The 2023 MDPI Annual Report has
been released!
 
28 pages, 2589 KiB  
Review
AI-Driven Sensing Technology: Review
by Long Chen, Chenbin Xia, Zhehui Zhao, Haoran Fu and Yunmin Chen
Sensors 2024, 24(10), 2958; https://doi.org/10.3390/s24102958 - 07 May 2024
Abstract
Machine learning and deep learning technologies are rapidly advancing the capabilities of sensing technologies, bringing about significant improvements in accuracy, sensitivity, and adaptability. These advancements are making a notable impact across a broad spectrum of fields, including industrial automation, robotics, biomedical engineering, and [...] Read more.
Machine learning and deep learning technologies are rapidly advancing the capabilities of sensing technologies, bringing about significant improvements in accuracy, sensitivity, and adaptability. These advancements are making a notable impact across a broad spectrum of fields, including industrial automation, robotics, biomedical engineering, and civil infrastructure monitoring. The core of this transformative shift lies in the integration of artificial intelligence (AI) with sensor technology, focusing on the development of efficient algorithms that drive both device performance enhancements and novel applications in various biomedical and engineering fields. This review delves into the fusion of ML/DL algorithms with sensor technologies, shedding light on their profound impact on sensor design, calibration and compensation, object recognition, and behavior prediction. Through a series of exemplary applications, the review showcases the potential of AI algorithms to significantly upgrade sensor functionalities and widen their application range. Moreover, it addresses the challenges encountered in exploiting these technologies for sensing applications and offers insights into future trends and potential advancements. Full article
(This article belongs to the Section State-of-the-Art Sensors Technologies)
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4 pages, 160 KiB  
Editorial
Design and Synthesis of Biomedical Polymer Materials
by Jie Chen
Int. J. Mol. Sci. 2024, 25(10), 5088; https://doi.org/10.3390/ijms25105088 - 07 May 2024
Abstract
Due to their biocompatibility and non-toxic nature, biomedical polymer materials have found widespread applications and significantly propelled the progress of the biomedical field [...] Full article
(This article belongs to the Special Issue Design and Synthesis of Biomedical Polymer Materials)
15 pages, 1104 KiB  
Article
MiR-148a-3p/SIRT7 Axis Relieves Inflammatory-Induced Endothelial Dysfunction
by Camilla Anastasio, Isabella Donisi, Antonino Colloca, Nunzia D’Onofrio and Maria Luisa Balestrieri
Int. J. Mol. Sci. 2024, 25(10), 5087; https://doi.org/10.3390/ijms25105087 - 07 May 2024
Abstract
In endothelial cells, miR-148a-3p is involved in several pathological pathways, including chronic inflammatory conditions. However, the molecular mechanism of miR-148a-3p in endothelial inflammatory states is, to date, not fully elucidated. To this end, we investigated the involvement of miR-148a-3p in mitochondrial dysfunction and [...] Read more.
In endothelial cells, miR-148a-3p is involved in several pathological pathways, including chronic inflammatory conditions. However, the molecular mechanism of miR-148a-3p in endothelial inflammatory states is, to date, not fully elucidated. To this end, we investigated the involvement of miR-148a-3p in mitochondrial dysfunction and cell death pathways in human aortic endothelial cells (teloHAECs) treated with interleukin-6 (IL-6), a major driver of vascular dysfunction. The results showed that during IL6-activated inflammatory pathways, including increased protein levels of sirtuin 7 (SIRT7) (p < 0.01), mitochondrial stress (p < 0.001), and apoptosis (p < 0.01), a decreased expression of miR-148a-3p was observed (p < 0.01). The employment of a miR-148a mimic counteracted the IL-6-induced cytokine release (p < 0.01) and apoptotic cell death (p < 0.01), and ameliorated mitochondria redox homeostasis and respiration (p < 0.01). The targeted relationship between miR-148a-3p and SIRT7 was predicted by a bioinformatics database analysis and validated via the dual-luciferase reporter assay. Mechanistically, miR-148a-3p targets the 3′ untranslated regions of SIRT7 mRNA, downregulating its expression (p < 0.01). Herein, these in vitro results support the role of the miR-148a-3p/SIRT7 axis in counteracting mitochondrial damage and apoptosis during endothelial inflammation, unveiling a novel target for future strategies to prevent endothelial dysfunction. Full article
19 pages, 1820 KiB  
Article
Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1
by Jing Jiang, Hu Li, Mei Tang, Lei Lei, Hong-Ying Li, Biao Dong, Jian-Rui Li, Xue-Kai Wang, Han Sun, Jia-Yu Li, Jing-Chen Xu, Yue Gong, Jian-Dong Jiang and Zong-Gen Peng
Int. J. Mol. Sci. 2024, 25(10), 5086; https://doi.org/10.3390/ijms25105086 - 07 May 2024
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades [...] Read more.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common metabolic disease of the liver, characterized by hepatic steatosis in more than 5% of hepatocytes. However, despite the recent approval of the first drug, resmetirom, for the management of metabolic dysfunction-associated steatohepatitis, decades of target exploration and hundreds of clinical trials have failed, highlighting the urgent need to find new druggable targets for the discovery of innovative drug candidates against MASLD. Here, we found that glutathione S-transferase alpha 1 (GSTA1) expression was negatively associated with lipid droplet accumulation in vitro and in vivo. Overexpression of GSTA1 significantly attenuated oleic acid-induced steatosis in hepatocytes or high-fat diet-induced steatosis in the mouse liver. The hepatoprotective and anti-inflammatory drug bicyclol also attenuated steatosis by upregulating GSTA1 expression. A detailed mechanism showed that GSTA1 directly interacts with fatty acid binding protein 1 (FABP1) and facilitates the degradation of FABP1, thereby inhibiting intracellular triglyceride synthesis by impeding the uptake and transportation of free fatty acids. Conclusion: GSTA1 may be a good target for the discovery of innovative drug candidates as GSTA1 stabilizers or enhancers against MASLD. Full article
24 pages, 936 KiB  
Review
Chronic Stress-Induced Neuroinflammation: Relevance of Rodent Models to Human Disease
by Abigail G. White, Elias Elias, Andrea Orozco, Shivon A. Robinson and Melissa T. Manners
Int. J. Mol. Sci. 2024, 25(10), 5085; https://doi.org/10.3390/ijms25105085 - 07 May 2024
Abstract
The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This [...] Read more.
