Molecules

19 pages, 8371 KiB

Open AccessArticle

Nano-Graphene Layer from Facile, Scalable and Eco-Friendly Liquid Phase Exfoliation Strategy as Effective Barrier Layer for High-Performance and Durable Direct Liquid Alcohol Fuel Cells

by Prabhuraj Balakrishnan, Fereshteh Dehghani Sanij, Zhixin Chang, P. K. Leung, Huaneng Su, Lei Xing and Qian Xu

Molecules 2022, 27(9), 3044; https://doi.org/10.3390/molecules27093044 - 9 May 2022

Cited by 2 | Viewed by 6405

Abstract

Graphene, in spite of exceptional physio-chemical properties, still faces great limitations in its use and industrial scale-up as highly selective membranes (enhanced ratio of proton conductivity to fuel cross-over) in liquid alcohol fuel cells (LAFCs), due to complexity and high cost of prevailing [...] Read more.

Graphene, in spite of exceptional physio-chemical properties, still faces great limitations in its use and industrial scale-up as highly selective membranes (enhanced ratio of proton conductivity to fuel cross-over) in liquid alcohol fuel cells (LAFCs), due to complexity and high cost of prevailing production methods. To resolve these issues, a facile, low-cost and eco-friendly approach of liquid phase exfoliation (bath sonication) of graphite to obtain graphene and spray depositing the prepared graphene flakes, above anode catalyst layer (near the membrane in the membrane electrode assembly (MEA)) as barrier layer at different weight percentages relative to the base membrane Nafion 115 was utilized in this work. The 5 wt.% nano-graphene layer raises 1 M methanol/oxygen fuel cell power density by 38% to 91 mW·cm⁻², compared to standard membrane electrode assembly (MEA) performance of 63 mW·cm⁻², owing to less methanol crossover with mild decrease in proton conductivity, showing negligible voltage decays over 20 h of operation at 50 mA·cm⁻². Overall, this work opens three prominent favorable prospects: exploring the usage of nano-materials prepared by liquid phase exfoliation approach, their effective usage in ion-transport membrane region of MEA and enhancing fuel cell power performance. Full article

(This article belongs to the Special Issue Fuel Cells in China)

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18 pages, 6318 KiB

Open AccessFeature PaperArticle

Molecular Transport within Polymer Brushes: A FRET View at Aqueous Interfaces

by Quinn A. Besford, Simon Schubotz, Soosang Chae, Ayşe B. Özdabak Sert, Alessia C. G. Weiss, Günter K. Auernhammer, Petra Uhlmann, José Paulo S. Farinha and Andreas Fery

Molecules 2022, 27(9), 3043; https://doi.org/10.3390/molecules27093043 - 9 May 2022

Cited by 7 | Viewed by 2820

Abstract

Molecular permeability through polymer brush chains is implicated in surface lubrication, wettability, and solute capture and release. Probing molecular transport through polymer brushes can reveal information on the polymer nanostructure, with a permeability that is dependent on chain conformation and grafting density. Herein, [...] Read more.

Molecular permeability through polymer brush chains is implicated in surface lubrication, wettability, and solute capture and release. Probing molecular transport through polymer brushes can reveal information on the polymer nanostructure, with a permeability that is dependent on chain conformation and grafting density. Herein, we introduce a brush system to study the molecular transport of fluorophores from an aqueous droplet into the external “dry” polymer brush with the vapour phase above. The brushes consist of a random copolymer of N-isopropylacrylamide and a Förster resonance energy transfer (FRET) donor-labelled monomer, forming ultrathin brush architectures of about 35 nm in solvated height. Aqueous droplets containing a separate FRET acceptor are placed onto the surfaces, with FRET monitored spatially around the 3-phase contact line. FRET is used to monitor the transport from the droplet to the outside brush, and the changing internal distributions with time as the droplets prepare to recede. This reveals information on the dynamics and distances involved in the molecular transport of the FRET acceptor towards and away from the droplet contact line, which are strongly dependent on the relative humidity of the system. We anticipate our system to be extremely useful for studying lubrication dynamics and surface droplet wettability processes. Full article

(This article belongs to the Special Issue Advances in Nanomaterials Design and Nanoarchitectonics of Functional Materials: A Themed Issue Honoring Professor Katsuhiko Ariga)

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15 pages, 3660 KiB

Open AccessArticle

Solubility and Permeability Enhancement of Oleanolic Acid by Solid Dispersion in Poloxamers and γ-CD

by Chiara De Stefani, Jessika Lodovichi, Laura Albonetti, Maria Cristina Salvatici, José Carlos Quintela, Anna Rita Bilia and Maria Camilla Bergonzi

Molecules 2022, 27(9), 3042; https://doi.org/10.3390/molecules27093042 - 9 May 2022

Cited by 9 | Viewed by 3823

Abstract

Oleanolic acid (OA) is a pentacyclic triterpenoid widely found in the Oleaceae family, and it represents 3.5% of the dry weight of olive leaves. OA has many pharmacological activities, such as hepatoprotection, anti-inflammatory, anti-oxidant, anti-diabetic, anti-tumor, and anti-microbic activities. Its therapeutic application is [...] Read more.

Oleanolic acid (OA) is a pentacyclic triterpenoid widely found in the Oleaceae family, and it represents 3.5% of the dry weight of olive leaves. OA has many pharmacological activities, such as hepatoprotection, anti-inflammatory, anti-oxidant, anti-diabetic, anti-tumor, and anti-microbic activities. Its therapeutic application is limited by its poor water solubility, bioavailability, and permeability. In this study, solid dispersions (SDs) were developed to overcome these OA limitations. Solubility studies were conducted to evaluate different hydrophilic polymers, drug-to-polymer ratios, and preparation methods. Poloxamer 188, Poloxamer 407, and γ-CD exhibited the highest increases in terms of OA solubility, regardless of the method of preparation. Binary systems were characterized using differential scanning calorimetry (DSC), X-ray diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). In addition, pure compounds and SDs were analyzed using scanning electron microscopy (SEM) in order to observe both the morphology and the particle surface. In vitro dissolution studies were performed for P407, P188, and γ-CD SDs. Preparation using the solvent evaporation method (SEM) produced the highest increase in the dissolution profiles of all three polymers with respect to the OA solution. Finally, the effect of SDs on OA permeability was evaluated with an in vitro parallel artificial membrane permeability assay (PAMPA). The formulation improved passive permeation across the simulated barrier due to OA increased solubility. The dissolution and PAMPA results indicate that the amorphization of OA by SD preparation could be a useful method to enhance its oral absorption, and it is also applicable on an industrial scale. Full article

(This article belongs to the Special Issue Molecules in 2022)

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18 pages, 4438 KiB

Open AccessArticle

Accelerating AutoDock Vina with GPUs

by Shidi Tang, Ruiqi Chen, Mengru Lin, Qingde Lin, Yanxiang Zhu, Ji Ding, Haifeng Hu, Ming Ling and Jiansheng Wu

Molecules 2022, 27(9), 3041; https://doi.org/10.3390/molecules27093041 - 9 May 2022

Cited by 48 | Viewed by 7894

Abstract

AutoDock Vina is one of the most popular molecular docking tools. In the latest benchmark CASF-2016 for comparative assessment of scoring functions, AutoDock Vina won the best docking power among all the docking tools. Modern drug discovery is facing a common scenario of [...] Read more.

