Biomolecules

11 pages, 1054 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Novel Imidazole Derivatives as Antimicrobial Agents

by Huda A. Al-Ghamdi, Fahad A. Almughem, Manal A. Alshabibi, Abrar A. Bakr, Abdullah A. Alshehri, Alhassan H. Aodah, Nourah A. Al Zahrani, Essam A. Tawfik and Laila A. Damiati

Biomolecules 2024, 14(9), 1198; https://doi.org/10.3390/biom14091198 - 23 Sep 2024

Viewed by 1136

Abstract

Imidazole derivatives are considered potential chemical compounds that could be therapeutically effective against several harmful pathogenic microbes. The chemical structure of imidazole, with a five-membered heterocycle, three carbon atoms, and two double bonds, tends to show antibacterial activities. In the present study, novel [...] Read more.

Imidazole derivatives are considered potential chemical compounds that could be therapeutically effective against several harmful pathogenic microbes. The chemical structure of imidazole, with a five-membered heterocycle, three carbon atoms, and two double bonds, tends to show antibacterial activities. In the present study, novel imidazole derivatives were designed and synthesized to be evaluated as antimicrobial agents owing to the low number of attempts to discover new antimicrobial agents and the emerging cases of antimicrobial resistance. Two imidazole compounds were prepared and evaluated as promising candidates regarding in vitro cytotoxicity against human skin fibroblast cells and antimicrobial activity against several bacterial strains. The synthesized imidazole derivatives were chemically identified using nuclear magnetic resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR). The results demonstrated a relatively high cell viability of one of the imidazole derivatives, i.e., HL2, upon 24 and 48 h cell exposure. Both derivatives were able to inhibit the growth of the tested bacterial strains. This study provides valuable insight into the potential application of imidazole derivatives for treating microbial infections; however, further in vitro and in vivo studies are required to confirm their safety and effectiveness. Full article

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12 pages, 2297 KiB

Open AccessBrief Report

Enhanced Anticancer Activity of 7MeERT over Ertredin: A Comparative Study on Cancer Cell Proliferation and NDUFA12 Binding

by Sonoko Atsumi, Chisato Nosaka, Takefumi Onodera, Hayamitsu Adachi, Takumi Watanabe, Manabu Kawada, Masabumi Shibuya, Se In Park and Ho Jeong Kwon

Biomolecules 2024, 14(9), 1197; https://doi.org/10.3390/biom14091197 - 23 Sep 2024

Viewed by 764

Abstract

We have previously identified Ertredin (3-(2-amino-5-bromophenyl) quinoxalin-2(1H)-one) as a compound that suppresses 3D spheroid formation and tumorigenesis in NIH3T3 cells induced by Epidermal Growth Factor Receptor variant III (EGFRvIII) transduction. One of its targets has been shown to be NDUFA12 (NADH [...] Read more.

We have previously identified Ertredin (3-(2-amino-5-bromophenyl) quinoxalin-2(1H)-one) as a compound that suppresses 3D spheroid formation and tumorigenesis in NIH3T3 cells induced by Epidermal Growth Factor Receptor variant III (EGFRvIII) transduction. One of its targets has been shown to be NDUFA12 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex Subunit 12), a component protein of oxidative phosphorylation complex I. In this report, we compared the growth inhibitory activity of Ertredin with its methylated analogue 7MeERT (3-(2-amino-5-bromophenyl)-7-methylquinoxalin-2(1H)-one) on human cancer cells. 7MeERT induced the inhibition of the proliferation of various cancer cells similarly to Ertredin and showed higher activity in glioblastoma cells, A431 cells overexpressing EGFR (wild type), and multiple myeloma cells. Molecular docking analysis and a Cellular Thermal Shift Assay (CETSA) suggested that 7MeERT binds to NDUFA12 similarly to Ertredin. The binding of 7MeERT and Ertredin to NDUFA12 in glioblastoma was further supported by the inhibition of the oxygen consumption rate. These results suggest that 7MeERT also binds to NDUFA12, inhibits oxidative phosphorylation, and has a higher anti-cancer cell growth inhibitory activity than Ertredin. Full article

(This article belongs to the Special Issue Biomolecules and Their Impact on Biology and Translational Applications: Celebrating the Pioneering Work of Prof. Ho Jeong Kwon)

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16 pages, 2232 KiB

Open AccessArticle

Engineering a Bifunctional Fusion Purine/Pyrimidine Nucleoside Phosphorylase for the Production of Nucleoside Analogs

by Daniel Hormigo, Jon Del Arco, Javier Acosta, Maximilian J. L. J. Fürst and Jesús Fernández-Lucas

Biomolecules 2024, 14(9), 1196; https://doi.org/10.3390/biom14091196 - 23 Sep 2024

Viewed by 827

Abstract

Nucleoside phosphorylases (NPs) are pivotal enzymes in the salvage pathway, catalyzing the reversible phosphorolysis of nucleosides to produce nucleobases and α-D-ribose 1-phosphate. Due to their efficiency in catalyzing nucleoside synthesis from purine or pyrimidine bases, these enzymes hold significant industrial importance in the [...] Read more.

Nucleoside phosphorylases (NPs) are pivotal enzymes in the salvage pathway, catalyzing the reversible phosphorolysis of nucleosides to produce nucleobases and α-D-ribose 1-phosphate. Due to their efficiency in catalyzing nucleoside synthesis from purine or pyrimidine bases, these enzymes hold significant industrial importance in the production of nucleoside-based drugs. Given that the thermodynamic equilibrium for purine NPs (PNPs) is favorable for nucleoside synthesis—unlike pyrimidine NPs (PyNPs, UP, and TP)—multi-enzymatic systems combining PNPs with PyNPs, UPs, or TPs are commonly employed in the synthesis of nucleoside analogs. In this study, we report the first development of two engineered bifunctional fusion enzymes, created through the genetic fusion of purine nucleoside phosphorylase I (PNP I) and thymidine phosphorylase (TP) from Thermus thermophilus. These fusion constructs, PNP I/TP-His and TP/PNP I-His, provide an innovative one-pot, single-step alternative to traditional multi-enzymatic synthesis approaches. Interestingly, both fusion enzymes retain phosphorolytic activity for both purine and pyrimidine nucleosides, demonstrating significant activity at elevated temperatures (60–90 °C) and within a pH range of 6–8. Additionally, both enzymes exhibit high thermal stability, maintaining approximately 80–100% of their activity when incubated at 60–80 °C over extended periods. Furthermore, the transglycosylation capabilities of the fusion enzymes were explored, demonstrating successful catalysis between purine (2′-deoxy)ribonucleosides and pyrimidine bases, and vice versa. To optimize reaction conditions, the effects of pH and temperature on transglycosylation activity were systematically examined. Finally, as a proof of concept, these fusion enzymes were successfully employed in the synthesis of various purine and pyrimidine ribonucleoside and 2′-deoxyribonucleoside analogs, underscoring their potential as versatile biocatalysts in nucleoside-based drug synthesis. Full article

(This article belongs to the Section Enzymology)

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16 pages, 7408 KiB

Open AccessArticle

Lactate Suppresses Growth of Esophageal Adenocarcinoma Patient-Derived Organoids through Alterations in Tumor NADH/NAD+ Redox State

by Steven H. Su, Yosuke Mitani, Tianxia Li, Uma Sachdeva, Samuel Flashner, Andres Klein-Szanto, Karen J. Dunbar, Julian Abrams, Hiroshi Nakagawa and Joel Gabre

Biomolecules 2024, 14(9), 1195; https://doi.org/10.3390/biom14091195 - 22 Sep 2024

Viewed by 1087

Abstract

Barrett’s esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria [...] Read more.

