Biomolecules

21 pages, 1385 KiB

Open AccessReview

New Insights into Microglial Mechanisms of Memory Impairment in Alzheimer’s Disease

by Na Li, Mingru Deng, Gonghui Hu, Nan Li, Haicheng Yuan and Yu Zhou

Biomolecules 2022, 12(11), 1722; https://doi.org/10.3390/biom12111722 - 21 Nov 2022

Cited by 10 | Viewed by 2755

Alzheimer’s disease (AD) is the most common progressive and irreversible neurodegeneration characterized by the impairment of memory and cognition. Despite years of studies, no effective treatment and prevention strategies are available yet. Identifying new AD therapeutic targets is crucial for better elucidating the [...] Read more.

Alzheimer’s disease (AD) is the most common progressive and irreversible neurodegeneration characterized by the impairment of memory and cognition. Despite years of studies, no effective treatment and prevention strategies are available yet. Identifying new AD therapeutic targets is crucial for better elucidating the pathogenesis and establishing a valid treatment of AD. Growing evidence suggests that microglia play a critical role in AD. Microglia are resident macrophages in the central nervous system (CNS), and their core properties supporting main biological functions include surveillance, phagocytosis, and the release of soluble factors. Activated microglia not only directly mediate the central immune response, but also participate in the pathological changes of AD, including amyloid-beta (Aβ) aggregation, tau protein phosphorylation, synaptic dissection, neuron loss, memory function decline, etc. Based on these recent findings, we provide a new framework to summarize the role of microglia in AD memory impairment. This evidence suggests that microglia have the potential to become new targets for AD therapy. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

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17 pages, 293 KiB

Open AccessReview

Endometriosis-Associated Ovarian Cancer: What Are the Implications for Women with Intact Endometrioma Planning for a Future Pregnancy? A Reproductive Clinical Outlook

by Johnny S. Younis

Biomolecules 2022, 12(11), 1721; https://doi.org/10.3390/biom12111721 - 21 Nov 2022

Cited by 6 | Viewed by 2631

Abstract

Endometriosis is a chronic, universal, and prevalent disease estimated to affect up to 1:10 women of reproductive age. Endometriosis-associated ovarian cancer (EAOC) developing at reproductive age is challenging and of concern for women and practitioners alike. This outlook review focuses on the occurrence [...] Read more.

Endometriosis is a chronic, universal, and prevalent disease estimated to affect up to 1:10 women of reproductive age. Endometriosis-associated ovarian cancer (EAOC) developing at reproductive age is challenging and of concern for women and practitioners alike. This outlook review focuses on the occurrence of EAOC, especially in infertile women or those planning for a future pregnancy, from the perspective of a reproductive endocrinologist, based on recent evidence. Contemporary pathogenesis, genetic profiles, evidence of causality, clinical diagnosis, prognosis, and up-to-date management are discussed. EAOC seems to be merely associated with endometrioma and includes clear-cell and endometrioid ovarian carcinoma. Although endometrioma is frequently found in women of reproductive age (up to 1:18 of women), EAOC appears to be a rare occurrence. These women are of more advanced reproductive age, nulliparous, and hyperestrogenic, with a large-sized unilateral endometrioma (>9 cm) containing solid components and papillary projections. Each case suspected to have EAOC has specific characteristics, and a multidisciplinary discussion and appropriate patient counseling should be conducted to reach an optimal therapeutic plan. Since most of these cases are diagnosed at an early stage with a favorable prognosis, fertility-sparing surgery may be feasible. The pros and cons of fertility preservation techniques should be discussed. Full article

(This article belongs to the Special Issue Molecular and Cell Biology in Endometriosis and Endometrial Cancer)

28 pages, 3496 KiB

Open AccessReview

The Ethnopharmacological Uses, Metabolite Diversity, and Bioactivity of Rhaponticum uniflorum (Leuzea uniflora): A Comprehensive Review

by Daniil N. Olennikov

Biomolecules 2022, 12(11), 1720; https://doi.org/10.3390/biom12111720 - 20 Nov 2022

Cited by 6 | Viewed by 1944

Abstract

Rhaponticum uniflorum (L.) DC. (syn. Leuzea uniflora (L.) Holub) is a plant species of the Compositae (Asteraceae) family that is widely used in Asian traditional medicines in China, Siberia, and Mongolia as an anti-inflammatory and stimulant remedy. Currently, R. uniflorum is [...] Read more.