AutoDock Vina is one of the most popular molecular docking tools. In the latest benchmark CASF-2016 for comparative assessment of scoring functions, AutoDock Vina won the best docking power among all the docking tools. Modern drug discovery is facing a common scenario of large virtual screening of drug hits from huge compound databases. Due to the seriality characteristic of the AutoDock Vina algorithm, there is no successful report on its parallel acceleration with GPUs. Current acceleration of AutoDock Vina typically relies on the stack of computing power as well as the allocation of resource and tasks, such as the VirtualFlow platform. The vast resource expenditure and the high access threshold of users will greatly limit the popularity of AutoDock Vina and the flexibility of its usage in modern drug discovery. In this work, we proposed a new method, Vina-GPU, for accelerating AutoDock Vina with GPUs, which is greatly needed for reducing the investment for large virtual screens and also for wider application in large-scale virtual screening on personal computers, station servers or cloud computing, etc. Our proposed method is based on a modified Monte Carlo using simulating annealing AI algorithm. It greatly raises the number of initial random conformations and reduces the search depth of each thread. Moreover, a classic optimizer named BFGS is adopted to optimize the ligand conformations during the docking progress, before a heterogeneous OpenCL implementation was developed to realize its parallel acceleration leveraging thousands of GPU cores. Large benchmark tests show that Vina-GPU reaches an average of 21-fold and a maximum of 50-fold docking acceleration against the original AutoDock Vina while ensuring their comparable docking accuracy, indicating its potential for pushing the popularization of AutoDock Vina in large virtual screens. Full article

(This article belongs to the Special Issue Recent Advances in Artificial Intelligence-Based Drug Discovery)

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22 pages, 1104 KiB

Open AccessReview

Biotechnological Approaches for Production of Artemisinin, an Anti-Malarial Drug from Artemisia annua L.

by Jameel M. Al-Khayri, Wudali N. Sudheer, Vasantha V. Lakshmaiah, Epsita Mukherjee, Aatika Nizam, Muthu Thiruvengadam, Praveen Nagella, Fatima M. Alessa, Muneera Q. Al-Mssallem, Adel A. Rezk, Wael F. Shehata and Mahesh Attimarad

Molecules 2022, 27(9), 3040; https://doi.org/10.3390/molecules27093040 - 9 May 2022

Cited by 10 | Viewed by 5668

Abstract

Artemisinin is an anti-malarial sesquiterpene lactone derived from Artemisia annua L. (Asteraceae family). One of the most widely used modes of treatment for malaria is an artemisinin-based combination therapy. Artemisinin and its associated compounds have a variety of pharmacological qualities that have helped [...] Read more.

Artemisinin is an anti-malarial sesquiterpene lactone derived from Artemisia annua L. (Asteraceae family). One of the most widely used modes of treatment for malaria is an artemisinin-based combination therapy. Artemisinin and its associated compounds have a variety of pharmacological qualities that have helped achieve economic prominence in recent years. So far, research on the biosynthesis of this bioactive metabolite has revealed that it is produced in glandular trichomes and that the genes responsible for its production must be overexpressed in order to meet demand. Using biotechnological applications such as tissue culture, genetic engineering, and bioreactor-based approaches would aid in the upregulation of artemisinin yield, which is needed for the future. The current review focuses on the tissue culture aspects of propagation of A. annua and production of artemisinin from A. annua L. cell and organ cultures. The review also focuses on elicitation strategies in cell and organ cultures, as well as artemisinin biosynthesis and metabolic engineering of biosynthetic genes in Artemisia and plant model systems. Full article

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12 pages, 1300 KiB

Open AccessArticle

Beta-Carotene Affects the Effects of Heme Oxygenase-1 in Isolated, Ischemic/Reperfused Rat Hearts: Potential Role of the Iron

by Evelin Csepanyi, Alexandra Gyongyosi, Istvan Lekli, Arpad Tosaki and Istvan Bak

Molecules 2022, 27(9), 3039; https://doi.org/10.3390/molecules27093039 - 9 May 2022

Cited by 2 | Viewed by 1849

Abstract

Beta-carotene (BC) is a well-known antioxidant. However, increasing evidence shows that under severe oxidative conditions, BC can become pro-oxidant, an effect that may be enhanced in the presence of iron (II). In our earlier studies, we observed that despite increasing heme oxygenase-1 (HO-1) [...] Read more.

Beta-carotene (BC) is a well-known antioxidant. However, increasing evidence shows that under severe oxidative conditions, BC can become pro-oxidant, an effect that may be enhanced in the presence of iron (II). In our earlier studies, we observed that despite increasing heme oxygenase-1 (HO-1) levels in the heart, the protective effects of BC have been lost when it was used at a high concentration. Since iron releases from heme as a consequence of HO-1 activity, we hypothesized that the application of an iron-chelator (IC) would reverse the lost cardiac protection associated with an elevated HO-1 level. Thus, in the present study, we investigated the effects of desferrioxiamine (DFO) in isolated, ischemic/reperfused rat hearts after long-term treatment with vehicle or high-dose (HD) BC. Vehicle or 150 mg/bw kg daily doses of BC were administered to the rats for 4 weeks, and then their hearts were removed and subjected to 30 min of global ischemia (ISA) followed by 120 min of reperfusion (REP). During the experiments, cardiac function was registered, and at the end of the REP period, infarct size (IS) and HO-1 expression were measured. The results show that DFO treatment alone during REP significantly ameliorated postischemic cardiac function and decreased IS, although HO-1 expression was not increased significantly. In hearts isolated from BC-treated rats, no cardioprotective effects, despite an elevated HO-1 level, were observed, while DFO administration after ISA resulted in a mild improvement in heart function and IS. Our results suggest that iron could have a role whether BC exerts antioxidant or pro-oxidant effects in ISA/REP-injured hearts. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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22 pages, 1031 KiB

Open AccessReview

Rediscovering the Therapeutic Potential of Agarwood in the Management of Chronic Inflammatory Diseases

by Juman Mohammed Rasmi Alamil, Keshav Raj Paudel, Yinghan Chan, Dikaia Xenaki, Jithendra Panneerselvam, Sachin Kumar Singh, Monica Gulati, Niraj Kumar Jha, Deepak Kumar, Parteek Prasher, Gaurav Gupta, Raniya Malik, Brian George Oliver, Philip Michael Hansbro, Kamal Dua and Dinesh Kumar Chellappan

Molecules 2022, 27(9), 3038; https://doi.org/10.3390/molecules27093038 - 9 May 2022

Cited by 21 | Viewed by 5056

Abstract

The inflammatory response is a central aspect of the human immune system that acts as a defense mechanism to protect the body against infections and injuries. A dysregulated inflammatory response is a major health concern, as it can disrupt homeostasis and lead to [...] Read more.

The inflammatory response is a central aspect of the human immune system that acts as a defense mechanism to protect the body against infections and injuries. A dysregulated inflammatory response is a major health concern, as it can disrupt homeostasis and lead to a plethora of chronic inflammatory conditions. These chronic inflammatory diseases are one of the major causes of morbidity and mortality worldwide and the need for them to be managed in the long term has become a crucial task to alleviate symptoms and improve patients’ overall quality of life. Although various synthetic anti-inflammatory agents have been developed to date, these medications are associated with several adverse effects that have led to poor therapeutic outcomes. The hunt for novel alternatives to modulate underlying chronic inflammatory processes has unveiled nature to be a plentiful source. One such example is agarwood, which is a valuable resinous wood from the trees of Aquilaria spp. Agarwood has been widely utilized for medicinal purposes since ancient times due to its ability to relieve pain, asthmatic symptoms, and arrest vomiting. In terms of inflammation, the major constituent of agarwood, agarwood oil, has been shown to possess multiple bioactive compounds that can regulate molecular mechanisms of chronic inflammation, thereby producing a multitude of pharmacological functions for treating various inflammatory disorders. As such, agarwood oil presents great potential to be developed as a novel anti-inflammatory therapeutic to overcome the drawbacks of existing therapies and improve treatment outcomes. In this review, we have summarized the current literature on agarwood and its bioactive components and have highlighted the potential roles of agarwood oil in treating various chronic inflammatory diseases. Full article

(This article belongs to the Special Issue Phytochemistry and Biological Properties of Medicinal Plants)

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16 pages, 3502 KiB

Open AccessArticle

Characterization of β-Glucan-Peanut Protein Isolate/Soy Protein Isolate Conjugates and Their Application on Low-Fat Sausage

by Manli Zhang, Hongzhi Liu and Qiang Wang

Molecules 2022, 27(9), 3037; https://doi.org/10.3390/molecules27093037 - 9 May 2022

Cited by 9 | Viewed by 4037

Abstract

Polysaccharide–protein conjugates can improve the functional properties and expand the application field. The emulsifying, thermal properties of WSG-PPI conjugates and WSG-SPI conjugates were improved, compared to WSG, PPI and SPI. The Maillard reaction was confirmed by Fourier transform infrared spectroscopy (FT-IR). Circular dichroism [...] Read more.