Barrett’s esophagus (BE) is a common precancerous lesion that can progress to esophageal adenocarcinoma (EAC). There are significant alterations in the esophageal microbiome in the progression from healthy esophagus to BE to EAC, including an increased abundance of a variety of lactate-producing bacteria and an increase of lactate in the tumor microenvironment, as predicted by metabolic modeling. The role of bacterial lactate in EAC is unknown. Here, we utilize patient-derived organoid (PDO) models of EAC and demonstrate that lactate inhibits the growth and proliferation of EAC PDOs through alterations in the tumor NADH/NAD+ redox state. Further RNA sequencing of EAC PDOs identifies ID1 and RSAD2 as potential regulatory molecules crucial in mediating lactate’s ability to suppress glycolysis and proliferation. Gene ontology analysis also identifies the activation of inflammatory and immunological pathways in addition to alterations in the metabolic pathways in EAC PDOs exposed to lactate, suggesting a multi-faceted role for lactate in the pathogenesis of EAC. Full article

(This article belongs to the Section Molecular Medicine)

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20 pages, 2267 KiB

Open AccessReview

SEPT9_i1 and Septin Dynamics in Oncogenesis and Cancer Treatment

by Piotr Jędrzejczak, Kamil Saramowicz, Justyna Kuś, Julia Barczuk, Wioletta Rozpędek-Kamińska, Natalia Siwecka, Grzegorz Galita, Wojciech Wiese and Ireneusz Majsterek

Biomolecules 2024, 14(9), 1194; https://doi.org/10.3390/biom14091194 - 22 Sep 2024

Viewed by 1051

Abstract

Despite significant advancements in the field of oncology, cancers still pose one of the greatest challenges of modern healthcare. Given the cytoskeleton’s pivotal role in regulating mechanisms critical to cancer development, further studies of the cytoskeletal elements could yield new practical applications. Septins [...] Read more.

Despite significant advancements in the field of oncology, cancers still pose one of the greatest challenges of modern healthcare. Given the cytoskeleton’s pivotal role in regulating mechanisms critical to cancer development, further studies of the cytoskeletal elements could yield new practical applications. Septins represent a group of relatively well-conserved GTP-binding proteins that constitute the fourth component of the cytoskeleton. Septin 9 (SEPT9) has been linked to a diverse spectrum of malignancies and appears to be the most notable septin member in that category. SEPT9 constitutes a biomarker of colorectal cancer (CRC) and has been positively correlated with a high clinical stage in breast cancer, cervical cancer, and head and neck squamous cell carcinoma. SEPT9_i1 represents the most extensively studied isoform of SEPT9, which substantially contributes to carcinogenesis, metastasis, and treatment resistance. Nevertheless, the mechanistic basis of SEPT9_i1 oncogenicity remains to be fully elucidated. In this review, we highlight SEPT9’s and SEPT9_i1’s structures and interactions with Hypoxia Inducible Factor α (HIF-1 α) and C-Jun N-Terminal Kinase (JNK), as well as discuss SEPT9_i1’s contribution to aneuploidy, cell invasiveness, and taxane resistance—key phenomena in the progression of malignancies. Finally, we emphasize forchlorfenuron and other septin inhibitors as potential chemotherapeutics and migrastatics. Full article

(This article belongs to the Special Issue Cytoskeleton Structure and Dynamics in Health and Disease)

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17 pages, 5795 KiB

Open AccessArticle

Single-Atom Ce-N-C Nanozyme Ameliorates Type 2 Diabetes Mellitus by Improving Glucose Metabolism Disorders and Reducing Oxidative Stress

by Yitong Lin, Yanan Wang, Qi Zhang, Ruxin Gao, Fei Chang, Boran Li, Kunlun Huang, Nan Cheng and Xiaoyun He

Biomolecules 2024, 14(9), 1193; https://doi.org/10.3390/biom14091193 - 22 Sep 2024

Cited by 1 | Viewed by 912

Abstract

Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance [...] Read more.

Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance and contributing to the development of T2DM via several molecular mechanisms. Besides, the reduction in hepatic glycogen synthesis also leads to a decrease in peripheral insulin sensitivity. Thus, reducing oxidative stress and promoting glycogen synthesis are both targets for improving insulin resistance and treating T2DM. The current study aims to investigate the pharmacological effects of single-atom Ce-N-C nanozyme (SACe-N-C) on the improvement of insulin resistance and to elucidate its underlying mechanisms using HFD/STZ-induced C57BL/6J mice and insulin-resistant HepG2 cells. The results indicate that SACe-N-C significantly improves hepatic glycogen synthesis and reduces oxidative stress, as well as pancreatic and liver injury. Specifically, compared to the T2DM model group, fasting blood glucose decreased by 29%, hepatic glycogen synthesis increased by 17.13%, and insulin secretion increased by 18.87%. The sod and GPx in the liver increased by 17.80% and 25.28%, respectively. In terms of mechanism, SACe-N-C modulated glycogen synthesis through the PI3K/AKT/GSK3β signaling pathway and activated the Keap1/Nrf2 pathway to alleviate oxidative stress. Collectively, this study suggests that SACe-N-C has the potential to treat T2DM. Full article

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20 pages, 2585 KiB

Open AccessReview

Significance of Necroptosis in Cartilage Degeneration

by Md Abdul Khaleque, Jea-Hoon Kim, Md Amit Hasan Tanvir, Jong-Beom Park and Young-Yul Kim

Biomolecules 2024, 14(9), 1192; https://doi.org/10.3390/biom14091192 - 21 Sep 2024

Viewed by 1445

Abstract

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue [...] Read more.

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue damage. Key mediators such as receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3(RIPK3), and mixed lineage kinase domain-like (MLKL) are pivotal in this process. Studies reveal necroptosis contributes significantly to OA and RA pathophysiology, where elevated RIPK3 and associated proteins drive cartilage degradation. Targeting necroptotic pathways shows promise; inhibitors like Necrostatin-1 (Nec-1), GSK’872, and Necrosulfonamide (NSA) reduce necroptotic cell death, offering potential therapeutic avenues. Additionally, autophagy’s role in mitigating necroptosis-induced damage highlights the need for comprehensive strategies addressing multiple pathways. Despite these insights, further research is essential to fully understand necroptosis’ mechanisms and develop effective treatments. This review synthesizes current knowledge on necroptosis in cartilage degeneration, aiming to inform novel therapeutic approaches for OA, RA, and trauma. Full article

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20 pages, 6344 KiB

Open AccessArticle

USP18 Is Associated with PD-L1 Antitumor Immunity and Improved Prognosis in Colorectal Cancer

by Cili Jifu, Linxia Lu, Jiaxin Ding, Mengjun Lv, Jun Xia, Jingtao Wang and Peijun Wang

Biomolecules 2024, 14(9), 1191; https://doi.org/10.3390/biom14091191 - 21 Sep 2024

Viewed by 1187

Abstract

Background: Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to [...] Read more.