The brain is the central organ of adaptation to stress because it perceives and determines threats that induce behavioral, physiological, and molecular responses. In humans, chronic stress manifests as an enduring consistent feeling of pressure and being overwhelmed for an extended duration. This can result in a persistent proinflammatory response in the peripheral and central nervous system (CNS), resulting in cellular, physiological, and behavioral effects. Compounding stressors may increase the risk of chronic-stress-induced inflammation, which can yield serious health consequences, including mental health disorders. This review summarizes the current knowledge surrounding the neuroinflammatory response in rodent models of chronic stress—a relationship that is continually being defined. Many studies investigating the effects of chronic stress on neuroinflammation in rodent models have identified significant changes in inflammatory modulators, including nuclear factor-κB (NF-κB) and toll-like receptors (TLRs), and cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6. This suggests that these are key inflammatory factors in the chronic stress response, which may contribute to the establishment of anxiety and depression-like symptoms. The behavioral and neurological effects of modulating inflammatory factors through gene knockdown (KD) and knockout (KO), and conventional and alternative medicine approaches, are discussed. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy)
18 pages, 622 KiB  
Article
A New Approach in Lipase-Octyl-Agarose Biocatalysis of 2-Arylpropionic Acid Derivatives
by Joanna Siódmiak, Jacek Dulęba, Natalia Kocot, Rafał Mastalerz, Gudmundur G. Haraldsson, Michał Piotr Marszałł and Tomasz Siódmiak
Int. J. Mol. Sci. 2024, 25(10), 5084; https://doi.org/10.3390/ijms25105084 - 07 May 2024
Abstract
The use of lipase immobilized on an octyl-agarose support to obtain the optically pure enantiomers of chiral drugs in reactions carried out in organic solvents is a great challenge for chemical and pharmaceutical sciences. Therefore, it is extremely important to develop optimal procedures [...] Read more.
The use of lipase immobilized on an octyl-agarose support to obtain the optically pure enantiomers of chiral drugs in reactions carried out in organic solvents is a great challenge for chemical and pharmaceutical sciences. Therefore, it is extremely important to develop optimal procedures to achieve a high enantioselectivity of the biocatalysts in the organic medium. Our paper describes a new approach to biocatalysis performed in an organic solvent with the use of CALB-octyl-agarose support including the application of a polypropylene reactor, an appropriate buffer for immobilization (Tris base—pH 9, 100 mM), a drying step, and then the storage of immobilized lipases in a climatic chamber or a refrigerator. An immobilized lipase B from Candida antarctica (CALB) was used in the kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification with methanol, reaching a high enantiomeric excess (eep = 89.6% ± 2.0%). As part of the immobilization optimization, the influence of different buffers was investigated. The effect of the reactor material and the reaction medium on the lipase activity was also studied. Moreover, the stability of the immobilized lipases: lipase from Candida rugosa (CRL) and CALB during storage in various temperature and humidity conditions (climatic chamber and refrigerator) was tested. The application of the immobilized CALB in a polypropylene reactor allowed for receiving over 9-fold higher conversion values compared to the results achieved when conducting the reaction in a glass reactor, as well as approximately 30-fold higher conversion values in comparison with free lipase. The good stability of the CALB-octyl-agarose support was demonstrated. After 7 days of storage in a climatic chamber or refrigerator (with protection from humidity) approximately 60% higher conversion values were obtained compared to the results observed for the immobilized form that had not been stored. The new approach involving the application of the CALB-octyl-agarose support for reactions performed in organic solvents indicates a significant role of the polymer reactor material being used in achieving high catalytic activity. Full article
(This article belongs to the Special Issue Developments and Advances in Biocatalysis of Chiral Drugs)
21 pages, 809 KiB  
Review
About a Possible Impact of Endodontic Infections by Fusobacterium nucleatum or Porphyromonas gingivalis on Oral Carcinogenesis: A Literature Overview
by Luca Ciani, Antonio Libonati, Maria Dri, Silvia Pomella, Vincenzo Campanella and Giovanni Barillari
Int. J. Mol. Sci. 2024, 25(10), 5083; https://doi.org/10.3390/ijms25105083 - 07 May 2024
Abstract
Periodontitis is linked to the onset and progression of oral squamous cell carcinoma (OSCC), an epidemiologically frequent and clinically aggressive malignancy. In this context, Fusobacterium (F.) nucleatum and Porphyromonas (P.) gingivalis, two bacteria that cause periodontitis, are found in OSCC tissues as [...] Read more.