Polysaccharide–protein conjugates can improve the functional properties and expand the application field. The emulsifying, thermal properties of WSG-PPI conjugates and WSG-SPI conjugates were improved, compared to WSG, PPI and SPI. The Maillard reaction was confirmed by Fourier transform infrared spectroscopy (FT-IR). Circular dichroism (CD) exhibited that the structure of the conjugates was more expanded. Cryo-SEM and AFM demonstrated that the WSG, WSG-PPI and WSG-SPI conjugates had a morphology of a chain. When the conjugates were added as fat substitutes to low-fat sausage, the cooking yield, hardness and chewiness increased. The objective of this research was to study the emulsifying property, thermal property and structural changes of β-glucan-peanut protein isolate (WSG-PPI) conjugates and β-glucan-soy protein isolate (WSG-SPI) conjugates prepared through wet-heated Maillard reaction, and their effect on the texture of low-fat sausage. Full article

(This article belongs to the Special Issue Recent Advances in Food Carbohydrates)

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31 pages, 5554 KiB

Open AccessReview

A Review on Mechanistic Insight of Plant Derived Anticancer Bioactive Phytocompounds and Their Structure Activity Relationship

by Kishor Mazumder, Asma Aktar, Priyanka Roy, Biswajit Biswas, Md. Emran Hossain, Kishore Kumar Sarkar, Sitesh Chandra Bachar, Firoj Ahmed, A. S. M. Monjur-Al-Hossain and Koichi Fukase

Molecules 2022, 27(9), 3036; https://doi.org/10.3390/molecules27093036 - 9 May 2022

Cited by 42 | Viewed by 5657

Abstract

Cancer is a disorder that rigorously affects the human population worldwide. There is a steady demand for new remedies to both treat and prevent this life-threatening sickness due to toxicities, drug resistance and therapeutic failures in current conventional therapies. Researchers around the world [...] Read more.

Cancer is a disorder that rigorously affects the human population worldwide. There is a steady demand for new remedies to both treat and prevent this life-threatening sickness due to toxicities, drug resistance and therapeutic failures in current conventional therapies. Researchers around the world are drawing their attention towards compounds of natural origin. For decades, human beings have been using the flora of the world as a source of cancer chemotherapeutic agents. Currently, clinically approved anticancer compounds are vincristine, vinblastine, taxanes, and podophyllotoxin, all of which come from natural sources. With the triumph of these compounds that have been developed into staple drug products for most cancer therapies, new technologies are now appearing to search for novel biomolecules with anticancer activities. Ellipticine, camptothecin, combretastatin, curcumin, homoharringtonine and others are plant derived bioactive phytocompounds with potential anticancer properties. Researchers have improved the field further through the use of advanced analytical chemistry and computational tools of analysis. The investigation of new strategies for administration such as nanotechnology may enable the development of the phytocompounds as drug products. These technologies have enhanced the anticancer potential of plant-derived drugs with the aim of site-directed drug delivery, enhanced bioavailability, and reduced toxicity. This review discusses mechanistic insights into anticancer compounds of natural origins and their structural activity relationships that make them targets for anticancer treatments. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources II)

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14 pages, 2486 KiB

Open AccessArticle

Antifungal Activity and In Silico Studies on 2-Acylated Benzo- and Naphthohydroquinones

by David Ríos, Jaime A. Valderrama, Gonzalo Quiroga, Jonathan Michea, Felipe Salas, Eduardo Álvarez Duarte, Edmundo A. Venegas-Casanova, Rafael Jara-Aguilar, Carlos Navarro-Retamal, Pedro Buc Calderon and Julio Benites

Molecules 2022, 27(9), 3035; https://doi.org/10.3390/molecules27093035 - 9 May 2022

Cited by 4 | Viewed by 2222

Abstract

The high rates of morbidity and mortality due to fungal infections are associated with a limited antifungal arsenal and the high toxicity of drugs. Therefore, the identification of novel drug targets is challenging due to the several resemblances between fungal and human cells. [...] Read more.

The high rates of morbidity and mortality due to fungal infections are associated with a limited antifungal arsenal and the high toxicity of drugs. Therefore, the identification of novel drug targets is challenging due to the several resemblances between fungal and human cells. Here, we report the in vitro antifungal evaluation of two acylphenols series, namely 2-acyl-1,4-benzo- and 2-acyl-1,4-naphthohydroquinones. The antifungal properties were assessed on diverse Candida and filamentous fungi strains through the halo of inhibition (HOI) and minimal inhibitory concentration (MIC). The antifungal activities of 2-acyl-1,4-benzohydroquinone derivatives were higher than those of the 2-acyl-1,4-naphthohydroquinone analogues. The evaluation indicates that 2-octanoylbenzohydroquinone 4 is the most active member of the 2-acylbenzohydroquinone series, with MIC values ranging from 2 to 16 μg/mL. In some fungal strains (i.e., Candida krusei and Rhizopus oryzae), such MIC values of compound 4 (2 and 4 μg/mL) were comparable to that obtained by amphotericin B (1 μg/mL). The compound 4 was evaluated for its antioxidant activity by means of FRAP, ABTS and DPPH assays, showing moderate activity as compared to standard antioxidants. Molecular docking studies of compound 4 and ADMET predictions make this compound a potential candidate for topical pharmacological use. The results obtained using the most active acylbenzohydroquinones are promising because some evaluated Candida strains are known to have decreased sensitivity to standard antifungal treatments. Full article

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21 pages, 10738 KiB

Open AccessArticle

Biocomputational Assessment of Natural Compounds as a Potent Inhibitor to Quorum Sensors in Ralstonia solanacearum

by Sunil Kumar, Khurshid Ahmad, Santosh Kumar Behera, Dipak T. Nagrale, Anurag Chaurasia, Manoj Kumar Yadav, Sneha Murmu, Yachana Jha, Mahendra Vikram Singh Rajawat, Deepti Malviya, Udai B. Singh, Raja Shankar, Minaketan Tripathy and Harsh Vardhan Singh

Molecules 2022, 27(9), 3034; https://doi.org/10.3390/molecules27093034 - 9 May 2022

Cited by 4 | Viewed by 2925

Abstract

Ralstonia solanacearum is among the most damaging bacterial phytopathogens with a wide number of hosts and a broad geographic distribution worldwide. The pathway of phenotype conversion (Phc) is operated by quorum-sensing signals and modulated through the (R)-methyl 3-hydroxypalmitate (3-OH PAME) in R. solanacearum [...] Read more.

Ralstonia solanacearum is among the most damaging bacterial phytopathogens with a wide number of hosts and a broad geographic distribution worldwide. The pathway of phenotype conversion (Phc) is operated by quorum-sensing signals and modulated through the (R)-methyl 3-hydroxypalmitate (3-OH PAME) in R. solanacearum. However, the molecular structures of the Phc pathway components are not yet established, and the structural consequences of 3-OH PAME on quorum sensing are not well studied. In this study, 3D structures of quorum-sensing proteins of the Phc pathway (PhcA and PhcR) were computationally modeled, followed by the virtual screening of the natural compounds library against the predicted active site residues of PhcA and PhcR proteins that could be employed in limiting signaling through 3-OH PAME. Two of the best scoring common ligands ZINC000014762512 and ZINC000011865192 for PhcA and PhcR were further analyzed utilizing orbital energies such as HOMO and LUMO, followed by molecular dynamics simulations of the complexes for 100 ns to determine the ligands binding stability. The findings indicate that ZINC000014762512 and ZINC000011865192 may be capable of inhibiting both PhcA and PhcR. We believe that, after further validation, these compounds may have the potential to disrupt bacterial quorum sensing and thus control this devastating phytopathogenic bacterial pathogen. Full article

(This article belongs to the Topic Advances in Natural Products from Plants and Associated Microbes)

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21 pages, 3440 KiB

Open AccessArticle

Production, Bioprocessing and Anti-Proliferative Activity of Camptothecin from Penicillium chrysogenum, “An Endozoic of Marine Sponge, Cliona sp.”, as a Metabolically Stable Camptothecin Producing Isolate

by Ashraf S. A. El-Sayed, Wafaa H. B. Hassan, Sherouk Hussein Sweilam, Mohammed Hamed Saeed Alqarni, Zeinab I. El Sayed, Mahmoud M. Abdel-Aal, Eman Abdelsalam and Sahar Abdelaziz

Molecules 2022, 27(9), 3033; https://doi.org/10.3390/molecules27093033 - 9 May 2022

Cited by 14 | Viewed by 4619

Abstract

Exploring the metabolic potency of fungi as camptothecin producers raises the hope of their usage as an industrial source of camptothecin, due to their short-life span and the feasibility of metabolic engineering. However, the tiny yield and loss of camptothecin productivity of fungi [...] Read more.