Background: Compared with conventional chemotherapy and targeted therapy, immunotherapy has improved the treatment outlook for a variety of solid tumors, including lung cancer, colorectal cancer (CRC), and melanoma. However, it is effective only in certain patients, necessitating the search for alternative strategies to targeted immunotherapy. The deubiquitinating enzyme USP18 is known to play an important role in various aspects of the immune response, but its role in tumor immunity in CRC remains unclear. Methods: In this study, multiple online datasets were used to systematically analyze the expression, prognosis, and immunomodulatory role of USP18 in CRC. The effect of USP18 on CRC was assessed via shRNA-mediated knockdown of USP18 expression in combination with CCK-8 and colony formation assays. Finally, molecular docking analysis of USP18/ISG15 and programmed death-ligand 1 (PD-L1) was performed via HDOCK, and an ELISA was used to verify the potential of USP18 to regulate PD-L1. Results: Our study revealed that USP18 expression was significantly elevated in CRC patients and closely related to clinicopathological characteristics. The experimental data indicated that silencing USP18 significantly promoted the proliferation and population-dependent growth of CRC cells. In addition, high USP18 expression was positively correlated with the CRC survival rate and closely associated with tumor-infiltrating CD8+ T cells and natural killer (NK) cells. Interestingly, USP18 was correlated with the expression of various chemokines and immune checkpoint genes. The results of molecular docking simulations suggest that USP18 may act as a novel regulator of PD-L1 and that its deficiency may potentiate the antitumor immune response to PD-L1 blockade immunotherapy in CRC. Conclusions: In summary, USP18 shows great promise for research and clinical application as a potential target for CRC immunotherapy. Full article

(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)

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14 pages, 398 KiB

Open AccessReview

Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets

by Elena Conte, Brigida Boccanegra, Giorgia Dinoi, Michael Pusch, Annamaria De Luca, Antonella Liantonio and Paola Imbrici

Biomolecules 2024, 14(9), 1190; https://doi.org/10.3390/biom14091190 - 21 Sep 2024

Viewed by 1441

Abstract

Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, [...] Read more.

Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by heterozygous loss-of-function pathogenic variants in the tumour suppressor genes TSC1 and TSC2 encoding the tuberin and hamartin proteins, respectively. Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation, and is stimulated by various energy sources and hormonal signaling pathways. Pathogenic variants in TSC1 and TSC2 lead to mTORC1 hyperactivation, producing benign tumours in multiple organs, including the brain and kidneys, and drug-resistant epilepsy, a typical sign of TSC. Brain tumours, sudden unexpected death from epilepsy, and respiratory conditions are the three leading causes of morbidity and mortality. Even though several therapeutic options are available for the treatment of TSC, there is further need for a better understanding of the pathophysiological basis of the neurologic and other manifestations seen in TSC, and for novel therapeutic approaches. This review provides an overview of the main current therapies for TSC and discusses recent studies highlighting the repurposing of approved drugs and the emerging role of novel targets for future drug design. Full article

(This article belongs to the Special Issue Neurological Disorders: From Molecular Mechanisms to Therapy Strategies)

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17 pages, 879 KiB

Open AccessArticle

Identification of Exhaled Metabolites Correlated with Respiratory Function and Clinical Features in Adult Patients with Cystic Fibrosis by Real-Time Proton Mass Spectrometry

by Malika Mustafina, Artemiy Silantyev, Stanislav Krasovskiy, Alexander Chernyak, Zhanna Naumenko, Aleksandr Suvorov, Daria Gognieva, Magomed Abdullaev, Olga Suvorova, Anna Schmidt, Aida Gadzhiakhmedova, Aleksandra Bykova, Sergey Avdeev, Vladimir Betelin, Abram Syrkin and Philipp Kopylov

Biomolecules 2024, 14(9), 1189; https://doi.org/10.3390/biom14091189 - 21 Sep 2024

Viewed by 646

Abstract

Cystic fibrosis (CF) is a hereditary disease characterized by the progression of respiratory disorders, especially in adult patients. The purpose of the study was to identify volatile organic compounds (VOCs) as predictors of respiratory dysfunction, chronic respiratory infections of Staphylococcus aureus, Pseudomonas [...] Read more.

Cystic fibrosis (CF) is a hereditary disease characterized by the progression of respiratory disorders, especially in adult patients. The purpose of the study was to identify volatile organic compounds (VOCs) as predictors of respiratory dysfunction, chronic respiratory infections of Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, and VOCs associated with severe genotype and highly effective modulator treatment (HEMT). Exhaled breath samples from 102 adults with CF were analyzed using PTR-TOF-MS, obtained during a forced expiratory maneuver and normal quiet breathing. Using cross-validation and building gradient boosting classifiers (XGBoost), the importance of VOCs for functional and clinical outcomes was determined. The presence of the previously identified VOCs indole, phenol, and dimethyl sulfide were metabolic outcomes associated with impaired respiratory function. New VOCs associated with respiratory disorders were methyl acetate, carbamic acid, 1,3-Pentadiene, and 2,3-dimethyl-2-butene; VOCs associated with the above mentioned respiratory pathogens were non-differentiable nitrogen-containing organic compounds m/z = 47.041 (CH5NO)+ and m/z = 44.044 (C2H5NH+), hydrocarbons (cyclopropane, propene) and methanethiol; and VOCs associated with severe CFTR genotype were non-differentiable VOC m/z = 281.053. No significant features associated with the use of HEMT were identified. Early non-invasive determination of VOCs as biomarkers of the severity of CF and specific pathogenic respiratory flora could make it possible to prescribe adequate therapy and assess the prognosis of the disease. However, further larger standardized studies are needed for clinical use. Full article

(This article belongs to the Special Issue Airway Diseases: Molecular Updates and Perspectives)

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16 pages, 2509 KiB

Open AccessArticle

Molecular Identification and Engineering a Salt-Tolerant GH11 Xylanase for Efficient Xylooligosaccharides Production

by Jiao Ma, Zhongke Sun, Zifu Ni, Yanli Qi, Qianhui Sun, Yuansen Hu and Chengwei Li

Biomolecules 2024, 14(9), 1188; https://doi.org/10.3390/biom14091188 - 20 Sep 2024

Cited by 1 | Viewed by 800

Abstract

This study identified a salt-tolerant GH11 xylanase, Xyn^st, which was isolated from a soil bacterium Bacillus sp. SC1 and can resist as high as 4 M NaCl. After rational design and high-throughput screening of site-directed mutant libraries, a double mutant W6F/Q7H [...] Read more.

This study identified a salt-tolerant GH11 xylanase, Xyn^st, which was isolated from a soil bacterium Bacillus sp. SC1 and can resist as high as 4 M NaCl. After rational design and high-throughput screening of site-directed mutant libraries, a double mutant W6F/Q7H with a 244% increase in catalytic activity and a 10 °C increment in optimal temperature was obtained. Both Xyn^st and W6F/Q7H xylanases were stimulated by high concentrations of salts. In particular, the activity of W6F/Q7H was more than eight times that of Xyn^st in the presence of 2 M NaCl at 65 °C. Kinetic parameters indicated they have the highest affinity for beechwood xylan (K_m = 0.30 mg mL⁻¹ for Xyn^st and 0.18 mg mL⁻¹ for W6F/Q7H), and W6F/Q7H has very high catalytic efficiency (K_cat/K_m = 15483.33 mL mg⁻¹ s⁻¹). Molecular dynamic simulation suggested that W6F/Q7H has a more compact overall structure, improved rigidity of the active pocket edge, and a flexible upper-end alpha helix. Hydrolysis of different xylans by W6F/Q7H released more xylooligosaccharides and yielded higher proportions of xylobiose and xylotriose than Xyn^st did. The conversion efficiencies of Xyn^st and W6F/Q7H on all tested xylans exceeded 20%, suggesting potential applications in the agricultural and food industries. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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15 pages, 1665 KiB

Open AccessArticle

Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension

by Jason Shirian, Alexandra Hockla, Justyna J. Gleba, Matt Coban, Naama Rotenberg, Laura M. Strik, Aylin Alasonyalilar Demirer, Matt L. Pawlush, John A. Copland, Evette S. Radisky and Julia M. Shifman

Biomolecules 2024, 14(9), 1187; https://doi.org/10.3390/biom14091187 - 20 Sep 2024

Viewed by 897

Abstract

Matrix metalloproteinases (MMPs) are significant drivers of many diseases, including cancer, and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties for [...] Read more.