Periodontitis is linked to the onset and progression of oral squamous cell carcinoma (OSCC), an epidemiologically frequent and clinically aggressive malignancy. In this context, Fusobacterium (F.) nucleatum and Porphyromonas (P.) gingivalis, two bacteria that cause periodontitis, are found in OSCC tissues as well as in oral premalignant lesions, where they exert pro-tumorigenic activities. Since the two bacteria are present also in endodontic diseases, playing a role in their pathogenesis, here we analyze the literature searching for information on the impact that endodontic infection by P. gingivalis or F. nucleatum could have on cellular and molecular events involved in oral carcinogenesis. Results from the reviewed papers indicate that infection by P. gingivalis and/or F. nucleatum triggers the production of inflammatory cytokines and growth factors in dental pulp cells or periodontal cells, affecting the survival, proliferation, invasion, and differentiation of OSCC cells. In addition, the two bacteria and the cytokines they induce halt the differentiation and stimulate the proliferation and invasion of stem cells populating the dental pulp or the periodontium. Although most of the literature confutes the possibility that bacteria-induced endodontic inflammatory diseases could impact on oral carcinogenesis, the papers we have analyzed and discussed herein recommend further investigations on this topic. Full article
(This article belongs to the Special Issue Oral Microbiome and Oral Diseases 2.0)
21 pages, 4795 KiB  
Article
Silver Complexes of Miconazole and Metronidazole: Potential Candidates for Melanoma Treatment
by Małgorzata Fabijańska, Agnieszka J. Rybarczyk-Pirek, Justyna Dominikowska, Karolina Stryjska, Dominik Żyro, Magdalena Markowicz-Piasecka, Małgorzata Iwona Szynkowska-Jóźwik, Justyn Ochocki and Joanna Sikora
Int. J. Mol. Sci. 2024, 25(10), 5081; https://doi.org/10.3390/ijms25105081 - 07 May 2024
Abstract
Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3 [...] Read more.
Melanoma, arguably the deadliest form of skin cancer, is responsible for the majority of skin-cancer-related fatalities. Innovative strategies concentrate on new therapies that avoid the undesirable effects of pharmacological or medical treatment. This article discusses the chemical structures of [(MTZ)2AgNO3], [(MTZ)2Ag]2SO4, [Ag(MCZ)2NO3], [Ag(MCZ)2BF4], [Ag(MCZ)2SbF6] and [Ag(MCZ)2ClO4] (MTZ—metronidazole; MCZ—miconazole) silver(I) compounds and the possible relationship between the molecules and their cytostatic activity against melanoma cells. Molecular Hirshfeld surface analysis and computational methods were used to examine the possible association between the structure and anticancer activity of the silver(I) complexes and compare the cytotoxicity of the silver(I) complexes of metronidazole and miconazole with that of silver(I) nitrate, cisplatin, metronidazole and miconazole complexes against A375 and BJ cells. Additionally, these preliminary biological studies found the greatest IC50 values against the A375 line were demonstrated by [Ag(MCZ)2NO3] and [(MTZ)2AgNO3]. The compound [(MTZ)2AgNO3] was three-fold more toxic to the A375 cells than the reference (cisplatin) and 15 times more cytotoxic against the A375 cells than the normal BJ cells. Complexes of metronidazole with Ag(I) are considered biocompatible at a concentration below 50 µmol/L. Full article
(This article belongs to the Special Issue Recent Advances in Anti-Cancer Drugs)
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19 pages, 3487 KiB  
Article
Temperature-Wise Calibration Increases the Accuracy of DNA Methylation Levels Determined by High-Resolution Melting (HRM)
by Katja Zappe and Margit Cichna-Markl
Int. J. Mol. Sci. 2024, 25(10), 5082; https://doi.org/10.3390/ijms25105082 - 07 May 2024
Abstract
High-resolution melting (HRM) is a cost-efficient tool for targeted DNA methylation analysis. HRM yields the average methylation status across all CpGs in PCR products. Moreover, it provides information on the methylation pattern, e.g., the occurrence of monoallelic methylation. HRM assays have to be [...] Read more.
