cancer angiogenesis, progression, and chemoresistance. Hence, targeting derailed TM4SF for cancer therapy has become an emerging research area. As compared to others, this review aimed to present a focused insight and update on the biological roles of TM4SF1, TM4SF4, and TM4SF5 in the progression, metastasis, and chemoresistance of various cancers. Additionally, the mechanistic pathways, diagnostic and prognostic values, and the potential and efficacy of current anti-TM4SF antibody treatment were also deciphered. It also recommended the exploration of other interactive molecules to be implicated in cancer progression and chemoresistance, as well as potential therapeutic agents targeting TM4SF as future perspectives. Generally, these three TM4SF members interact with different integrins and receptors to significantly induce intracellular signaling and regulate the proliferation, migration, and invasion of cancer cells. Intriguingly, gene silencing or anti-TM4SF antibody could reverse their regulatory roles deciphered in different preclinical models. They also have prognostic and diagnostic value as their high expression was detected in clinical tissues and cells of various cancers. Hence, TM4SF1, TM4SF4, and TM4SF5 are promising therapeutic targets for different cancer types preclinically and deserve further investigation. Full article

(This article belongs to the Topic Advances in Anti-Cancer Drugs)

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25 pages, 10639 KiB

Open AccessArticle

Orthosiphon aristatus (Blume) Miq Alleviates Non-Alcoholic Fatty Liver Disease via Antioxidant Activities in C57BL/6 Obese Mice and Palmitic–Oleic Acid-Induced Steatosis in HepG2 Cells

by Salah Abdalrazak Alshehade, Raghdaa Hamdan Al Zarzour, Michael Mathai, Nelli Giribabu, Atefehalsadat Seyedan, Gurjeet Kaur, Fouad Saleih Resq Al-Suede, Amin Malik Shah Abdul Majid, Vikneswaran Murugaiyah, Hassan Almoustafa and Mohammed Abdullah Alshawsh

Pharmaceuticals 2023, 16(1), 109; https://doi.org/10.3390/ph16010109 - 11 Jan 2023

Cited by 4 | Viewed by 2790

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Orthosiphon aristatus (Blume) Miq, a traditional plant in South Asia, has previously been shown to attenuate obesity and hyperglycaemic conditions. Eight weeks of feeding C57BL/6 mice with the standardized O. [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of liver disease. Orthosiphon aristatus (Blume) Miq, a traditional plant in South Asia, has previously been shown to attenuate obesity and hyperglycaemic conditions. Eight weeks of feeding C57BL/6 mice with the standardized O. aristatus extract (400 mg/kg) inhibited the progression of NAFLD. Liver enzymes including alanine aminotransferase and aspartate transaminase were significantly reduced in treated mice by 74.2% ± 7.69 and 52.8% ± 7.83, respectively. Furthermore, the treated mice showed a reduction in serum levels of glucose (50% ± 5.71), insulin (70.2% ± 12.09), total cholesterol (27.5% ± 15.93), triglycerides (63.2% ± 16.5), low-density lipoprotein (62.5% ± 4.93) and atherogenic risk index relative to the negative control. Histologically, O. aristatus reversed hepatic fat accumulation and reduced NAFLD severity. Notably, our results showed the antioxidant activity of O. aristatus via increased superoxide dismutase activity and a reduction of hepatic malondialdehyde levels. In addition, the levels of serum pro-inflammatory mediators (IL-6 and TNFα) decreased, indicating anti-inflammatory activity. The aqueous, hydroethanolic and ethanolic fractions of O. aristatus extract significantly reduced intracellular fat accumulation in HepG2 cells that were treated with palmitic–oleic acid. Together, these findings suggest that antioxidant activities are the primary mechanism of action of O. aristatus underlying the anti-NAFLD effects. Full article

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

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19 pages, 2669 KiB

Open AccessArticle

One-Step Pharmaceutical Preparation of PEG-Modified Exosomes Encapsulating Anti-Cancer Drugs by a High-Pressure Homogenization Technique

by Tatsuya Fukuta, Mayumi Ikeda-Imafuku, Satoshi Kodama, Junko Kuse, Ko Matsui and Yasunori Iwao

Pharmaceuticals 2023, 16(1), 108; https://doi.org/10.3390/ph16010108 - 11 Jan 2023

Cited by 4 | Viewed by 2733

Abstract

The use of exosomes encapsulating therapeutic agents for the treatment of diseases is of increasing interest. However, some concerns such as limited efficiency and scalability of conventional drug encapsulation methods to exosomes have still remained; thus, a new approach that enables encapsulation of [...] Read more.