Matrix metalloproteinases (MMPs) are significant drivers of many diseases, including cancer, and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties for drug candidates, such as complete MMP inhibition, low toxicity, low immunogenicity, and high tissue permeability. However, a major challenge with TIMPs is their rapid clearance from the bloodstream due to their small size. This study explores a method for extending the plasma half-life of the N-terminal domain of TIMP2 (N-TIMP2) by appending it with a long, intrinsically unfolded tail containing Pro, Ala, and Thr (PATylation). We designed and produced two PATylated N-TIMP2 constructs with tail lengths of 100 and 200 amino acids (N-TIMP2-PAT₁₀₀ and N-TIMP2-PAT₂₀₀). Both constructs demonstrated higher apparent molecular weights and retained high inhibitory activity against MMP-9. N-TIMP2-PAT₂₀₀ significantly increased plasma half-life in mice compared to the non-PATylated variant, enhancing its therapeutic potential. PATylation offers distinct advantages for half-life extension, such as fully genetic encoding, monodispersion, and biodegradability. It can be easily applied to N-TIMP2 variants engineered for high affinity and selectivity toward individual MMPs, creating promising candidates for drug development against MMP-related diseases. Full article

(This article belongs to the Special Issue Harnessing Protein Design and Engineering for Therapeutic Applications)

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49 pages, 5746 KiB

Open AccessReview

Extracellular Matrix Components and Mechanosensing Pathways in Health and Disease

by Aikaterini Berdiaki, Monica Neagu, Petros Tzanakakis, Ioanna Spyridaki, Serge Pérez and Dragana Nikitovic

Biomolecules 2024, 14(9), 1186; https://doi.org/10.3390/biom14091186 - 20 Sep 2024

Cited by 1 | Viewed by 2669

Abstract

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to [...] Read more.

Glycosaminoglycans (GAGs) and proteoglycans (PGs) are essential components of the extracellular matrix (ECM) with pivotal roles in cellular mechanosensing pathways. GAGs, such as heparan sulfate (HS) and chondroitin sulfate (CS), interact with various cell surface receptors, including integrins and receptor tyrosine kinases, to modulate cellular responses to mechanical stimuli. PGs, comprising a core protein with covalently attached GAG chains, serve as dynamic regulators of tissue mechanics and cell behavior, thereby playing a crucial role in maintaining tissue homeostasis. Dysregulation of GAG/PG-mediated mechanosensing pathways is implicated in numerous pathological conditions, including cancer and inflammation. Understanding the intricate mechanisms by which GAGs and PGs modulate cellular responses to mechanical forces holds promise for developing novel therapeutic strategies targeting mechanotransduction pathways in disease. This comprehensive overview underscores the importance of GAGs and PGs as key mediators of mechanosensing in maintaining tissue homeostasis and their potential as therapeutic targets for mitigating mechano-driven pathologies, focusing on cancer and inflammation. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix, Cell Membrane and Nuclear Involvement in Cellular Driven Mechanotransduction)

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11 pages, 260 KiB

Open AccessReview

‘Whole-Body’ Perspectives of Schizophrenia and Related Psychotic Illness: miRNA-143 as an Exemplary Molecule Implicated across Multi-System Dysfunctions

by John L. Waddington, Xiaoyu Wang and Xuechu Zhen

Biomolecules 2024, 14(9), 1185; https://doi.org/10.3390/biom14091185 - 20 Sep 2024

Viewed by 959

Abstract

A wide array of biological abnormalities in psychotic illness appear to reflect non-cerebral involvement. This review first outlines the evidence for such a whole-body concept of schizophrenia pathobiology, focusing particularly on cardiovascular disease, metabolic syndrome and diabetes, immunity and inflammation, cancer, and the [...] Read more.

A wide array of biological abnormalities in psychotic illness appear to reflect non-cerebral involvement. This review first outlines the evidence for such a whole-body concept of schizophrenia pathobiology, focusing particularly on cardiovascular disease, metabolic syndrome and diabetes, immunity and inflammation, cancer, and the gut–brain axis. It then considers the roles of miRNAs in general and of miRNA-143 in particular as they relate to the epidemiology, pathobiology, and treatment of schizophrenia. This is followed by notable evidence that miRNA-143 is also implicated in each of these domains of cardiovascular disease, metabolic syndrome and diabetes, immunity and inflammation, cancer, and the gut–brain axis. Thus, miRNA-143 is an exemplar of what may be a class of molecules that play a role across the multiple domains of bodily dysfunction that appear to characterize a whole-body perspective of illness in schizophrenia. Importantly, the existence of such an exemplary molecule across these multiple domains implies a coordinated rather than stochastic basis. One candidate process would be a pleiotropic effect of genetic risk for schizophrenia across the whole body. Full article

(This article belongs to the Special Issue Mechanisms of Schizophrenia: Insights to Unlock the Brain Puzzle and Generate Effective Antipsychotic Drugs)

13 pages, 2866 KiB

Open AccessArticle

Complexes of HMO1 with DNA: Structure and Affinity

by Daria K. Malinina, Grigoriy A. Armeev, Olga V. Geraskina, Anna N. Korovina, Vasily M. Studitsky and Alexey V. Feofanov

Biomolecules 2024, 14(9), 1184; https://doi.org/10.3390/biom14091184 - 20 Sep 2024

Viewed by 648

Abstract

Saccharomyces cerevisiae HMO1 is an architectural nuclear DNA-binding protein that stimulates the activity of some remodelers and regulates the transcription of ribosomal protein genes, often binding to a DNA motif called IFHL. However, the molecular mechanism dictating this sequence specificity is unclear. Our [...] Read more.

Saccharomyces cerevisiae HMO1 is an architectural nuclear DNA-binding protein that stimulates the activity of some remodelers and regulates the transcription of ribosomal protein genes, often binding to a DNA motif called IFHL. However, the molecular mechanism dictating this sequence specificity is unclear. Our circular dichroism spectroscopy studies show that the HMO1:DNA complex forms without noticeable changes in the structure of DNA and HMO1. Molecular modeling/molecular dynamics studies of the DNA complex with HMO1 Box B reveal two extended sites at the N-termini of helices I and II of Box B that are involved in the formation of the complex and stabilize the DNA bend induced by intercalation of the F114 side chain between base pairs. A comparison of the affinities of HMO1 for 24 bp DNA fragments containing either randomized or IFHL sequences reveals a twofold increase in the stability of the complex in the latter case, which may explain the selectivity in the recognition of the IFHL-containing promoter regions. Full article

(This article belongs to the Special Issue Mechanisms of Formation of Biomolecule Complexes: Theory, Experiment, Applications)

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15 pages, 3792 KiB

Open AccessArticle

by Elif Funda Sener, Halime Dana, Reyhan Tahtasakal, Serpil Taheri and Minoo Rassoulzadegan

Biomolecules 2024, 14(9), 1183; https://doi.org/10.3390/biom14091183 - 20 Sep 2024