High-resolution melting (HRM) is a cost-efficient tool for targeted DNA methylation analysis. HRM yields the average methylation status across all CpGs in PCR products. Moreover, it provides information on the methylation pattern, e.g., the occurrence of monoallelic methylation. HRM assays have to be calibrated by analyzing DNA methylation standards of known methylation status and mixtures thereof. In general, DNA methylation levels determined by the classical calibration approach, including the whole temperature range in between normalization intervals, are in good agreement with the mean of the DNA methylation status of individual CpGs determined by pyrosequencing (PSQ), the gold standard of targeted DNA methylation analysis. However, the classical calibration approach leads to highly inaccurate results for samples with heterogeneous DNA methylation since they result in more complex melt curves, differing in their shape compared to those of DNA standards and mixtures thereof. Here, we present a novel calibration approach, i.e., temperature-wise calibration. By temperature-wise calibration, methylation profiles over temperature are obtained, which help in finding the optimal calibration range and thus increase the accuracy of HRM data, particularly for heterogeneous DNA methylation. For explaining the principle and demonstrating the potential of the novel calibration approach, we selected the promoter and two enhancers of MGMT, a gene encoding the repair protein MGMT. Full article
(This article belongs to the Special Issue Biomarkers in Cancers: New Advances)
23 pages, 681 KiB  
Article
Monocytic Differentiation of Human Acute Myeloid Leukemia Cells: A Proteomic and Phosphoproteomic Comparison of FAB-M4/M5 Patients with and without Nucleophosmin 1 Mutations
by Frode Selheim, Elise Aasebø, Håkon Reikvam, Øystein Bruserud and Maria Hernandez-Valladares
Int. J. Mol. Sci. 2024, 25(10), 5080; https://doi.org/10.3390/ijms25105080 - 07 May 2024
Abstract
Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased [...] Read more.
Even though morphological signs of differentiation have a minimal impact on survival after intensive cytotoxic therapy for acute myeloid leukemia (AML), monocytic AML cell differentiation (i.e., classified as French/American/British (FAB) subtypes M4/M5) is associated with a different responsiveness both to Bcl-2 inhibition (decreased responsiveness) and possibly also bromodomain inhibition (increased responsiveness). FAB-M4/M5 patients are heterogeneous with regard to genetic abnormalities, even though monocytic differentiation is common for patients with Nucleophosmin 1 (NPM1) insertions/mutations; to further study the heterogeneity of FAB-M4/M5 patients we did a proteomic and phosphoproteomic comparison of FAB-M4/M5 patients with (n = 13) and without (n = 12) NPM1 mutations. The proteomic profile of NPM1-mutated FAB-M4/M5 patients was characterized by increased levels of proteins involved in the regulation of endocytosis/vesicle trafficking/organellar communication. In contrast, AML cells without NPM1 mutations were characterized by increased levels of several proteins involved in the regulation of cytoplasmic translation, including a large number of ribosomal proteins. The phosphoproteomic differences between the two groups were less extensive but reflected similar differences. To conclude, even though FAB classification/monocytic differentiation are associated with differences in responsiveness to new targeted therapies (e.g., Bcl-2 inhibition), our results shows that FAB-M4/M5 patients are heterogeneous with regard to important biological characteristics of the leukemic cells. Full article
(This article belongs to the Special Issue Proteomics and Its Applications in Disease 2.0)
21 pages, 1685 KiB  
Article
Screening of Small-Molecule Libraries Using SARS-CoV-2-Derived Sequences Identifies Novel Furin Inhibitors
by Alireza Jorkesh, Sylvia Rothenberger, Laura Baldassar, Birute Grybaite, Povilas Kavaliauskas, Vytautas Mickevicius, Monica Dettin, Filippo Vascon, Laura Cendron and Antonella Pasquato
Int. J. Mol. Sci. 2024, 25(10), 5079; https://doi.org/10.3390/ijms25105079 - 07 May 2024
Abstract
SARS-CoV-2 is the pathogen responsible for the most recent global pandemic, which has claimed hundreds of thousands of victims worldwide. Despite remarkable efforts to develop an effective vaccine, concerns have been raised about the actual protection against novel variants. Thus, researchers are eager [...] Read more.
SARS-CoV-2 is the pathogen responsible for the most recent global pandemic, which has claimed hundreds of thousands of victims worldwide. Despite remarkable efforts to develop an effective vaccine, concerns have been raised about the actual protection against novel variants. Thus, researchers are eager to identify alternative strategies to fight against this pathogen. Like other opportunistic entities, a key step in the SARS-CoV-2 lifecycle is the maturation of the envelope glycoprotein at the RARR685↓ motif by the cellular enzyme Furin. Inhibition of this cleavage greatly affects viral propagation, thus representing an ideal drug target to contain infection. Importantly, no Furin-escape variants have ever been detected, suggesting that the pathogen cannot replace this protease by any means. Here, we designed a novel fluorogenic SARS-CoV-2-derived substrate to screen commercially available and custom-made libraries of small molecules for the identification of new Furin inhibitors. We found that a peptide substrate mimicking the cleavage site of the envelope glycoprotein of the Omicron variant (QTQTKSHRRAR-AMC) is a superior tool for screening Furin activity when compared to the commercially available Pyr-RTKR-AMC substrate. Using this setting, we identified promising novel compounds able to modulate Furin activity in vitro and suitable for interfering with SARS-CoV-2 maturation. In particular, we showed that 3-((5-((5-bromothiophen-2-yl)methylene)-4-oxo-4,5 dihydrothiazol-2-yl)(3-chloro-4-methylphenyl)amino)propanoic acid (P3, IC50 = 35 μM) may represent an attractive chemical scaffold for the development of more effective antiviral drugs via a mechanism of action that possibly implies the targeting of Furin secondary sites (exosites) rather than its canonical catalytic pocket. Overall, a SARS-CoV-2-derived peptide was investigated as a new substrate for in vitro high-throughput screening (HTS) of Furin inhibitors and allowed the identification of compound P3 as a promising hit with an innovative chemical scaffold. Given the key role of Furin in infection and the lack of any Food and Drug Administration (FDA)-approved Furin inhibitor, P3 represents an interesting antiviral candidate Full article
22 pages, 868 KiB  
Review
Advances in the Modulation of Potato Tuber Dormancy and Sprouting
by Xueni Di, Qiang Wang, Feng Zhang, Haojie Feng, Xiyao Wang and Chengcheng Cai
Int. J. Mol. Sci. 2024, 25(10), 5078; https://doi.org/10.3390/ijms25105078 - 07 May 2024
Abstract
The post-harvest phase of potato tuber dormancy and sprouting are essential in determining the economic value. The intricate transition from dormancy to active growth is influenced by multiple factors, including environmental factors, carbohydrate metabolism, and hormonal regulation. Well-established environmental factors such as temperature, [...] Read more.