The use of exosomes encapsulating therapeutic agents for the treatment of diseases is of increasing interest. However, some concerns such as limited efficiency and scalability of conventional drug encapsulation methods to exosomes have still remained; thus, a new approach that enables encapsulation of therapeutic agents with superior efficiency and scalability is required. Herein, we used RAW264 macrophage cell-derived exosomes (RAW-Exos) and demonstrated that high-pressure homogenization (HPH) using a microfluidizer decreased their particle size without changing their morphology, the amount of exosomal marker proteins, and cellular uptake efficiency into RAW264 and colon-26 cancer cells. Moreover, HPH allowed for modification of polyethylene glycol (PEG)-conjugated lipids onto RAW-Exos, as well as encapsulation of the anti-cancer agent doxorubicin. Importantly, the doxorubicin encapsulation efficiency became higher upon increasing the process pressure and simultaneous HPH with PEG-lipids. Moreover, treatment with PEG-modified RAW-Exos encapsulating doxorubicin significantly suppressed tumor growth in colon-26-bearing mice. Taken together, these results suggest that HPH using a microfluidizer could be useful to prepare PEG-modified Exos encapsulating anti-cancer drugs via a one-step pharmaceutical process, and that the prepared functional Exos could be applied for the treatment of cancer in vivo. Full article

(This article belongs to the Special Issue Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives)

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9 pages, 956 KiB

Open AccessArticle

The Influence of Exercise Intensity on Tryptophan Metabolites in Thoroughbred Horses

by Magdalena Staniszewska, Sylwester Kowalik, Ilona Sadok and Witold Kędzierski

Pharmaceuticals 2023, 16(1), 107; https://doi.org/10.3390/ph16010107 - 11 Jan 2023

Cited by 1 | Viewed by 1496

Abstract

Catabolism of tryptophan (Trp) is modulated by physical activity and provides a pool of active compounds: Trp is considered a calmative agent, kynurenine (Kyn) and 3-hydroxykynurenine (3-HKyn) show neurotoxic effects, kynurenic acid (Kyna) and xanthurenic acid (XA) have neuroprotective properties like nicotinamide (NAm), [...] Read more.

Catabolism of tryptophan (Trp) is modulated by physical activity and provides a pool of active compounds: Trp is considered a calmative agent, kynurenine (Kyn) and 3-hydroxykynurenine (3-HKyn) show neurotoxic effects, kynurenic acid (Kyna) and xanthurenic acid (XA) have neuroprotective properties like nicotinamide (NAm), while serotonin is the neurotransmitter. The study was conducted to investigate the dependence of exercise intensity, measured by plasma lactic acid (LA) concentration, on the level of Trp, its catabolites (serotonin, Kyn, 3-HKyn, Kyna and XA), and NAm in Thoroughbred horses. A total of 18 young race Thoroughbred horses were investigated during exercise tests. Blood samples for analysis were collected: at rest, 10 min after the end of the exercise, and 60 min after the end of the exercise. Plasma LA was determined by the enzymatic method, Trp, and other metabolites using liquid chromatography coupled with mass spectrometry. In horses performing intense exercise, the concentration of LA, Kyn, XA and NAm was increased, while Trp was decreased. Significant correlations were detected for exercise-induced increase in LA and 3-HKyn, XA, and NAm. Considering the scope of changes in analyzed data, there is an expected neutral effect on the health status of exercised horses. Full article

(This article belongs to the Special Issue Tryptophan Metabolism as the Therapeutic and Biomarker Target)

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14 pages, 4069 KiB

Open AccessArticle

CX08005, a Protein Tyrosine Phosphatase 1B Inhibitor, Attenuated Hepatic Lipid Accumulation and Microcirculation Dysfunction Associated with Nonalcoholic Fatty Liver Disease

by Jiang Li, Xiaolin Zhang, Jinying Tian, Juan Li, Xuechen Li, Song Wu, Yuying Liu, Jingyan Han and Fei Ye

Pharmaceuticals 2023, 16(1), 106; https://doi.org/10.3390/ph16010106 - 11 Jan 2023

Cited by 2 | Viewed by 1477

Abstract

Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC₅₀ of 0.75 ± 0.07 μM, has been [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is one of the common metabolic diseases characterized by hepatic lipid accumulation. Insulin resistance and microcirculation dysfunction are strongly associated with NAFLD. CX08005, an inhibitor of PTP1B with the IC₅₀ of 0.75 ± 0.07 μM, has been proven to directly enhance insulin sensitivity. The present study aimed to investigate the effects of CX08005 on hepatic lipid accumulation and microcirculation dysfunction in both KKAy mice and diet-induced obesity (DIO) mice. Hepatic lipid accumulation was evaluated by hepatic triglyceride determination and B-ultrasound analysis in KKAy mice. Insulin sensitivity and blood lipids were assessed by insulin tolerance test (ITT) and triglyceride (TG)/total cholesterol (TC) contents, respectively. In addition, the hepatic microcirculation was examined in DIO mice by in vivo microscopy. The results showed that CX08005 intervention significantly reduced the TG and echo-intensity attenuation coefficient in the livers of KKAy mice. Furthermore, we found that CX08005 treatment significantly enhanced insulin sensitivity, and decreased plasma TG and/or TC contents in KKAy and DIO mice, respectively. In addition, CX08005 treatment ameliorated hepatic microcirculation dysfunction in DIO mice, as evidenced by increased RBCs velocity and shear rate of the blood flow in central veins and in the interlobular veins, as well as enhanced rate of perfused hepatic sinusoids in central vein area. Additionally, CX08005 administration decreased the adhered leukocytes both in the center veins and in the hepatic sinusoids area. Taken together, CX08005 exhibited beneficial effects on hepatic lipid accumulation and microcirculation dysfunction associated with NAFLD, which was involved with modulating insulin sensitivity and leukocyte recruitment, as well as restoration of normal microcirculatory blood flow. Full article