Viewed by 767

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a highly variable expression of phenotypes (restricted interest or activity and repetitive behavior in communication and social interactions), genes (mutation), markers (alteration of transcription) and pathways. Loss of function of the CC2D1A gene [...] Read more.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a highly variable expression of phenotypes (restricted interest or activity and repetitive behavior in communication and social interactions), genes (mutation), markers (alteration of transcription) and pathways. Loss of function of the CC2D1A gene appears to primarily affect the brain, leading to a range of behavioral problems in humans. In our study published in 2020, we found that the expressions of miR-19a-3p, miR-361-5p, miR-150-5p, miR-3613-3p, miR-126-3p and miR-499a-5p were downregulated in the serum samples of autistic patients, their families and mouse models (Cc2d1a +/− and valproic acid treated males). Here, acquired non-Mendelian hereditary character in a genetically defined mouse model of autism (Cc2d1a +/−) correlates with the transcriptional alteration of five miRNAs. We seek to test the hypothesis that miRNA levels vary by changes in RNA/DNA structure during development, thereby creating transcription alteration and cell memory. Behavioral tests were conducted on the offspring of Cc2d1a (+/−) mutant and control mice, such as novel object, social interaction, marble burying and tail suspension behavior. Two RNA fractions were isolated from mouse hippocampal tissues and sperm cells via standard TRIzol extraction: free RNA and the fraction of RNA bound to DNA in the form of a DNA/RNA hybrid (R-loop). The expression levels of miR-19a-3p, miR-361-5p, miR-150-5p, miR-126-3p and miR-499a-5p were investigated by quantitative real-time RT-PCR. We report differences in the distribution of five miRNAs in the hippocampus between male and female mice, particularly in colonies of Cc2d1a (+/−) mice. Furthermore, the number of miRNAs engaged in the DNA/RNA hybrid fraction is generally higher in the mutant pedigree than in the control group. On the other hand, in sperm, both fractions are at lower levels than in controls. R-loops contribute to the physiology and pathology of organisms including human disease. Here, we report a variation in five miRNA levels between gender and tissue. Our results suggest that the transcription levels of these five miRNAs are directly regulated by their RNA. Full article

(This article belongs to the Collection Feature Papers in Molecular Genetics)

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23 pages, 12352 KiB

Open AccessArticle

Predicting Regression of Barrett’s Esophagus—Can All the King’s Men Put It Together Again?

by Martin Tobi, Nabiha Khoury, Omar Al-Subee, Seema Sethi, Harvinder Talwar, Michael Kam, James Hatfield, Edi Levi, Jason Hallman, Mary Pat Moyer, Laura Kresty, Michael J. Lawson and Benita McVicker

Biomolecules 2024, 14(9), 1182; https://doi.org/10.3390/biom14091182 - 20 Sep 2024

Viewed by 782

Abstract

The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett’s esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to [...] Read more.

The primary pre-neoplastic lesion of the lower esophagus in the vicinity of the gastroesophageal junction (GEJ) is any Barrett’s esophageal lesions (BE), and esophageal neoplasia has increased in the US population with predispositions (Caucasian males, truncal obesity, age, and GERD). The responses to BE are endoscopic and screening cytologic programs with endoscopic ablation of various forms. The former have not been proven to be cost-effective and there are mixed results for eradication. A fresh approach is sorely needed. We prospectively followed 2229 mostly male veterans at high risk for colorectal cancer in a 27-year longitudinal long-term study, collecting data on colorectal neoplasia development and other preneoplastic lesions, including BE and spontaneous regression (SR). Another cross-sectional BE study at a similar time period investigated antigenic changes at the GEJ in both BE glandular and squamous mucosa immunohistochemistry and the role of inflammation. Ten of the prospective cohort (21.7%) experienced SR out of a total of forty-six BE patients. Significant differences between SR and stable BE were younger age (p < 0.007); lower platelet levels (p < 0.02); rectal p87 elevation in SR (p < 0.049); a reduced innate immune system (InImS) FEREFF ratio (ferritin: p87 colonic washings) (p < 0.04). Ancillary testing showed a broad range of neoplasia biomarkers. InImS markers may be susceptible to intervention using commonplace and safe medical interventions and encourage SR. Full article

(This article belongs to the Special Issue Insights of Innate Immunology into Inflammation and Infections)

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14 pages, 686 KiB

Open AccessCommentary

Multi-Target and Multi-Phase Adjunctive Cerebral Protection for Acute Ischemic Stroke in the Reperfusion Era

by Min Zhao, Jing Wang, Guiyou Liu, Sijie Li, Yuchuan Ding, Xunming Ji and Wenbo Zhao

Biomolecules 2024, 14(9), 1181; https://doi.org/10.3390/biom14091181 - 20 Sep 2024

Viewed by 1506

Abstract

Stroke remains the leading cause of death and disability in some countries, predominantly attributed to acute ischemic stroke (AIS). While intravenous thrombolysis and endovascular thrombectomy are widely acknowledged as effective treatments for AIS, boasting a high recanalization rate, there is a significant discrepancy [...] Read more.

Stroke remains the leading cause of death and disability in some countries, predominantly attributed to acute ischemic stroke (AIS). While intravenous thrombolysis and endovascular thrombectomy are widely acknowledged as effective treatments for AIS, boasting a high recanalization rate, there is a significant discrepancy between the success of revascularization and the mediocre clinical outcomes observed among patients with AIS. It is now increasingly understood that the implementation of effective cerebral protection strategies, serving as adjunctive treatments to reperfusion, can potentially improve the outcomes of AIS patients following recanalization therapy. Herein, we reviewed several promising cerebral protective methods that have the potential to slow down infarct growth and protect ischemic penumbra. We dissect the underlying reasons for the mismatch between high recanalization rates and moderate prognosis and introduce a novel concept of “multi-target and multi-phase adjunctive cerebral protection” to guide our search for neuroprotective agents that can be administered alongside recanalization therapy. Full article

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16 pages, 6419 KiB

Open AccessArticle

Phospholipase Cδ-4 (PLCδ4) Acts as a Nuclear Player to Influence Cyclin B Expression in the Embryonal Rhabdomyosarcoma Cell Lines RD and A204

by Sara Salucci, Alberto Bavelloni, Ilaria Versari, Sabrina Burattini, Francesco Bavelloni, Pietro Gobbi, Alessandro Fanzani, Silvia Codenotti, William Blalock, Katia Scotlandi and Irene Faenza

Biomolecules 2024, 14(9), 1180; https://doi.org/10.3390/biom14091180 - 20 Sep 2024

Viewed by 789

Abstract

Rhabdomyosarcoma (RMS), the most common form of sarcoma typical of pediatric age, arises from the malignant transformation of the mesenchymal precursors that fail to differentiate into skeletal muscle cells. Here, we investigated whether the protein phospholipase C δ4 (PLCδ4), a member of the [...] Read more.

Rhabdomyosarcoma (RMS), the most common form of sarcoma typical of pediatric age, arises from the malignant transformation of the mesenchymal precursors that fail to differentiate into skeletal muscle cells. Here, we investigated whether the protein phospholipase C δ4 (PLCδ4), a member of the PLC family involved in proliferation and senescence mechanisms of mesenchymal stromal stem cells, may play a role in RMS. Our molecular and morpho-functional data reveal that PLCδ4 is highly expressed in the fusion-negative, p53-positive, SMARCB1 heterozygous mutated embryonal RMS (ERMS) cell line A204, while it is poorly expressed in the ERMS cell lines RD (fusion-negative, MYC amplification, N-RAS (Q61H), homozygous mutated p53) and Hs729 (homozygous mutated p53) and the alveolar rhabdosarcoma (ARMS) cell line SJCRH30 (RH30; fusion positive, heterozygous mutated RARA, polyheterozygous mutated p53). To characterize the role of PLCδ4, the RD cell line was stably transfected with wild-type PLCδ4 (RD/PLCδ4). Overexpressed PLCδ4 mainly localized to the nucleus in RD cells and contributed to the phosphorylation of PRAS40 (T246), Chk2(T68), WNK1(T60), and Akt 1/273 (S473), as revealed by proteome profiler array analysis. Overexpression of PLCδ4 in RD cells enhanced cyclin B1 expression and resulted in G2/M-phase cell cycle arrest. In contrast, siRNA-mediated knockdown of PLCδ4 in A204 cells resulted in reduced cyclin B1 expression. Our study identifies a novel role for nuclear PLCδ4 as a regulator of cyclin B1 via Akt-dependent phosphorylation. The modulation of PLCδ4 expression and its downstream targets could represent a crucial signaling pathway to block embryonal RMS cell proliferation. Full article