The post-harvest phase of potato tuber dormancy and sprouting are essential in determining the economic value. The intricate transition from dormancy to active growth is influenced by multiple factors, including environmental factors, carbohydrate metabolism, and hormonal regulation. Well-established environmental factors such as temperature, humidity, and light play pivotal roles in these processes. However, recent research has expanded our understanding to encompass other novel influences such as magnetic fields, cold plasma treatment, and UV-C irradiation. Hormones like abscisic acid (ABA), gibberellic acid (GA), cytokinins (CK), auxin, and ethylene (ETH) act as crucial messengers, while brassinosteroids (BRs) have emerged as key modulators of potato tuber sprouting. In addition, jasmonates (JAs), strigolactones (SLs), and salicylic acid (SA) also regulate potato dormancy and sprouting. This review article delves into the intricate study of potato dormancy and sprouting, emphasizing the impact of environmental conditions, carbohydrate metabolism, and hormonal regulation. It explores how various environmental factors affect dormancy and sprouting processes. Additionally, it highlights the role of carbohydrates in potato tuber sprouting and the intricate hormonal interplay, particularly the role of BRs. This review underscores the complexity of these interactions and their importance in optimizing potato dormancy and sprouting for agricultural practices. Full article
(This article belongs to the Special Issue Molecular Genetics and Plant Breeding 4.0)
18 pages, 3760 KiB  
Article
Inhibition of Shikimate Kinase from Methicillin-Resistant Staphylococcus aureus by Benzimidazole Derivatives. Kinetic, Computational, Toxicological, and Biological Activity Studies
by Lluvia Rios-Soto, Alicia Hernández-Campos, David Tovar-Escobar, Rafael Castillo, Erick Sierra-Campos, Mónica Valdez-Solana, Alfredo Téllez-Valencia and Claudia Avitia-Domínguez
Int. J. Mol. Sci. 2024, 25(10), 5077; https://doi.org/10.3390/ijms25105077 - 07 May 2024
Abstract
Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health [...] Read more.
Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity (C1 and C2) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA. Full article
(This article belongs to the Special Issue Recent Advances: Heterocycles in Drugs and Drug Discovery 2.0)
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15 pages, 1689 KiB  
Article
Simultaneous Treatment of 5-Aminosalicylic Acid and Treadmill Exercise More Effectively Improves Ulcerative Colitis in Mice
by Jun-Jang Jin, Il-Gyu Ko, Lakkyong Hwang, Sang-Hoon Kim, Yong-Seok Jee, Hyeon Jeon, Su Bee Park and Jung Won Jeon
Int. J. Mol. Sci. 2024, 25(10), 5076; https://doi.org/10.3390/ijms25105076 - 07 May 2024
Abstract
Ulcerative colitis (UC) is characterized by continuous mucosal ulceration of the colon, starting in the rectum. 5-Aminosalicylic acid (5-ASA) is the main therapy for ulcerative colitis; however, it has side effects. Physical exercise effectively increases the number of anti-inflammatory and anti-immune cells in [...] Read more.
Ulcerative colitis (UC) is characterized by continuous mucosal ulceration of the colon, starting in the rectum. 5-Aminosalicylic acid (5-ASA) is the main therapy for ulcerative colitis; however, it has side effects. Physical exercise effectively increases the number of anti-inflammatory and anti-immune cells in the body. In the current study, the effects of simultaneous treatment of treadmill exercise and 5-ASA were compared with monotherapy with physical exercise or 5-ASA in UC mice. To induce the UC animal model, the mice consumed 2% dextran sulfate sodium dissolved in drinking water for 7 days. The mice in the exercise groups exercised on a treadmill for 1 h once a day for 14 days after UC induction. The 5-ASA-treated groups received 5-ASA by enema injection using a 200 μL polyethylene catheter once a day for 14 days. Simultaneous treatment improved histological damage and increased body weight, colon weight, and colon length, whereas the disease activity index score and collagen deposition were decreased. Simultaneous treatment with treadmill exercise and 5-ASA suppressed pro-inflammatory cytokines and apoptosis following UC. The benefits of this simultaneous treatment may be due to inhibition on nuclear factor-κB/mitogen-activated protein kinase signaling activation. Based on this study, simultaneous treatment of treadmill exercise and 5-ASA can be considered as a new therapy of UC. Full article
(This article belongs to the Special Issue Molecular Insights into the Role of Exercise in Disease and Health)
16 pages, 9570 KiB  
Review
Investigating the Balance between Structural Conservation and Functional Flexibility in Photosystem I
by Nathan Nelson
Int. J. Mol. Sci. 2024, 25(10), 5073; https://doi.org/10.3390/ijms25105073 - 07 May 2024
Abstract
Photosynthesis, as the primary source of energy for all life forms, plays a crucial role in maintaining the global balance of energy, entropy, and enthalpy in living organisms. Among its various building blocks, photosystem I (PSI) is responsible for light-driven electron transfer, crucial [...] Read more.