Exploring the metabolic potency of fungi as camptothecin producers raises the hope of their usage as an industrial source of camptothecin, due to their short-life span and the feasibility of metabolic engineering. However, the tiny yield and loss of camptothecin productivity of fungi during storage and sub-culturing are challenges that counteract this approach. Marine fungi could be a novel source for camptothecin production, with higher yield and reliable metabolic sustainability. The marine fungal isolate Penicillium chrysogenum EFBL # OL597937.1 derived from the sponge “Cliona sp.” has been morphologically identified and molecularly confirmed, based on the Internal Transcribed Spacer sequence, exhibiting the highest yield of camptothecin (110 μg/L). The molecular structure and chemical identity of P. chrysogenum derived camptothecin has been resolved by HPLC, FTIR and LC-MS/MS analyses, giving the same spectroscopic profiles and mass fragmentation patterns as authentic camptothecin. The extracted camptothecin displayed a strong anti-proliferative activity towards HEP-2 and HCT-116 (IC₅₀ values 0.33–0.35 µM). The yield of camptothecin was maximized by nutritional optimization of P. chrysogenum with a Plackett-Burman design, and the productivity of camptothecin increased by 1.8 fold (200 µg/L), compared to control fungal cultures. Upon storage at 4 °C as slope culture for 8 months, the productivity of camptothecin for P. chrysogenum was reduced by 40% compared to the initial culture. Visual fading of the mycelial pigmentation of P. chrysogenum was observed during fungal storage, matched with loss of camptothecin productivity. Methylene chloride extracts of Cliona sp. had the potency to completely restore the camptothecin productivity of P. chrysogenum, ensuring the partial dependence of the expression of the camptothecin biosynthetic machinery of P. chrysogenum on the chemical signals derived from the sponge, or the associated microbial flora. This is the first report describing the feasibility of P. chrysogenum, endozoic of Cliona sp., for camptothecin production, along with reliable metabolic biosynthetic stability, which could be a new platform for scaling-up camptothecin production. Full article

(This article belongs to the Topic Advances in Natural Products from Plants and Associated Microbes)

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17 pages, 4753 KiB

Open AccessArticle

Omega-3 Polyunsaturated Fatty Acids Provoke Apoptosis in Hepatocellular Carcinoma through Knocking Down the STAT3 Activated Signaling Pathway: In Vivo and In Vitro Study

by Noura M. Darwish, Mohamed M. A. Elshaer, Saeedah Musaed Almutairi, Tse-Wei Chen, Mohamed Othman Mohamed, Wael B. A. Ghaly and Rabab Ahmed Rasheed

Molecules 2022, 27(9), 3032; https://doi.org/10.3390/molecules27093032 - 9 May 2022

Cited by 3 | Viewed by 2640

Abstract

Hepatocellular carcinoma (HCC) is a common type of liver cancer and is a leading cause of death worldwide. Signal transducer and activator of transcription 3 (STAT3) is involved in HCC progression, migration, and suppression of apoptosis. This study investigates the apoptotic effect of [...] Read more.

Hepatocellular carcinoma (HCC) is a common type of liver cancer and is a leading cause of death worldwide. Signal transducer and activator of transcription 3 (STAT3) is involved in HCC progression, migration, and suppression of apoptosis. This study investigates the apoptotic effect of the dietary antioxidant (n-3 PUFAs) on HepG2 cells and analyzes the underlying molecular mechanisms of this effect both in vivo and in vitro. In vivo study: Seventy-five adult male albino rats were divided into three groups (n = 25): Group I (control): 0.9% normal saline, intraperitoneal. Group II: N-Nitrosodiethylamine (200 mg/kg b.wt) intraperitoneal, followed by phenobarbital 0.05% in drinking water. Group III: as group II followed by n-3 PUFAs intubation (400 mg/kg/day). In vivo study: liver specimens for biochemical, histopathological, and immunohistochemical examination. In vitro study: MTT assay, cell morphology, PCR, Western blot, and immunohistochemical analysis. n-3 PUFAs significantly improved the histopathologic features of HCC and decreased the expression of anti-apoptotic proteins. Further, HepG2 cells proliferation was suppressed through inhibition of the STAT3 signaling pathway, cyclin D1, and Bcl-2 activity. Here we report that n-3 PUFAs may be an ideal cancer chemo-preventive candidate by targeting STAT3 signaling, which is involved in cell proliferation and apoptosis. Full article

(This article belongs to the Special Issue New Anticancer Agents Based on Natural Products)

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19 pages, 2355 KiB

Open AccessArticle

A Sensitive LC-MS/MS Method for the Simultaneous Determination of Two Thia-Analogous Indirubin N-Glycosides and Indirubin-3′-Monoxime in Plasma and Cell Culture Medium

by Alica Fischle, Rico Schwarz, Franziska Wendt, Marcel Kordt, Robert Ramer, Lars Boeckmann, Martin Hein, Peter Langer, Steffen Emmert, Brigitte Vollmar and Burkhard Hinz

Molecules 2022, 27(9), 3031; https://doi.org/10.3390/molecules27093031 - 9 May 2022

Cited by 4 | Viewed by 4337

Abstract

Indirubin was identified as an active component of Danggui Longhui Wan, an herbal mixture used in traditional Chinese medicine, and showed anticancer activity in clinical trials in patients with chronic leukemia. Investigations on the mechanisms of antitumor action of indirubins have mainly focused [...] Read more.

Indirubin was identified as an active component of Danggui Longhui Wan, an herbal mixture used in traditional Chinese medicine, and showed anticancer activity in clinical trials in patients with chronic leukemia. Investigations on the mechanisms of antitumor action of indirubins have mainly focused on the indirubin derivative indirubin-3′-monoxime (I3M). Meanwhile, antiproliferative and cytotoxic properties on cancer cells have also been demonstrated for several synthetic indirubin N-glycosides. In the present study, we demonstrate cytotoxic activity of the thia-analogous indirubin N-glycosides KD87 (3-[3′-oxo-benzo[b]thiophen-2′-(Z)-ylidene]-1-(β-d-glucopyranosyl)-oxindole) and KD85 (3-[3′-oxo-benzo[b]thiophen-2′-(Z)-ylidene]-1-(β-d-mannopyranosyl)-oxindole) against melanoma and squamous cell carcinoma cells as well as lung cancer and glioblastoma cells. The advanced state of preclinical studies on the effects of indirubins conducted to date underscores the need for pharmacokinetic data from cellular, animal, and human studies for which reliable quantification is required. Therefore, a sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed and validated for the simultaneous measurement of KD87, KD85, and I3M in plasma and cell culture medium. Experimental conditions for sample preparation were optimized for human plasma protein precipitation and liquid-liquid extraction from plasma and cell culture medium. The methods were successfully validated in accordance with the U.S. Food and Drug Administration Bioanalytical Method Validation and evaluated for selectivity, sensitivity, matrix effect, recovery, carryover, calibration curve linearity, accuracy, precision, and stability. The applicability of the methods was demonstrated by the determination of KD87 in mouse plasma after prior intraperitoneal administration to mice. Full article

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16 pages, 3447 KiB

Open AccessArticle

Effects of Two Natural Bisbenzylisoquinolines, Curine and Guattegaumerine, Extracted from Isolona hexaloba on Rhodamine Efflux by Abcb1b from Rat Glycocholic-Acid-Resistant Hepatocarcinoma Cells

by Jacques-Aurélien Sergent, Hilarion Mathouet, Christian Hulen, Pedro Lameiras, Marc Feuilloley, Abdelhakim Elomri and Nour-Eddine Lomri

Molecules 2022, 27(9), 3030; https://doi.org/10.3390/molecules27093030 - 9 May 2022

Cited by 1 | Viewed by 1773

Abstract

To develop new therapeutic molecules, it is essential to understand the biological effects and targets of clinically relevant compounds. In this article, we describe the extraction and characterization of two alkaloids from the roots of Isolona hexaloba—curine and guattegaumerine. The effect of [...] Read more.