Rhaponticum uniflorum (L.) DC. (syn. Leuzea uniflora (L.) Holub) is a plant species of the Compositae (Asteraceae) family that is widely used in Asian traditional medicines in China, Siberia, and Mongolia as an anti-inflammatory and stimulant remedy. Currently, R. uniflorum is of scientific interest to chemists, biologists, and pharmacologists, and this review includes information from the scientific literature from 1991 to 2022. The study of the chemodiversity of R. uniflorum revealed the presence of 225 compounds, including sesquiterpenes, ecdysteroids, triterpenes, sterols, thiophenes, hydroxycinnamates, flavonoids, lignans, nucleosides and vitamins, alkanes, fatty acids, and carbohydrates. The most studied groups of substances are phenolics (76 compounds) and triterpenoids (69 compounds). Information on the methods of chromatographic analysis of selected compounds, as well as on the quantitative content of some components in various organs of R. uniflorum, is summarized in this work. It has been shown that the extracts and some compounds of R. uniflorum have a wide range of biological activities, including anti-inflammatory, antitumor, immunostimulatory, anxiolytic, stress-protective, actoprotective, antihypoxic, anabolic, hepatoprotective, inhibition of PPARγ receptors, anti-atherosclerotic, and hypolipidemic. Published research on the metabolites and bioactivity of R. uniflorum does not include clinical studies of extracts and pure compounds; therefore, an accurate study of this traditional medicinal plant is needed. Full article

(This article belongs to the Special Issue Plant Polyphenols in the Immune and Inflammatory Responses)

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29 pages, 41316 KiB

Open AccessArticle

Hybrid-Enhanced Siamese Similarity Models in Ligand-Based Virtual Screen

by Mohammed Khaldoon Altalib and Naomie Salim

Biomolecules 2022, 12(11), 1719; https://doi.org/10.3390/biom12111719 - 20 Nov 2022

Cited by 2 | Viewed by 1578

Abstract

Information technology has become an integral aspect of the drug development process. The virtual screening process (VS) is a computational technique for screening chemical compounds in a reasonable amount of time and cost. The similarity search is one of the primary tasks in [...] Read more.

Information technology has become an integral aspect of the drug development process. The virtual screening process (VS) is a computational technique for screening chemical compounds in a reasonable amount of time and cost. The similarity search is one of the primary tasks in VS that estimates a molecule’s similarity. It is predicated on the idea that molecules with similar structures may also have similar activities. Many techniques for comparing the biological similarity between a target compound and each compound in the database have been established. Although the approaches have a strong performance, particularly when dealing with molecules with homogenous active structural, they are not enough good when dealing with structurally heterogeneous compounds. The previous works examined many deep learning methods in the enhanced Siamese similarity model and demonstrated that the Enhanced Siamese Multi-Layer Perceptron similarity model (SMLP) and the Siamese Convolutional Neural Network-one dimension similarity model (SCNN1D) have good outcomes when dealing with structurally heterogeneous molecules. To further improve the retrieval effectiveness of the similarity model, we incorporate the best two models in one hybrid model. The reason is that each method gives good results in some classes, so combining them in one hybrid model may improve the retrieval recall. Many designs of the hybrid models will be tested in this study. Several experiments on real-world data sets were conducted, and the findings demonstrated that the new approaches outperformed the previous method. Full article

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10 pages, 1924 KiB

Open AccessArticle

Bacterial and Cellular Response to Yellow-Shaded Surface Modifications for Dental Implant Abutments

by Tullio Genova, Giorgia Chinigò, Luca Munaron, Paola Rivolo, Anna Luganini, Giorgio Gribaudo, Davide Cavagnetto, Pietro Mandracci and Federico Mussano

Biomolecules 2022, 12(11), 1718; https://doi.org/10.3390/biom12111718 - 20 Nov 2022

Cited by 1 | Viewed by 1480

Abstract

Dental implants have dramatically changed the rehabilitation procedures in dental prostheses but are hindered by the possible onset of peri-implantitis. This paper aims to assess whether an anodization process applied to clinically used surfaces could enhance the adhesion of fibroblasts and reduce bacterial [...] Read more.