(This article belongs to the Special Issue State of the Art of Myology in 2024)

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13 pages, 2343 KiB

Open AccessArticle

Collagen I Increases Palmitate-Induced Lipotoxicity in HepG2 Cells via Integrin-Mediated Death

by Tumisang Edward Maseko, Eva Peterová, Moustafa Elkalaf, Darja Koutová, Jan Melek, Pavla Staňková, Veronika Špalková, Reem Matar, Halka Lotková, Zuzana Červinková and Otto Kučera

Biomolecules 2024, 14(9), 1179; https://doi.org/10.3390/biom14091179 - 20 Sep 2024

Viewed by 848

Abstract

Various strategies have been employed to improve the reliability of 2D, 3D, and co-culture in vitro models of nonalcoholic fatty liver disease, including using extracellular matrix proteins such as collagen I to promote cell adhesion. While studies have demonstrated the significant benefits of [...] Read more.

Various strategies have been employed to improve the reliability of 2D, 3D, and co-culture in vitro models of nonalcoholic fatty liver disease, including using extracellular matrix proteins such as collagen I to promote cell adhesion. While studies have demonstrated the significant benefits of culturing cells on collagen I, its effects on the HepG2 cell line after exposure to palmitate (PA) have not been investigated. Therefore, this study aimed to assess the effects of PA-induced lipotoxicity in HepG2 cultured in the absence or presence of collagen I. HepG2 cultured in the absence or presence of collagen I was exposed to PA, followed by analyses that assessed cell proliferation, viability, adhesion, cell death, mitochondrial respiration, reactive oxygen species production, gene and protein expression, and triacylglycerol accumulation. Culturing HepG2 on collagen I was associated with increased cell proliferation, adhesion, and expression of integrin receptors, and improved cellular spreading compared to culturing them in the absence of collagen I. However, PA-induced lipotoxicity was greater in collagen I-cultured HepG2 than in those cultured in the absence of collagen I and was associated with increased α2β1 receptors. In summary, the present study demonstrated for the first time that collagen I-cultured HepG2 exhibited exacerbated cell death following exposure to PA through integrin-mediated death. The findings from this study may serve as a caution to those using 2D models or 3D scaffold-based models of HepG2 in the presence of collagen I. Full article

(This article belongs to the Special Issue New Insights into Integrins)

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19 pages, 3791 KiB

Open AccessArticle

Synergistic Inhibition of Pancreatic Cancer Cell Growth and Migration by Gemcitabine and Withaferin A

by Renata Szydlak

Biomolecules 2024, 14(9), 1178; https://doi.org/10.3390/biom14091178 - 19 Sep 2024

Viewed by 815

Abstract

Pancreatic cancer remains one of the most lethal malignancies due to its aggressive nature and resistance to conventional therapies. This study investigates the anti-proliferative, pro-apoptotic, and anti-migratory effects of Gemcitabine (GC) and Withaferin A (WFA) on pancreatic cancer cell lines PANC-1 and Hs766t. [...] Read more.

Pancreatic cancer remains one of the most lethal malignancies due to its aggressive nature and resistance to conventional therapies. This study investigates the anti-proliferative, pro-apoptotic, and anti-migratory effects of Gemcitabine (GC) and Withaferin A (WFA) on pancreatic cancer cell lines PANC-1 and Hs766t. The MTS assay revealed that both compounds effectively inhibit cell proliferation, with WFA showing a stronger effect in Hs766t cells. Flow cytometry analysis demonstrated that GC and WFA, particularly in combination, significantly induce apoptosis in both cell lines. Migration assays confirmed the potent inhibition of cell migration by both compounds, with the combination treatment being the most effective. Furthermore, actin cytoskeleton analysis indicated substantial changes in cell morphology and stiffness, suggesting that GC and WFA disrupt the structural integrity of cancer cells. Additionally, the study highlights a ROS-mediated mechanism underlying the effects of GC and WFA, as evidenced by increased ROS levels following treatment, which were attenuated by N-acetylcysteine. Importantly, NF-κB activity was significantly modulated, with WFA reducing NF-κB activation induced by GC, potentially contributing to the synergistic pro-apoptotic effect of the combination. These findings suggest that the combination of GC and WFA may offer a synergistic therapeutic approach for treating pancreatic cancer by targeting multiple aspects of tumor cell behavior. Full article

(This article belongs to the Topic Advances in Natural Products and Phytochemicals in Cancer Prevention and Therapeutics)

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20 pages, 9189 KiB

Open AccessArticle

Identification of the Novel Small Compound Stress Response Regulators 1 and 2 That Affect Plant Abiotic Stress Signaling

by Seojung Kim and Tae-Houn Kim

Biomolecules 2024, 14(9), 1177; https://doi.org/10.3390/biom14091177 - 19 Sep 2024

Viewed by 692

Abstract

Abiotic stresses, such as drought, salinity, and extreme temperatures, limit plant growth and development, reducing crop yields. Therefore, a more comprehensive understanding of the signaling mechanisms and responses of plants to changing environmental conditions is crucial for improving sustainable agricultural productivity. Chemical screening [...] Read more.

Abiotic stresses, such as drought, salinity, and extreme temperatures, limit plant growth and development, reducing crop yields. Therefore, a more comprehensive understanding of the signaling mechanisms and responses of plants to changing environmental conditions is crucial for improving sustainable agricultural productivity. Chemical screening was conducted to find novel small compounds that act as regulators of the abiotic stress signaling pathway using the ABA-inducible transgenic reporter line. Small molecules called stress response regulators (SRRs) were isolated by screening a synthetic library composed of 14,400 small compounds, affecting phenotypes such as seed germination, root growth, and gene expression in response to multiple abiotic stresses. Seeds pretreated with SRR compounds positively affected the germination rate and radicle emergence of Arabidopsis and tomato plants under abiotic stress conditions. The SRR-priming treatment enhanced the transcriptional responses of abiotic stress-responsive genes in response to subsequent salt stress. The isolation of the novel molecules SRR1 and SRR2 will provide a tool to elucidate the complex molecular networks underlying the plant stress-tolerant responses. Full article

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19 pages, 3373 KiB

Open AccessArticle

Effects of Plant Meristem-Cell-Based Cosmetics on Menopausal Skin: Clinical Data and Mechanisms

by Liudmila Korkina, Zaira Kharaeva, Albina Shokarova, Elena Barokova, Wolfgang Mayer, Ilya Trakhtman, Roberto Dal Toso and Chiara De Luca

Biomolecules 2024, 14(9), 1176; https://doi.org/10.3390/biom14091176 - 19 Sep 2024

Viewed by 948

Abstract

A randomised open clinical/laboratory study was performed to evaluate the safety and cosmetic efficacy of facial cosmetics for females during the menopausal period. The cosmetics contain active ingredients of meristem cells derived from the medicinal plants Leontopodium alpinum, Buddeleja davidii, Centella [...] Read more.