To develop new therapeutic molecules, it is essential to understand the biological effects and targets of clinically relevant compounds. In this article, we describe the extraction and characterization of two alkaloids from the roots of Isolona hexaloba—curine and guattegaumerine. The effect of these alkaloids on the multidrug efflux pump ABCB1 (MDR1/P-Glycoprotein) and their antiproliferative properties were studied. Compared to verapamil, a widely used inhibitor of P-gp, curine and guattegaumerine were found to be weak inhibitors of MDR1/P-Glycoprotein. The highest inhibition of efflux produced by verapamil disappeared in the presence of curine or guattegaumerine as competitors, and the most pronounced effect was achieved with curine. Altogether, this work has provided new insights into the biological effects of these alkaloids on the rat Mdr1b P-gp efflux mechanism and would be beneficial in the design of potent P-gp inhibitors. Full article

(This article belongs to the Section Natural Products Chemistry)

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16 pages, 1696 KiB

Open AccessArticle

Apple Fibers as Carriers of Blackberry Juice Polyphenols: Development of Natural Functional Food Additives

by Ivana Buljeta, Mario Nosić, Anita Pichler, Ivana Ivić, Josip Šimunović and Mirela Kopjar

Molecules 2022, 27(9), 3029; https://doi.org/10.3390/molecules27093029 - 8 May 2022

Cited by 12 | Viewed by 2835

Abstract

Blackberry polyphenols possess various health-promoting properties. Since they are very sensitive to environmental conditions such as the presence of light, oxygen and high temperatures, the application of such compounds is restricted. Fibers are recognized as efficient carriers of polyphenols and are often used [...] Read more.

Blackberry polyphenols possess various health-promoting properties. Since they are very sensitive to environmental conditions such as the presence of light, oxygen and high temperatures, the application of such compounds is restricted. Fibers are recognized as efficient carriers of polyphenols and are often used in polyphenols encapsulation. In the present study, the ability of apple fiber to adsorb blackberry juice polyphenols was examined. Freeze-dried apple fiber/blackberry juice complexes were prepared with different amounts of fibers (1%, 2%, 4%, 6%, 8% and 10%) and a constant amount of blackberry juice. Polyphenol profile, antioxidant activity, inhibition of the α-amylase, color parameters, as well as the IR spectra, of the obtained complexes were assessed. The results showed a negative effect of higher amounts of fiber (more than 2%) on the adsorption of polyphenols and the antioxidant activity of complexes. With the proper formulation, apple fibers can serve as polyphenol carriers, and thus the application as novel food additives can be considered. Full article

(This article belongs to the Special Issue Delivery Systems of Bioactive Compounds)

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19 pages, 1525 KiB

Open AccessArticle

Effect of Collagen Types, Bacterial Strains and Storage Duration on the Quality of Probiotic Fermented Sheep’s Milk

by Kamil Szopa, Agata Znamirowska-Piotrowska, Katarzyna Szajnar and Małgorzata Pawlos

Molecules 2022, 27(9), 3028; https://doi.org/10.3390/molecules27093028 - 8 May 2022

Cited by 7 | Viewed by 3175

Abstract

Collagen has become popular in dietary supplements, beverages and sports nutrition products. Therefore, the aim of this study was to evaluate the possibility of using various doses of collagen and collagen hydrolysate to produce probiotic sheep’s milk fermented with Lactobacillus acidophilus, Lacticaseibacillus casei, [...] Read more.

Collagen has become popular in dietary supplements, beverages and sports nutrition products. Therefore, the aim of this study was to evaluate the possibility of using various doses of collagen and collagen hydrolysate to produce probiotic sheep’s milk fermented with Lactobacillus acidophilus, Lacticaseibacillus casei, Lacticaseibacillus paracasei and Lacticaseibacillus rhamnosus. The effects of storage time, type and dose of collagen, and different probiotic bacteria on the physicochemical, organoleptic and microbiological properties of fermented sheep’s milk at 1 and 21 days of refrigerated storage were investigated. The addition of collagen to sheep’s milk increased the pH value after fermentation and reduced the lactic acid contents of fermented milk compared to control samples. After fermentation, the number of probiotic bacteria cells was higher than 8 log cfu g⁻¹. In sheep’s milk fermented by L. acidophilus and L. casei, good survival of bacteria during storage was observed, and there was no effect of collagen dose on the growth and survival of both strains. The addition of collagen, both in the form of hydrolysate and bovine collagen, resulted in darkening of the color of the milk and increased the sweet taste intensity of the fermented sheep’s milk. However, the addition of hydrolysate was effective in reducing syneresis in each milk sample compared to its control counterpart. Full article

(This article belongs to the Special Issue The Impact of Advances in Fermentation Processes on the Chemical Composition of the Final Product)

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13 pages, 1201 KiB

Open AccessArticle

Physicochemical Properties and Anticoagulant Activity of Purified Heteropolysaccharides from Laminaria japonica

by Tingting Li, Haiqiong Ma, Hong Li, Hao Tang, Jinwen Huang, Shiying Wei, Qingxia Yuan, Xiaohuo Shi, Chenghai Gao, Shunli Mi, Longyan Zhao, Shengping Zhong and Yonghong Liu

Molecules 2022, 27(9), 3027; https://doi.org/10.3390/molecules27093027 - 8 May 2022

Cited by 14 | Viewed by 2655

Abstract

Laminaria japonica is widely consumed as a key food and medicine. Polysaccharides are one of the most plentiful constituents of this marine plant. In this study, several polysaccharide fractions with different charge numbers were obtained. Their physicochemical properties and anticoagulant activities were determined [...] Read more.

Laminaria japonica is widely consumed as a key food and medicine. Polysaccharides are one of the most plentiful constituents of this marine plant. In this study, several polysaccharide fractions with different charge numbers were obtained. Their physicochemical properties and anticoagulant activities were determined by chemical and instrumental methods. The chemical analysis showed that Laminaria japonica polysaccharides (LJPs) and the purified fractions LJP0, LJP04, LJP06, and LJP08 mainly consisted of mannose, glucuronic acid, galactose, and fucose in different mole ratios. LJP04 and LJP06 also contained minor amounts of xylose. The polysaccharide fractions eluted by higher concentration of NaCl solutions showed higher contents of uronic acid and sulfate group. Biological activity assays showed that LJPs LJP06 and LJP08 could obviously prolong the activated partial thromboplastin time (APTT), indicating that they had strong anticoagulant activity. Furthermore, we found that LJP06 exerted this activity by inhibiting intrinsic factor Xase with higher selectivity than other fractions, which may have negligible bleeding risk. The sulfate group may play an important role in the anticoagulant activity. In addition, the carboxyl group and surface morphology of these fractions may affect their anticoagulant activities. The results provide information for applications of L. japonica polysaccharides, especially LJP06 as anticoagulants in functional foods and therapeutic agents. Full article

(This article belongs to the Special Issue Food Polysaccharides: Structure, Properties and Application)

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18 pages, 3078 KiB

Open AccessArticle

Exploring In Vitro Biological Cellular Responses of Pegylated β-Cyclodextrins

by Juliana Rincón-López, Miguelina Martínez-Aguilera, Patricia Guadarrama, Karla Juarez-Moreno and Yareli Rojas-Aguirre

Molecules 2022, 27(9), 3026; https://doi.org/10.3390/molecules27093026 - 8 May 2022

Cited by 1 | Viewed by 2587

Abstract

βCDPEG5 and βCDPEG2 are two derivatives comprising seven PEG linear chains of 5 and 2 kDa, respectively, conjugated to βCD. As βCDPEGs display different physicochemical properties than their precursors, they could also trigger distinct cellular responses. To investigate the biological behavior of βCDPEGs [...] Read more.