Photosynthesis, as the primary source of energy for all life forms, plays a crucial role in maintaining the global balance of energy, entropy, and enthalpy in living organisms. Among its various building blocks, photosystem I (PSI) is responsible for light-driven electron transfer, crucial for generating cellular reducing power. PSI acts as a light-driven plastocyanin-ferredoxin oxidoreductase and is situated in the thylakoid membranes of cyanobacteria and the chloroplasts of eukaryotic photosynthetic organisms. Comprehending the structure and function of the photosynthetic machinery is essential for understanding its mode of action. New insights are offered into the structure and function of PSI and its associated light-harvesting proteins, with a specific focus on the remarkable structural conservation of the core complex and high plasticity of the peripheral light-harvesting complexes. Full article
(This article belongs to the Special Issue New Insights into Photosystem I)
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14 pages, 1013 KiB  
Article
Synergy of Oxygen Vacancy and Surface Modulation Endows Hollow Hydrangea-Like MnCo2O4.5 with Enhanced Capacitive Performance
by Gaofeng Li, Yanyan Li, Pengfei Wang, Lingling Chen, Longfei Li, Chen Bao, Jianfei Tu and Dianbo Ruan
Int. J. Mol. Sci. 2024, 25(10), 5075; https://doi.org/10.3390/ijms25105075 - 07 May 2024
Abstract
Surface chemistry and bulk structure jointly play crucial roles in achieving high-performance supercapacitors. Here, the synergistic effect of surface chemistry properties (vacancy and phosphorization) and structure-derived properties (hollow hydrangea-like structure) on energy storage is explored by the surface treatment and architecture design of [...] Read more.
Surface chemistry and bulk structure jointly play crucial roles in achieving high-performance supercapacitors. Here, the synergistic effect of surface chemistry properties (vacancy and phosphorization) and structure-derived properties (hollow hydrangea-like structure) on energy storage is explored by the surface treatment and architecture design of the nanostructures. The theoretical calculations and experiments prove that surface chemistry modulation is capable of improving electronic conductivity and electrolyte wettability. The structural engineering of both hollow and nanosheets produces a high specific surface area and an abundant pore structure, which is favorable in exposing more active sites and shortens the ion diffusion distance. Benefiting from its admirable physicochemical properties, the surface phosphorylated MnCo2O4.5 hollow hydrangea-like structure (P-MnCoO) delivers a high capacitance of 425 F g−1 at 1 A g−1, a superior capability rate of 63.9%, capacitance retention at 10 A g−1, and extremely long cyclic stability (91.1% after 10,000 cycles). The fabricated P-MnCoO/AC asymmetric supercapacitor achieved superior energy and power density. This work opens a new avenue to further improve the electrochemical performance of metal oxides for supercapacitors. Full article
12 pages, 2403 KiB  
Article
Lignin Degradation by Klebsiella aerogenes TL3 under Anaerobic Conditions
by Zhuowei Tu, Alei Geng, Yuhua Xiang, Anaiza Zayas-Garriga, Hao Guo, Daochen Zhu, Rongrong Xie and Jianzhong Sun
Molecules 2024, 29(10), 2177; https://doi.org/10.3390/molecules29102177 - 07 May 2024
Abstract
Lignin, the largest non-carbohydrate component of lignocellulosic biomass, is also a recalcitrant component of the plant cell wall. While the aerobic degradation mechanism of lignin has been well-documented, the anaerobic degradation mechanism is still largely elusive. In this work, a versatile facultative anaerobic [...] Read more.
Lignin, the largest non-carbohydrate component of lignocellulosic biomass, is also a recalcitrant component of the plant cell wall. While the aerobic degradation mechanism of lignin has been well-documented, the anaerobic degradation mechanism is still largely elusive. In this work, a versatile facultative anaerobic lignin-degrading bacterium, Klebsiella aerogenes TL3, was isolated from a termite gut, and was found to metabolize a variety of carbon sources and produce a single kind or multiple kinds of acids. The percent degradation of alkali lignin reached 14.8% under anaerobic conditions, and could reach 17.4% in the presence of glucose within 72 h. Based on the results of infrared spectroscopy and 2D nuclear magnetic resonance analysis, it can be inferred that the anaerobic degradation of lignin may undergo the cleavage of the C-O bond (β-O-4), as well as the C-C bond (β-5 and β-β), and involve the oxidation of the side chain, demethylation, and the destruction of the aromatic ring skeleton. Although the anaerobic degradation of lignin by TL3 was slightly weaker than that under aerobic conditions, it could be further enhanced by adding glucose as an electron donor. These results may shed new light on the mechanisms of anaerobic lignin degradation. Full article
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18 pages, 1470 KiB  
Review
Recent Advances in the Synthesis of Rosettacin
by Xiao Tang, Yukang Jiang, Liangliang Song and Erik V. Van der Eycken
Molecules 2024, 29(10), 2176; https://doi.org/10.3390/molecules29102176 - 07 May 2024
Abstract
Camptothecin and its analogues show important antitumor activity and have been used in clinical studies. However, hydrolysis of lactone in the E ring seriously attenuates the antitumor activity. To change this situation, aromathecin alkaloids are investigated in order to replace camptothecins. Potential antitumor [...] Read more.