A randomised open clinical/laboratory study was performed to evaluate the safety and cosmetic efficacy of facial cosmetics for females during the menopausal period. The cosmetics contain active ingredients of meristem cells derived from the medicinal plants Leontopodium alpinum, Buddeleja davidii, Centella asiatica, and Echinacea angustifolia. Recently, the major bioactive molecules of these medicinal plants (leontopodic acid, verbascoside, asiaticoside, and echinacoside, respectively) have been thoroughly evaluated in vitro for molecular pathways and cellular mechanisms and their preventive/curative effects on human skin cells exposed to factors promoting premature skin ageing and cellular senescence. Nevertheless, clinical data on their safety/efficacy to ageing human skin are scarce. This clinical study enrolled 104 Caucasian females in pre-menopause, menopause, or post-menopause periods. They applied cosmetic serums daily for 1 month. Questionnaires and instrumental and biochemical methods were used to assess dermatological/ophthalmological safety and cosmetic efficacy through changes of the skin physiology markers characteristic of ageing/menopause (elasticity, barrier functions, moisture, sebum, ultrasonic properties, and collagen content and structure). Quantitative microbiological tests were carried out for skin microbiota fluctuations. Data showed that the cosmetics were safe, and they shifted the skin physiology parameters to a younger biological age, enhanced collagen synthesis, inhibited lipid peroxidation, and favoured normal microbiota. Full article

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25 pages, 2599 KiB

Open AccessReview

Lactylation: A Novel Post-Translational Modification with Clinical Implications in CNS Diseases

by Junyan Liu, Fengyan Zhao and Yi Qu

Biomolecules 2024, 14(9), 1175; https://doi.org/10.3390/biom14091175 - 19 Sep 2024

Viewed by 2838

Abstract

Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, [...] Read more.

Lactate, an important metabolic product, provides energy to neural cells during energy depletion or high demand and acts as a signaling molecule in the central nervous system. Recent studies revealed that lactate-mediated protein lactylation regulates gene transcription and influences cell fate, metabolic processes, inflammation, and immune responses. This review comprehensively examines the regulatory roles and mechanisms of lactylation in neurodevelopment, neuropsychiatric disorders, brain tumors, and cerebrovascular diseases. This analysis indicates that lactylation has multifaceted effects on central nervous system function and pathology, particularly in hypoxia-induced brain damage. Highlighting its potential as a novel therapeutic target, lactylation may play a significant role in treating neurological diseases. By summarizing current findings, this review aims to provide insights and guide future research and clinical strategies for central nervous system disorders. Full article

(This article belongs to the Special Issue Neurological Disorders: From Molecular Mechanisms to Therapy Strategies)

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14 pages, 31917 KiB

Open AccessArticle

Connexin Expression Is Altered in the Eye Development of Yotari Mice: A Preliminary Study

by Ljubica Skelin, Anita Racetin, Nela Kelam, Marin Ogorevc, Ljubo Znaor, Mirna Saraga-Babić, Natalija Filipović, Yu Katsuyama, Zenon Pogorelić and Katarina Vukojević

Biomolecules 2024, 14(9), 1174; https://doi.org/10.3390/biom14091174 - 19 Sep 2024

Viewed by 827

Abstract

This study aimed to explore how Dab1 functional silencing influences the expression patterns of different connexins in the developing yotari (yot) mice eyes as potential determinants of retinogenesis. Using immunofluorescence staining, the protein expression of Dab1, Reelin, and connexin 37, 40, [...] Read more.

This study aimed to explore how Dab1 functional silencing influences the expression patterns of different connexins in the developing yotari (yot) mice eyes as potential determinants of retinogenesis. Using immunofluorescence staining, the protein expression of Dab1, Reelin, and connexin 37, 40, 43, and 45 (Cx37, Cx40, Cx43, and Cx45) in the wild-type (wt) and yot eyes at embryonic days 13.5 and 15.5 (E13.5 and E15.5) were analyzed. Different expression patterns of Cx37 were seen between the wt and yot groups. The highest fluorescence intensity of Cx37 was observed in the yot animals at E15.5. Cx40 had higher expression at the E13.5 when differentiation of retinal layers was still beginning, whereas it decreased at the E15.5 when differentiation was at the advanced stage. Higher expression of Cx43 was found in the yot group at both time points. Cx45 was predominantly expressed at E13.5 in both groups. Our results reveal the altered expression of connexins during retinogenesis in yot mice and their potential involvement in retinal pathology, where they might serve as prospective therapeutic targets. Full article

(This article belongs to the Special Issue Neurological Disorders: From Molecular Mechanisms to Therapy Strategies)

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20 pages, 802 KiB

Open AccessReview

DNA Adductomics: A Narrative Review of Its Development, Applications, and Future

by Mengqiu Cao and Xinyu Zhang

Biomolecules 2024, 14(9), 1173; https://doi.org/10.3390/biom14091173 - 19 Sep 2024

Viewed by 1002

Abstract

DNA adductomics is the global study of all DNA adducts and was first proposed in 2006 by the Matsuda group. Its development has been greatly credited to the advances in mass spectrometric techniques, particularly tandem and multiple-stage mass spectrometry. In fact, liquid chromatography-mass [...] Read more.

DNA adductomics is the global study of all DNA adducts and was first proposed in 2006 by the Matsuda group. Its development has been greatly credited to the advances in mass spectrometric techniques, particularly tandem and multiple-stage mass spectrometry. In fact, liquid chromatography-mass spectrometry (LC-MS)-based methods are virtually the sole technique with practicality for DNA adductomic studies to date. At present, DNA adductomics is primarily used as a tool to search for DNA adducts, known and unknown, providing evidence for exposure to exogenous genotoxins and/or for the molecular mechanisms of their genotoxicity. Some DNA adducts discovered in this way have the potential to predict cancer risks and/or to be associated with adverse health outcomes. DNA adductomics has been successfully used to identify and determine exogenous carcinogens that may contribute to the etiology of certain cancers, including bacterial genotoxins and an N-nitrosamine. Also using the DNA adductomic approach, multiple DNA adducts have been observed to show age dependence and may serve as aging biomarkers. These achievements highlight the capability and power of DNA adductomics in the studies of medicine, biological science, and environmental science. Nonetheless, DNA adductomics is still in its infancy, and great advances are expected in the future. Full article

(This article belongs to the Special Issue Endogenous versus Exogenous DNA Adducts: Their Role in Carcinogenesis, Inflammation, Epidemiology, and Risk Assessment)

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17 pages, 2964 KiB

Open AccessArticle

Biomolecular Dynamics of Nitric Oxide Metabolites and HIF1α in HPV Infection

by Clara Matei, Ilinca Nicolae, Madalina Irina Mitran, Cristina Iulia Mitran, Corina Daniela Ene, Gheorghe Nicolae, Simona Roxana Georgescu and Mircea Tampa

Biomolecules 2024, 14(9), 1172; https://doi.org/10.3390/biom14091172 - 18 Sep 2024

Viewed by 625

Abstract

Introduction: Viral infections cause oxygen deprivation, leading to hypoxia or anoxia in certain tissues. The limitation of mitochondrial respiration is one of the major events during hypoxia that induces alternative metabolic activities and increased levels of certain biomolecules such as nitric oxide (NO) [...] Read more.