βCDPEG5 and βCDPEG2 are two derivatives comprising seven PEG linear chains of 5 and 2 kDa, respectively, conjugated to βCD. As βCDPEGs display different physicochemical properties than their precursors, they could also trigger distinct cellular responses. To investigate the biological behavior of βCDPEGs in comparison to their parent compounds, we performed broad toxicological assays on RAW 264.7 macrophages, MC3T3-E1 osteoblasts, and MDCK cells. By analyzing ROS and NO₂⁻ overproduction in macrophages, we found that βCDPEGs induced a moderate stress response without affecting cell viability. Although MC3T3-E1 osteoblasts were more sensitive than MDCK cells to βCDPEGs and the parent compounds, a similar pattern was observed: the effect of βCDPEG5 on cell viability and cell cycle progression was larger than that of βCDPEG2; PEG2 affected cell viability and cell cycle more than βCDPEG2; cell post-treatment recovery was favorable in all cases, and the compounds had similar behaviors regarding ROS generation. The effect on MDCK cell migration followed a similar pattern. In contrast, for osteoblasts, the interference of βCDPEG5 with cell migration was smaller than that of βCDPEG2; likewise, the effect of PEG2 was shorter than its conjugate. Overall, the covalent conjugation of βCD and PEGs, particularly to yield βCDPEG2, improved the biocompatibility profile, evidencing that a favorable biological response can be tuned through a thoughtful combination of materials. Moreover, this is the first time that an in vitro evaluation of βCD and PEG has been presented for MC3T3-E1 and MDCK cells, thus providing valuable knowledge for designing biocompatible nanomaterials constructed from βCD and PEGs. Full article

(This article belongs to the Special Issue Cyclodextrin Chemistry and Toxicology II)

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17 pages, 1400 KiB

Open AccessArticle

Extraction, Encapsulation into Lipid Vesicular Systems, and Biological Activity of Rosa canina L. Bioactive Compounds for Dermocosmetic Use

by Valentina Sallustio, Ilaria Chiocchio, Manuela Mandrone, Marco Cirrincione, Michele Protti, Giovanna Farruggia, Angela Abruzzo, Barbara Luppi, Federica Bigucci, Laura Mercolini, Ferruccio Poli and Teresa Cerchiara

Molecules 2022, 27(9), 3025; https://doi.org/10.3390/molecules27093025 - 8 May 2022

Cited by 11 | Viewed by 3261

Abstract

Valorization of wild plants to obtain botanical ingredients could be a strategy for sustainable production of cosmetics. This study aimed to select the rosehip extract containing the greatest amounts of bioactive compounds and to encapsulate it in vesicular systems capable of protecting their [...] Read more.

Valorization of wild plants to obtain botanical ingredients could be a strategy for sustainable production of cosmetics. This study aimed to select the rosehip extract containing the greatest amounts of bioactive compounds and to encapsulate it in vesicular systems capable of protecting their own antioxidant activity. Chemical analysis of Rosa canina L. extracts was performed by LC-DAD-MS/MS and ¹H-NMR and vitamins, phenolic compounds, sugars, and organic acids were detected as the main compounds of the extracts. Liposomes, prepared by the film hydration method, together with hyalurosomes and ethosomes, obtained by the ethanol injection method, were characterized in terms of vesicle size, polydispersity index, entrapment efficiency, zeta potential, in vitro release and biocompatibility on WS1 fibroblasts. Among all types of vesicular systems, ethosomes proved to be the most promising nanocarriers showing nanometric size (196 ± 1 nm), narrow polydispersity (0.20 ± 0.02), good entrapment efficiency (92.30 ± 0.02%), and negative zeta potential (−37.36 ± 0.55 mV). Moreover, ethosomes showed good stability over time, a slow release of polyphenols compared with free extract, and they were not cytotoxic. In conclusion, ethosomes could be innovative carriers for the encapsulation of rosehip extract. Full article

(This article belongs to the Special Issue New Trends in Skin Care: Topical Delivery of Cosmeceutical Molecules)

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22 pages, 11901 KiB

Open AccessArticle

Towards Asymmetrical Methylene Blue Analogues: Synthesis and Reactivity of 3-N′-Arylaminophenothiazines

by Alena Khadieva, Mansur Rayanov, Ksenia Shibaeva, Alexandr Piskunov, Pavel Padnya and Ivan Stoikov

Molecules 2022, 27(9), 3024; https://doi.org/10.3390/molecules27093024 - 8 May 2022

Cited by 6 | Viewed by 3759

Abstract

The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-N′-arylaminophenothiazines and asymmetrical 3,7-di(N′-arylamino)phenothiazines. This approach included the optimization [...] Read more.

The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-N′-arylaminophenothiazines and asymmetrical 3,7-di(N′-arylamino)phenothiazines. This approach included the optimization of synthetic strategy by quantification analysis of the positive charge distribution in the cation of 3-N′-arylaminophenothiazine derivative. The obtained experimental data are confirmed by DFT studies. Two synthetic routes for asymmetrical phenothiazine diarylamino derivatives were suggested and verified. The developed convenient and versatile synthetic approach makes it easy to obtain aromatic Methylene Blue isostructural analogues with various substituents. As a result, a series of novel 3-N′-arylaminophenothiazines and asymmetrical 3,7-di(N′-arylamino)phenothiazines containing ester, tert-butoxycarbonyl, sulfonic acid, hydroxyl and amine groups were obtained in high yields. Full article

(This article belongs to the Special Issue Modern Trends in Heterocyclic Chemistry)

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12 pages, 2949 KiB

Open AccessArticle

Synthesis and In-Vivo Evaluation of Benzoxazole Derivatives as Promising Anti-Psoriatic Drugs for Clinical Use

by Rami Ayoub, Jamal Jilani, Qais Jarrar, Raad Alani, Chrismawan Ardianto, Khang Wen Goh, Dalia Ali and Said Moshawih

Molecules 2022, 27(9), 3023; https://doi.org/10.3390/molecules27093023 - 8 May 2022

Cited by 5 | Viewed by 2689

Abstract

2-(4-Chlorophenyl)-5-benzoxazoleacetic acid (CBA) and its ester, methyl-2-(4-chloro-phenyl)-5-benzoxazoleacetate (MCBA), were synthesized, and their structures were confirmed by ¹HNMR, IR, and mass spectrophotometry. The anti-psoriatic activities of CBA and MCBA were tested using an imiquimod (IMQ)-induced psoriatic mouse model, in which mice were treated [...] Read more.

2-(4-Chlorophenyl)-5-benzoxazoleacetic acid (CBA) and its ester, methyl-2-(4-chloro-phenyl)-5-benzoxazoleacetate (MCBA), were synthesized, and their structures were confirmed by ¹HNMR, IR, and mass spectrophotometry. The anti-psoriatic activities of CBA and MCBA were tested using an imiquimod (IMQ)-induced psoriatic mouse model, in which mice were treated both topically (1% w/w) and orally (125 mg/kg) for 14 days. The erythema intensity, thickness, and desquamation of psoriasis were scored by calculating the psoriasis area severity index (PASI). The study also included the determination of histopathological alterations in the skin tissues of treated mice. Topical and oral administration of CBA and MCBA led to a reduction in erythema intensity, thickness, and desquamation, which was demonstrated by a significant decrease in the PASI value. In addition, skin tissues of mice treated with CBA and MCBA showed less evidence of psoriatic alterations, such as hyperkeratosis, parakeratosis, scale crust, edema, psoriasiform, and hyperplasia. After administration of either topical or oral dosing, the anti-psoriatic effects were found to be stronger in MCBA-treated than in CBA-treated mice. These effects were comparable to those produced by Clobetasol propionate, the reference drug. This drug discovery could be translated into a potential new drug for future clinical use in psoriasis treatment. Full article

(This article belongs to the Special Issue Biofunctional Molecule Exploratory Research on Application in Food and Health)

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12 pages, 1890 KiB

Open AccessArticle

Adaptive Laboratory Evolution of Halomonas bluephagenesis Enhances Acetate Tolerance and Utilization to Produce Poly(3-hydroxybutyrate)

by Jing Zhang, Biao Jin, Jing Fu, Zhiwen Wang and Tao Chen

Molecules 2022, 27(9), 3022; https://doi.org/10.3390/molecules27093022 - 8 May 2022

Cited by 10 | Viewed by 2926

Abstract

Acetate is a promising economical and sustainable carbon source for bioproduction, but it is also a known cell-growth inhibitor. In this study, adaptive laboratory evolution (ALE) with acetate as selective pressure was applied to Halomonas bluephagenesis TD1.0, a fast-growing and contamination-resistant halophilic bacterium [...] Read more.