Camptothecin and its analogues show important antitumor activity and have been used in clinical studies. However, hydrolysis of lactone in the E ring seriously attenuates the antitumor activity. To change this situation, aromathecin alkaloids are investigated in order to replace camptothecins. Potential antitumor activity has obtained more and more attention from organic and pharmaceutical chemists. As a member of the aromathecin alkaloids, rosettacin has been synthesized via different methods. This review summarizes recent advances in the synthesis of rosettacin. Full article
(This article belongs to the Special Issue Synthesis and Properties of Heterocyclic Compounds: Recent Advances)
11 pages, 2645 KiB  
Article
α-Amido Trifluoromethyl Xanthates: A New Class of RAFT/MADIX Agents
by Mathias Destarac, Juliette Ruchmann-Sternchuss, Eric Van Gramberen, Xavier Vila and Samir Z. Zard
Molecules 2024, 29(10), 2174; https://doi.org/10.3390/molecules29102174 - 07 May 2024
Abstract
Xanthates have long been described as poor RAFT/MADIX agents for styrene polymerization. Through the determination of chain transfer constants to xanthates, this work demonstrated beneficial capto-dative substituent effects for the leaving group of a new series of α-amido trifluoromethyl xanthates, with the best [...] Read more.
Xanthates have long been described as poor RAFT/MADIX agents for styrene polymerization. Through the determination of chain transfer constants to xanthates, this work demonstrated beneficial capto-dative substituent effects for the leaving group of a new series of α-amido trifluoromethyl xanthates, with the best effect observed with trifluoroacetyl group. The previously observed Z-group activation with a O-trifluoroethyl group compared to the O-ethyl counterpart was quantitatively established with Cex = 2.7 (3–4 fold increase) using the SEC peak resolution method. This study further confirmed the advantageous incorporation of trifluoromethyl substituents to activate xanthates in radical chain transfer processes and contributed to identify the most reactive xanthate reported to date for RAFT/MADIX polymerization of styrene. Full article
(This article belongs to the Special Issue Themed Issue Dedicated to Prof. Bernard Boutevin)
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16 pages, 813 KiB  
Article
Turn-On Coumarin Precursor: From Hydrazine Sensor to Covalent Inhibition and Fluorescence Detection of Rabbit Muscle Aldolase
by Sara Amer, Uri Miles, Michael Firer and Flavio Grynszpan
Molecules 2024, 29(10), 2175; https://doi.org/10.3390/molecules29102175 - 07 May 2024
Abstract
Hydrazine, a highly toxic compound, demands sensitive and selective detection methods. Building upon our previous studies with pre-coumarin OFF–ON sensors for fluoride anions, we extended our strategy to hydrazine sensing by adapting phenol protecting groups (propionate, levulinate, and γ-bromobutanoate) to our pre-coumarin scaffold. [...] Read more.
Hydrazine, a highly toxic compound, demands sensitive and selective detection methods. Building upon our previous studies with pre-coumarin OFF–ON sensors for fluoride anions, we extended our strategy to hydrazine sensing by adapting phenol protecting groups (propionate, levulinate, and γ-bromobutanoate) to our pre-coumarin scaffold. These probes reacted with hydrazine, yielding a fluorescent signal with low micromolar limits of detection. Mechanistic studies revealed that hydrazine deprotection may be outperformed by a retro-Knoevenagel reaction, where hydrazine acts as a nucleophile and a base yielding a fluorescent diimide compound (6,6′-((1E,1′E)-hydrazine-1,2diylidenebis(methaneylylidene))bis(3(diethylamino)phenol, 7). Additionally, our pre-coumarins unexpectedly reacted with primary amines, generating a fluorescent signal corresponding to phenol deprotection followed by cyclization and coumarin formation. The potential of compound 3 as a theranostic Turn-On coumarin precursor was also explored. We propose that its reaction with ALDOA produced a γ-lactam, blocking the catalytic nucleophilic amine in the enzyme’s binding site. The cleavage of the ester group in compound 3 induced the formation of fluorescent coumarin 4. This fluorescent signal was proportional to ALDOA concentration, demonstrating the potential of compound 3 for future theranostic studies in vivo. Full article
(This article belongs to the Section Organic Chemistry)
12 pages, 5325 KiB  
Article
The Peculiar H-Bonding Network of 4-Methylcatechol: A Coupled Diffraction and In Silico Study
by Mattia Lopresti, Luca Palin, Giovanni Calegari and Marco Milanesio
Molecules 2024, 29(10), 2173; https://doi.org/10.3390/molecules29102173 - 07 May 2024
Abstract
The crystal structure of 4-methylcatechol (4MEC) has, to date, never been solved, despite its very simple chemical formula C7O2H8 and the many possible applications envisaged for this molecule. In this work, this gap is filled and the structure [...] Read more.