Introduction: Viral infections cause oxygen deprivation, leading to hypoxia or anoxia in certain tissues. The limitation of mitochondrial respiration is one of the major events during hypoxia that induces alternative metabolic activities and increased levels of certain biomolecules such as nitric oxide (NO) metabolites. In this study, we aimed to investigate the role of NO metabolites and hypoxia in HPV infection. Materials and Methods: We included 36 patients with palmoplantar warts and 36 healthy subjects and performed serum determinations of NO metabolites (direct nitrite, total nitrite, nitrate, and 3-nitrotyrosine) and HIF1α, a marker of hypoxia. Results: We found elevated serum levels in NO metabolites and HIF1α, and decreased direct nitrite/nitrate ratios in patients with warts versus controls. Additionally, we identified statistically significant positive correlations between NO metabolites and HIF1α levels, except for 3-nitrotyrosine. Conclusions: Our findings show that HPV infection causes hypoxia and alterations in NO metabolism and suggest a link between wart development and cellular stress. Our research could provide new insights for a comprehensive understanding of the pathogenesis of cutaneous HPV infections. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Viral Infections)

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12 pages, 3403 KiB

Open AccessArticle

L-Cysteine Upregulates Testosterone Biosynthesis and Blood–Testis Barrier Genes in Cultured Human Leydig Cells and THP-1 Monocytes and Increases Testosterone Secretion in Human Leydig Cells

by Jeffrey Justin Margret and Sushil K. Jain

Biomolecules 2024, 14(9), 1171; https://doi.org/10.3390/biom14091171 - 18 Sep 2024

Cited by 1 | Viewed by 674

Abstract

Leydig cells are the primary source of testosterone or androgen production in male mammals. The blood–testis barrier (BTB) maintains structural integrity and safeguards germ cells from harmful substances by blocking their entry into the seminiferous tubules. L-cysteine is essential to the production of [...] Read more.

Leydig cells are the primary source of testosterone or androgen production in male mammals. The blood–testis barrier (BTB) maintains structural integrity and safeguards germ cells from harmful substances by blocking their entry into the seminiferous tubules. L-cysteine is essential to the production of glutathione, a powerful antioxidant crucial to protecting against oxidative stress-induced damage. Animal studies have demonstrated the protective effect of L-cysteine in preventing testicular damage caused by chemicals or radiation. This study examines whether L-cysteine enhances the expression of testosterone biosynthesis and the BTB genes in human Leydig cells and THP-1 monocytes. The Leydig cells and THP-1 monocytes were treated with L-cysteine for 24 h. RNA was extracted following treatment, and the gene expression was analyzed using quantitative RT-PCR. Testosterone levels in the cell supernatant were measured using an ELISA kit. L-cysteine treatment in Leydig cells significantly upregulated the expression of CYP11A1 (p = 0.03) and the BTB genes CLDN1 (p = 0.03), CLDN11 (p = 0.02), and TJP1 (p = 0.02). Similarly, L-cysteine significantly upregulated the expression of CYP11A1 (p = 0.03) and CYP19A1 (p < 0.01), and the BTB genes CLDN1 (p = 0.04), CLDN2 (p < 0.01), CLDN4 (p < 0.01), CLDN11 (p < 0.01), and TJP1 (p = 0.03) in THP-1 monocytes. Further, L-cysteine supplementation increased the testosterone secretion levels in human Leydig cells. The findings suggest that L-cysteine supplementation could be used as an adjuvant therapy to promote the integrity of the BTB genes, testosterone biosynthesis and secretion, and the maintenance of testicular functions, which in turn mitigates the risk of male infertility. Full article

(This article belongs to the Section Molecular Reproduction)

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28 pages, 9624 KiB

Open AccessArticle

Myco-Biosynthesis of Silver Nanoparticles, Optimization, Characterization, and In Silico Anticancer Activities by Molecular Docking Approach against Hepatic and Breast Cancer

by Noura El-Ahmady El-Naggar, Nada S. Shweqa, Hala M. Abdelmigid, Amal A. Alyamani, Naglaa Elshafey, Hoda M. Soliman and Yasmin M. Heikal

Biomolecules 2024, 14(9), 1170; https://doi.org/10.3390/biom14091170 - 18 Sep 2024

Cited by 1 | Viewed by 879

Abstract

This study explored the green synthesis of silver nanoparticles (AgNPs) using the extracellular filtrate of Fusarium oxysporum as a reducing agent and evaluated their antitumor potential through in vitro and in silico approaches. The biosynthesis of AgNPs was monitored by visual observation of [...] Read more.

This study explored the green synthesis of silver nanoparticles (AgNPs) using the extracellular filtrate of Fusarium oxysporum as a reducing agent and evaluated their antitumor potential through in vitro and in silico approaches. The biosynthesis of AgNPs was monitored by visual observation of the color change and confirmed by UV–Vis spectroscopy, revealing a characteristic peak at 418 nm. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed spherical nanoparticles ranging from 6.53 to 21.84 nm in size, with stable colloidal behavior and a negative zeta potential of −15.5 mV. Selected area electron diffraction (SAED) confirmed the crystalline nature of the AgNPs, whereas energy-dispersive X-ray (EDX) indicated the presence of elemental silver at 34.35%. A face-centered central composite design (FCCD) was employed to optimize the biosynthesis process, yielding a maximum AgNPs yield of 96.77 µg/mL under the optimized conditions. The antitumor efficacy of AgNPs against MCF-7 and HepG2 cancer cell lines was assessed, with IC₅₀ values of 35.4 µg/mL and 7.6 µg/mL, respectively. Molecular docking revealed interactions between Ag metal and key amino acids of BCL-2 (B-cell lymphoma-2) and FGF19 (fibroblast growth factor 19), consistent with in vitro data. These findings highlight the potential of biologically derived AgNPs as promising therapeutic agents for cancer treatment and demonstrate the utility of these methods for understanding the reaction mechanisms and optimizing nanomaterial synthesis. Full article

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20 pages, 10279 KiB

Open AccessArticle

Exploration into Galectin-3 Driven Endocytosis and Lattices

by Massiullah Shafaq-Zadah, Estelle Dransart, Satish Kailasam Mani, Julio Lopes Sampaio, Lydia Bouidghaghen, Ulf J. Nilsson, Hakon Leffler and Ludger Johannes

Biomolecules 2024, 14(9), 1169; https://doi.org/10.3390/biom14091169 - 18 Sep 2024

Viewed by 888

Abstract

Essentially all plasma membrane proteins are glycosylated, and their activity is regulated by tuning their cell surface dynamics. This is achieved by glycan-binding proteins of the galectin family that either retain glycoproteins within lattices or drive their endocytic uptake via the clathrin-independent glycolipid-lectin [...] Read more.

Essentially all plasma membrane proteins are glycosylated, and their activity is regulated by tuning their cell surface dynamics. This is achieved by glycan-binding proteins of the galectin family that either retain glycoproteins within lattices or drive their endocytic uptake via the clathrin-independent glycolipid-lectin (GL-Lect) mechanism. Here, we have used immunofluorescence-based assays to analyze how lattice and GL-Lect mechanisms affect the internalization of the cell adhesion and migration glycoprotein α₅β₁ integrin. In retinal pigment epithelial (RPE-1) cells, internalized α₅β₁ integrin is found in small peripheral endosomes under unperturbed conditions. Pharmacological compounds were used to competitively inhibit one of the galectin family members, galectin-3 (Gal3), or to inhibit the expression of glycosphingolipids, both of which are the fabric of the GL-Lect mechanism. We found that under acute inhibition conditions, endocytic uptake of α₅β₁ integrin was strongly reduced, in agreement with previous studies on the GL-Lect driven internalization of the protein. In contrast, upon prolonged inhibitor treatment, the uptake of α₅β₁ integrin was increased, and the protein was now internalized by alternative pathways into large perinuclear endosomes. Our findings suggest that under these prolonged inhibitor treatment conditions, α₅β₁ integrin containing galectin lattices are dissociated, leading to an altered endocytic compartmentalization. Full article

(This article belongs to the Special Issue Cell Biology and Biomedical Application of Galectins)

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