Acetate is a promising economical and sustainable carbon source for bioproduction, but it is also a known cell-growth inhibitor. In this study, adaptive laboratory evolution (ALE) with acetate as selective pressure was applied to Halomonas bluephagenesis TD1.0, a fast-growing and contamination-resistant halophilic bacterium that naturally accumulates poly(3-hydroxybutyrate) (PHB). After 71 transfers, the evolved strain, B71, was isolated, which not only showed better fitness (in terms of tolerance and utilization rate) to high concentrations of acetate but also produced a higher PHB titer compared with the parental strain TD1.0. Subsequently, overexpression of acetyl-CoA synthetase (ACS) in B71 resulted in a further increase in acetate utilization but a decrease in PHB production. Through whole-genome resequencing, it was speculated that genetic mutations (single-nucleotide variation (SNV) in phaB, mdh, and the upstream of OmpA, and insertion of TolA) in B71 might contribute to its improved acetate adaptability and PHB production. Finally, in a 5 L bioreactor with intermittent feeding of acetic acid, B71 was able to produce 49.79 g/L PHB and 70.01 g/L dry cell mass, which were 147.2% and 82.32% higher than those of TD1.0, respectively. These results highlight that ALE provides a reliable method to harness H. bluephagenesis to metabolize acetate for the production of PHB or other high-value chemicals more efficiently. Full article

(This article belongs to the Section Macromolecular Chemistry)

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21 pages, 1127 KiB

Open AccessArticle

Identifying Protein Features and Pathways Responsible for Toxicity Using Machine Learning and Tox21: Implications for Predictive Toxicology

by Lama Moukheiber, William Mangione, Mira Moukheiber, Saeed Maleki, Zackary Falls, Mingchen Gao and Ram Samudrala

Molecules 2022, 27(9), 3021; https://doi.org/10.3390/molecules27093021 - 8 May 2022

Cited by 10 | Viewed by 4054

Abstract

Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict [...] Read more.

Humans are exposed to numerous compounds daily, some of which have adverse effects on health. Computational approaches for modeling toxicological data in conjunction with machine learning algorithms have gained popularity over the last few years. Machine learning approaches have been used to predict toxicity-related biological activities using chemical structure descriptors. However, toxicity-related proteomic features have not been fully investigated. In this study, we construct a computational pipeline using machine learning models for predicting the most important protein features responsible for the toxicity of compounds taken from the Tox21 dataset that is implemented within the multiscale Computational Analysis of Novel Drug Opportunities (CANDO) therapeutic discovery platform. Tox21 is a highly imbalanced dataset consisting of twelve in vitro assays, seven from the nuclear receptor (NR) signaling pathway and five from the stress response (SR) pathway, for more than 10,000 compounds. For the machine learning model, we employed a random forest with the combination of Synthetic Minority Oversampling Technique (SMOTE) and the Edited Nearest Neighbor (ENN) method (SMOTE+ENN), which is a resampling method to balance the activity class distribution. Within the NR and SR pathways, the activity of the aryl hydrocarbon receptor (NR-AhR) and the mitochondrial membrane potential (SR-MMP) were two of the top-performing twelve toxicity endpoints with AUCROCs of 0.90 and 0.92, respectively. The top extracted features for evaluating compound toxicity were analyzed for enrichment to highlight the implicated biological pathways and proteins. We validated our enrichment results for the activity of the AhR using a thorough literature search. Our case study showed that the selected enriched pathways and proteins from our computational pipeline are not only correlated with AhR toxicity but also form a cascading upstream/downstream arrangement. Our work elucidates significant relationships between protein and compound interactions computed using CANDO and the associated biological pathways to which the proteins belong for twelve toxicity endpoints. This novel study uses machine learning not only to predict and understand toxicity but also elucidates therapeutic mechanisms at a proteomic level for a variety of toxicity endpoints. Full article

(This article belongs to the Special Issue Phenotypic Screening)

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22 pages, 7449 KiB

Open AccessReview

Decoding an Amino Acid Sequence to Extract Information on Protein Folding

by Takeshi Kikuchi

Molecules 2022, 27(9), 3020; https://doi.org/10.3390/molecules27093020 - 7 May 2022

Cited by 1 | Viewed by 2197

Abstract

Protein folding is a complicated phenomenon including various time scales (μs to several s), and various structural indices are required to analyze it. The methodologies used to study this phenomenon also have a wide variety and employ various experimental and computational techniques. Thus, [...] Read more.

Protein folding is a complicated phenomenon including various time scales (μs to several s), and various structural indices are required to analyze it. The methodologies used to study this phenomenon also have a wide variety and employ various experimental and computational techniques. Thus, a simple speculation does not serve to understand the folding mechanism of a protein. In the present review, we discuss the recent studies conducted by the author and their colleagues to decode amino acid sequences to obtain information on protein folding. We investigate globin-like proteins, ferredoxin-like fold proteins, IgG-like beta-sandwich fold proteins, lysozyme-like fold proteins and β-trefoil-like fold proteins. Our techniques are based on statistics relating to the inter-residue average distance, and our studies performed so far indicate that the information obtained from these analyses includes data on the protein folding mechanism. The relationships between our results and the actual protein folding phenomena are also discussed. Full article

(This article belongs to the Special Issue Advances in Protein Folding and Misfolding, and Relations to Functions)

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13 pages, 1762 KiB

Open AccessArticle

Synthesis and In Vitro Characterization of Selective Cannabinoid CB2 Receptor Agonists: Biological Evaluation against Neuroblastoma Cancer Cells

by Francesca Gado, Rebecca Ferrisi, Sarah Di Somma, Fabiana Napolitano, Kawthar A. Mohamed, Lesley A. Stevenson, Simona Rapposelli, Giuseppe Saccomanni, Giuseppe Portella, Roger G. Pertwee, Robert B. Laprairie, Anna Maria Malfitano and Clementina Manera

Molecules 2022, 27(9), 3019; https://doi.org/10.3390/molecules27093019 - 7 May 2022

Cited by 4 | Viewed by 2578

Abstract

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds [...] Read more.

1,8-naphthyridine-3-carboxamide structures were previously identified as a promising scaffold from which to obtain CB2R agonists with anticancer and anti-inflammatory activity. This work describes the synthesis and functional characterization of new 1,8-naphthyridin-2(1H)-one-3-carboxamides with high affinity and selectivity for CB2R. The new compounds were able to pharmacologically modulate the cAMP response without modulating CB2R-dependent β-arrestin2 recruitment. These structures were also evaluated for their anti-cancer activity against SH-SY5Y and SK-N-BE cells. They were able to reduce the cell viability of both neuroblastoma cancer cell lines with micromolar potency (IC₅₀ of FG158a = 11.8 μM and FG160a = 13.2 μM in SH-SY5Y cells) by a CB2R-mediated mechanism. Finally, in SH-SY5Y cells one of the newly synthesized compounds, FG158a, was able to modulate ERK1/2 expression by a CB2R-mediated effect, thus suggesting that this signaling pathway might be involved in its potential anti-cancer effect. Full article

(This article belongs to the Special Issue Cannabinergic Ligands: Chemistry, Pharmacology and Therapeutic Potential)

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15 pages, 1829 KiB

Open AccessArticle

Use of Microwave Maceration in Red Winemaking: Effect on Fermentation and Chemical Composition of Red Wines

by Raquel Muñoz García, Rodrigo Oliver-Simancas, María Arévalo Villena, Leticia Martínez-Lapuente, Belén Ayestarán, Lourdes Marchante-Cuevas, María Consuelo Díaz-Maroto and María Soledad Pérez-Coello

Molecules 2022, 27(9), 3018; https://doi.org/10.3390/molecules27093018 - 7 May 2022

Cited by 5 | Viewed by 2264

Abstract

The objective of this study was to evaluate the effect of microwave treatment of crushed grapes on the yeast population of the must and on the development of alcoholic fermentation, as well as on the extraction of different compounds from the grapes such [...] Read more.

The objective of this study was to evaluate the effect of microwave treatment of crushed grapes on the yeast population of the must and on the development of alcoholic fermentation, as well as on the extraction of different compounds from the grapes such as polysaccharides and amino acids that can affect the organoleptic quality and stability of the wine. This study demonstrated for the first time the effect of the microwave treatment of grapes on native yeast species and their diversity, producing an increase in fermentation kinetics and a decrease in the lag phase. The microwave treatment produced a positive effect on the extraction of amino acids and polysaccharides from the grapes, resulting in significantly higher amounts of the main amino acids of the must and some major volatile compounds in the treated samples. The polysaccharides most affected by the microwave treatment were the PRAGs, the main polysaccharides liberated from grapes during the maceration. Full article

(This article belongs to the Special Issue Wine Chemistry: The Key behind Wine Quality—2nd Edition)

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14 pages, 4838 KiB

Open AccessArticle

Detection of Ovine or Bovine Milk Components in Commercial Camel Milk Powder Using a PCR-Based Method

by Xiaoyun Wu, Qin Na, Shiqi Hao, Rimutu Ji and Liang Ming

Molecules 2022, 27(9), 3017; https://doi.org/10.3390/molecules27093017 - 7 May 2022

Cited by 6 | Viewed by 2670

Abstract

Food ingredient adulteration, especially the adulteration of milk and dairy products, is one of the important issues of food safety. The large price difference between camel milk powder, ovine, and bovine milk powder may be an incentive for the incorporation of ovine and [...] Read more.