The crystal structure of 4-methylcatechol (4MEC) has, to date, never been solved, despite its very simple chemical formula C7O2H8 and the many possible applications envisaged for this molecule. In this work, this gap is filled and the structure of 4MEC is obtained by combining X-ray powder diffraction and first principle calculations to carefully locate hydrogen atoms. Two molecules are present in the asymmetric unit. Hirshfeld analysis confirmed the reliability of the solved structure, since the two molecules show rather different environments and H-bond interactions of different directionality and strength. The packing is characterised by a peculiar hydrogen bond network with hydroxyl nests formed by two adjacent octagonal frameworks. It is noteworthy that the observed short contacts suggest strong inter-molecular interactions, further confirmed by strong inter-crystalline aggregation observed by microscopic images, indicating the growth, in many crystallization attempts, of single aggregates taller than half a centimetre and, often, with spherical shapes. These peculiarities are induced by the presence of methyl group in 4MEC, since the parent compound catechol, despite its chemical similarity, shows a standard layered packing alternating hydrophobic and polar layers. Finally, the complexity and peculiarity of the packing and crystal growth features explain why a single crystal could not be obtained for a standard structural analysis. Full article
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12 pages, 1497 KiB  
Article
Fabrication of Ternary Titanium Dioxide/Polypyrrole/Phosphorene Nanocomposite for Supercapacitor Electrode Applications
by Seungho Ha and Keun-Young Shin
Molecules 2024, 29(10), 2172; https://doi.org/10.3390/molecules29102172 - 07 May 2024
Abstract
In this paper, we report a titanium dioxide/polypyrrole/phosphorene (TiO2/PPy/phosphorene) nanocomposite as an active material for supercapacitor electrodes. Black phosphorus (BP) was fabricated by ball milling to induce a phase transition from red phosphorus, and urea-functionalized phosphorene (urea-FP) was obtained by urea-assisted [...] Read more.
In this paper, we report a titanium dioxide/polypyrrole/phosphorene (TiO2/PPy/phosphorene) nanocomposite as an active material for supercapacitor electrodes. Black phosphorus (BP) was fabricated by ball milling to induce a phase transition from red phosphorus, and urea-functionalized phosphorene (urea-FP) was obtained by urea-assisted ball milling of BP, followed by sonication. TiO2/PPy/phosphorene nanocomposites can be prepared via chemical oxidative polymerization, which has the advantage of mass production for a one-pot synthesis. The specific capacitance of the ternary nanocomposite was 502.6 F g−1, which was higher than those of the phosphorene/PPy (286.25 F g−1) and TiO2/PPy (150 F g−1) nanocomposites. The PPy fully wrapped around the urea-FP substrate provides an electron transport pathway, resulting in the enhanced electrical conductivity of phosphorene. Furthermore, the assistance of anatase TiO2 nanoparticles enhanced the structural stability and also improved the specific capacitance of the phosphorene. To the best of our knowledge, this is the first report on the potential of phosphorene hybridized with conducting polymers and metal oxides for practical supercapacitor applications. Full article
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19 pages, 987 KiB  
Article
Copper(II), Nickel(II) and Zinc(II) Complexes of Peptide Fragments of Tau Protein
by Zsuzsa Kastal, Adrienn Balabán, Szilvia Vida, Csilla Kállay, Lajos Nagy, Katalin Várnagy and Imre Sóvágó
Molecules 2024, 29(10), 2171; https://doi.org/10.3390/molecules29102171 - 07 May 2024
Abstract
Copper(II), nickel(II) and zinc(II) complexes of various peptide fragments of tau protein were studied by potentiometric and spectroscopic techniques. All peptides contained one histidyl residue and represented the sequences of tau(91–97) (Ac-AQPHTEI-NH2), tau(385–390) (Ac-KTDHGA-NH2) and tau(404–409) (Ac-SPRHLS-NH2). [...] Read more.
Copper(II), nickel(II) and zinc(II) complexes of various peptide fragments of tau protein were studied by potentiometric and spectroscopic techniques. All peptides contained one histidyl residue and represented the sequences of tau(91–97) (Ac-AQPHTEI-NH2), tau(385–390) (Ac-KTDHGA-NH2) and tau(404–409) (Ac-SPRHLS-NH2). Imidazole-N donors of histidine were the primary metal binding sites for all peptides and all metal ions, but in the case of copper(II) and nickel(II), the deprotonated amide groups were also involved in metal binding by increasing pH. The most stable complexes were formed with copper(II) ions, but the presence of prolyl residues resulted in significant changes in the thermodynamic stability and speciation of the systems. It was also demonstrated that nickel(II) and especially zinc(II) complexes have relatively low thermodynamic stability with these peptides. The copper(II)-catalyzed oxidation of the peptides was also studied. In the presence of H2O2, the fragmentation of peptides was detected in all cases. In the simultaneous presence of H2O2 and ascorbic acid, the fragmentation of the peptide is less preferred, and the formation of 2-oxo-histidine also occurs. Full article
(This article belongs to the Section Medicinal Chemistry)
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