(This article belongs to the Special Issue Drug Candidates for the Treatment of Metabolic Syndrome)

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19 pages, 2092 KiB

Open AccessReview

Research Progress of Bioinspired Nanostructured Systems for the Treatment of Ocular Disorders

by Xuan Chen, Rui Yang, Jinyan Shen, Qingyu Huang and Zhifeng Wu

Pharmaceuticals 2023, 16(1), 96; https://doi.org/10.3390/ph16010096 - 10 Jan 2023

Viewed by 2158

Abstract

How to enhance the bioavailability and prolong the residence time of drugs in the eye present the major barriers to traditional eye delivery. Nanotechnology has been widely used in ocular drug delivery systems because of its advantages of minimizing adverse reactions, decreasing the [...] Read more.

How to enhance the bioavailability and prolong the residence time of drugs in the eye present the major barriers to traditional eye delivery. Nanotechnology has been widely used in ocular drug delivery systems because of its advantages of minimizing adverse reactions, decreasing the frequency of administration, prolonging the release time, and improving the bioavailability of the drug in the eye. As natural product-based nanostructured systems, bioinspired nanostructured systems have presented as less toxic, easy to prepare, and cost-effective and have potential application value in the field of nanotechnology. A systematic classification of bioinspired nanostructured systems based on their inspiration source and formulation and their brief applications in disease are presented here. A review of recent research progress of the bioinspired nanostructured systems for the treatment of the anterior and posterior segment of ocular disorders is then presented in detail. Finally, current challenges and future directions with regard to manufacturing bioinspired nanomaterials are provided. Full article

(This article belongs to the Special Issue Recent Advances in Natural Product Based Nanostructured Systems)

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22 pages, 4480 KiB

Open AccessArticle

Combining the In Silico and In Vitro Assays to Identify Strobilanthes cusia Kuntze Bioactives against Penicillin-Resistant Streptococcus pneumoniae

by Xiaoyu Han, Lu Jin, Zhimin Zhao, Xinjun Xu, Shiyi Liu, Yuquan Huang, Xiaoli Liu, Yuehong Xu, Depo Yang, Wei Huang and Li Wang

Pharmaceuticals 2023, 16(1), 105; https://doi.org/10.3390/ph16010105 - 10 Jan 2023

Viewed by 1675

Abstract

Leaves of Strobilanthes cusia Kuntze (S. cusia) are a widely used alexipharmic Traditional Chinese Medicine (TCM) in southern China for the prevention of cold and respiratory tract infectious diseases. One of the most common bacterial pathogens in the respiratory tract is [...] Read more.

Leaves of Strobilanthes cusia Kuntze (S. cusia) are a widely used alexipharmic Traditional Chinese Medicine (TCM) in southern China for the prevention of cold and respiratory tract infectious diseases. One of the most common bacterial pathogens in the respiratory tract is the gram-positive bacterium Streptococcus pneumoniae. The antibiotic resistance of colonized S. pneumoniae makes it a more serious threat to public health. In this study, the leaves of S. cusia were found to perform antibacterial effects on the penicillin-resistant S. pneumoniae (PRSP). Confocal assay and Transmission Electron Microscopy (TEM) monitored the diminished cell wall integrity and capsule thickness of the PRSP with treatment. The following comparative proteomics analysis revealed that the glycometabolism-related pathways were enriched for the differentially expressed proteins between the samples with treatment and the control. To further delve into the specific single effective compound, the bio-active contents of leaves of S. cusia were analyzed by UPLC-UV-ESI-Q-TOF/MS, and 23 compounds were isolated for anti-PRSP screening. Among them, Tryptanthrin demonstrated the most promising effect, and it possibly inhibited the N-glycan degradation proteins, as suggested by reverse docking analysis in silico and further experimental verification by the surface plasmon resonance assay (SPR). Our study provided a research foundation for applications of the leaves of S. cusia as a TCM, and supplied a bio-active compound Tryptanthrin as a candidate drug skeleton for infectious diseases caused by the PRSP. Full article

(This article belongs to the Special Issue Antibiodegenerative and Antimicrobial Effects of Natural Products)

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Pharmaceuticals, Volume 16, Issue 1 (January 2023) – 133 articles

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