Food ingredient adulteration, especially the adulteration of milk and dairy products, is one of the important issues of food safety. The large price difference between camel milk powder, ovine, and bovine milk powder may be an incentive for the incorporation of ovine and bovine derived foods in camel milk products. This study evaluated the use of ordinary PCR and real-time PCR for the detection of camel milk powder adulteration based on the presence of ovine and bovine milk components. DNA was extracted from camel, ovine, and bovine milk powder using a deep-processed product column DNA extraction kit. The quality of the extracted DNA was detected by amplifying the target sequence from the mitochondrial Cytb gene, and the extracted DNA was used for the identification of milk powder based on PCR analysis. In addition, PCR-based methods (both ordinary PCR and real-time PCR) were used to detect laboratory adulteration models of milk powder using primers targeting mitochondrial genes. The results show that the ordinary PCR method had better sensitivity and could qualitatively detect ovine and bovine milk components in the range of 1% to 100% in camel milk powder. The commercial camel milk powder was used to verify the practicability of this method. The real-time PCR normalization system has a good exponential correlation (R² = 0.9822 and 0.9923) between ovine or bovine content and Ct ratio (specific/internal reference gene) and allows for the quantitative determination of ovine or bovine milk contents in adulterated camel milk powder samples. Accuracy was effectively validated using simulated adulterated samples, with recoveries ranging from 80% to 110% with a coefficient of variation of less than 7%, exhibiting sufficient parameters of trueness. The ordinary PCR qualitative detection and real-time PCR quantitative detection method established in this study proved to be a specific, sensitive, and effective technology, which is expected to be used for market detection. Full article

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23 pages, 5419 KiB

Open AccessArticle

Construction of Enzyme-Responsive Micelles Based on Theranostic Zwitterionic Conjugated Bottlebrush Copolymers with Brush-on-Brush Architecture for Cell Imaging and Anticancer Drug Delivery

by Fangjun Liu, Dun Wang, Jiaqi Wang, Liwei Ma, Cuiyun Yu and Hua Wei

Molecules 2022, 27(9), 3016; https://doi.org/10.3390/molecules27093016 - 7 May 2022

Cited by 7 | Viewed by 2720

Abstract

Bottlebrush copolymers with different chemical structures and compositions as well as diverse architectures represent an important kind of material for various applications, such as biomedical devices. To our knowledge, zwitterionic conjugated bottlebrush copolymers integrating fluorescence imaging and tumor microenvironment-specific responsiveness for efficient intracellular [...] Read more.

Bottlebrush copolymers with different chemical structures and compositions as well as diverse architectures represent an important kind of material for various applications, such as biomedical devices. To our knowledge, zwitterionic conjugated bottlebrush copolymers integrating fluorescence imaging and tumor microenvironment-specific responsiveness for efficient intracellular drug release have been rarely reported, likely because of the lack of an efficient synthetic approach. For this purpose, in this study, we reported the successful preparation of well-defined theranostic zwitterionic bottlebrush copolymers with unique brush-on-brush architecture. Specifically, the bottlebrush copolymers were composed of a fluorescent backbone of polyfluorene derivate (PFONPN) possessing the fluorescence resonance energy transfer with doxorubicin (DOX), primary brushes of poly(2-hydroxyethyl methacrylate) (PHEMA), and secondary graft brushes of an enzyme-degradable polytyrosine (PTyr) block as well as a zwitterionic poly(oligo (ethylene glycol) monomethyl ether methacrylate-co-sulfobetaine methacrylate) (P(OEGMA-co-SBMA)) chain with super hydrophilicity and highly antifouling ability via elegant integration of Suzuki coupling, NCA ROP and ATRP techniques. Notably, the resulting bottlebrush copolymer, PFONPN₉-g-(PHEMA₁₅-g-(PTyr₁₆-b-P(OEGMA₆-co-SBMA₆)₂)) (P₂) with a lower MW ratio of the hydrophobic side chains of PTyr and hydrophilic side chains of P(OEGMA-co-SBMA) could self-assemble into stabilized unimolecular micelles in an aqueous phase. The resulting unimolecular micelles showed a fluorescence quantum yield of 3.9% that is mainly affected by the pendant phenol groups of PTyr side chains and a drug-loading content (DLC) of approximately 15.4% and entrapment efficiency (EE) of 90.6% for DOX, higher than the other micelle analogs, because of the efficient supramolecular interactions of π–π stacking between the PTyr blocks and drug molecules, as well as the moderate hydrophilic chain length. The fluorescence of the PFONPN backbone enables fluorescence resonance energy transfer (FRET) with DOX and visualization of intracellular trafficking of the theranostic micelles. Most importantly, the drug-loaded micelles showed accelerated drug release in the presence of proteinase K because of the enzyme-triggered degradation of PTyr blocks and subsequent deshielding of P(OEGMA-co-SBMA) corona for micelle destruction. Taken together, we developed an efficient approach for the synthesis of enzyme-responsive theranostic zwitterionic conjugated bottlebrush copolymers with a brush-on-brush architecture, and the resulting theranostic micelles with high DLC and tumor microenvironment-specific responsiveness represent a novel nanoplatform for simultaneous cell image and drug delivery. Full article

(This article belongs to the Special Issue Design of Functional Polymer Materials for Drug Controlled Release)

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Open AccessArticle

Conversion of Polypropylene Waste into Value-Added Products: A Greener Approach

by Jan Nisar, Maria Aziz, Afzal Shah, Iltaf Shah and Munawar Iqbal

Molecules 2022, 27(9), 3015; https://doi.org/10.3390/molecules27093015 - 7 May 2022

Cited by 10 | Viewed by 3213

Abstract

Plastic has made our lives comfortable as a result of its widespread use in today’s world due to its low cost, longevity, adaptability, light weight and hardness; however, at the same time, it has made our lives miserable due to its non-biodegradable nature, [...] Read more.

Plastic has made our lives comfortable as a result of its widespread use in today’s world due to its low cost, longevity, adaptability, light weight and hardness; however, at the same time, it has made our lives miserable due to its non-biodegradable nature, which has resulted in environmental pollution. Therefore, the focus of this research work was on an environmentally friendly process. This research work investigated the decomposition of polypropylene waste using florisil as the catalyst in a salt bath over a temperature range of 350–430 °C. A maximum oil yield of 57.41% was recovered at 410 °C and a 40 min reaction time. The oil collected from the decomposition of polypropylene waste was examined using gas chromatography-mass spectrometry (GC-MS). The kinetic parameters of the reaction process were calculated from thermogravimetric data at temperature program rates of 3, 12, 20 and 30 °C·min⁻¹ using the Ozawa–Flynn–Wall (OFW) and Kissinger–Akahira–Sunnose (KAS) equations. The activation energy (Ea) and pre-exponential factor (A) for the thermo-catalytic degradation of polypropylene waste were observed in the range of 102.74–173.08 kJ·mol⁻¹ and 7.1 × 10⁸–9.3 × 10¹¹ min⁻¹ for the OFW method and 99.77–166.28 kJ·mol⁻¹ and 1.1 × 10⁸–5.3 × 10¹¹ min⁻¹ for the KAS method at a percent conversion (α) of 0.1 to 0.9, respectively. Moreover, the fuel properties of the oil were assessed and matched with the ASTM values of diesel, gasoline and kerosene oil. The oil was found to have a close resemblance to the commercial fuel. Therefore, it was concluded that utilizing florisil as the catalyst for the decomposition of waste polypropylene not only lowered the activation energy of the pyrolysis reaction but also upgraded the quantity and quality of the oil. Full article

(This article belongs to the Special Issue Chemical Recycling of Waste Plastics)

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Molecules, Volume 27, Issue 9 (May-1 2022) – 438 articles

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