Dental implants have dramatically changed the rehabilitation procedures in dental prostheses but are hindered by the possible onset of peri-implantitis. This paper aims to assess whether an anodization process applied to clinically used surfaces could enhance the adhesion of fibroblasts and reduce bacterial adhesion using as a reference the untreated machined surface. To this purpose, four different surfaces were prepared: (i) machined (MAC), (ii) machined and anodized (Y-MAC), (iii) anodized after sand-blasting and acid etching treatment (Y-SL), and (iv) anodized after double acid etching (Y-DM). All specimens were characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Moreover, the mean contact angle in both water and diiodomethane as well as surface free energy calculation was assessed. To evaluate changes in terms of biological responses, we investigated the adhesion of Streptococcus sanguinis (S. sanguinis) and Enterococcus faecalis (E. faecalis), fetal bovine serum (FBS) adsorption, and the early response of fibroblasts in terms of cell adhesion and viability. We found that the anodization reduced bacterial adhesion, while roughened surfaces outperformed the machined ones for protein adsorption, fibroblast adhesion, and viability independently of the treatment. It can be concluded that surface modification techniques such as anodization are valuable options to enhance the performance of dental implants. Full article

(This article belongs to the Special Issue Biomarkers in Oral Diseases 2.0)

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20 pages, 2935 KiB

Open AccessReview

Linking Cerebrovascular Dysfunction to Age-Related Hearing Loss and Alzheimer’s Disease—Are Systemic Approaches for Diagnosis and Therapy Required?

by Carola Y. Förster, Sergey Shityakov, Verena Scheper and Thomas Lenarz

Biomolecules 2022, 12(11), 1717; https://doi.org/10.3390/biom12111717 - 19 Nov 2022

Cited by 2 | Viewed by 2616

Abstract

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid β peptide (Aβ) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aβ [...] Read more.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid β peptide (Aβ) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aβ deposits and NFT formation are the central pathological hallmarks in AD brains, and the majority of AD cases have been shown to exhibit a complex combination of systemic comorbidities. While AD is the foremost common cause of dementia in the elderly, age-related hearing loss (ARHL) is the most predominant sensory deficit in the elderly. During aging, chronic inflammation and resulting endothelial dysfunction have been described and might be key contributors to AD; we discuss an intriguing possible link between inner ear strial microvascular pathology and blood–brain barrier pathology and present ARHL as a potentially modifiable and treatable risk factor for AD development. We present compelling evidence that ARHL might well be seen as an important risk factor in AD development: progressive hearing impairment, leading to social isolation, and its comorbidities, such as frailty, falls, and late-onset depression, link ARHL with cognitive decline and increased risk of dementia, rendering it tempting to speculate that ARHL might be a potential common molecular and pathological trigger for AD. Additionally, one could speculate that amyloid-beta might damage the blood–labyrinth barrier as it does to the blood–brain barrier, leading to ARHL pathology. Finally, there are options for the treatment of ARHL by targeted neurotrophic factor supplementation to the cochlea to improve cognitive outcomes; they can also prevent AD development and AD-related comorbidity in the future. Full article

(This article belongs to the Special Issue Regulation of the Endothelial Cell Barrier)

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17 pages, 6777 KiB

Open AccessArticle

Bicalutamide Anticancer Activity Enhancement by Formulation of Soluble Inclusion Complexes with Cyclodextrins

by Federica De Gaetano, Maria Chiara Cristiano, Donatella Paolino, Consuelo Celesti, Daniela Iannazzo, Venerando Pistarà, Nunzio Iraci and Cinzia Anna Ventura

Biomolecules 2022, 12(11), 1716; https://doi.org/10.3390/biom12111716 - 19 Nov 2022

Cited by 13 | Viewed by 1721

Abstract

Bicalutamide (BCL) is a nonsteroidal antiandrogen drug that represents an alternative to castration in the treatment of prostate cancer, due to its relatively long half-life and tolerable side effects. However, it possesses a very low water solubility that can affect its oral bioavailability. [...] Read more.

Bicalutamide (BCL) is a nonsteroidal antiandrogen drug that represents an alternative to castration in the treatment of prostate cancer, due to its relatively long half-life and tolerable side effects. However, it possesses a very low water solubility that can affect its oral bioavailability. In this work, we developed inclusion complexes of BCL with the highly soluble hydroxypropyl-β-cyclodextrin (HP-β-CyD) and sulfobutylether-β-cyclodextrin (SBE-β-CyD) to increase the water solubility and anticancer activity of BCL. The inclusion complexes were prepared using the freeze-drying method and were then characterized in a solid state via differential scanning calorimetry and X-ray analysis and in solution via phase-solubility studies and UV-vis and NMR spectroscopy. The BCL/HP-β-CyD and BCL/SBE-β-CyD inclusion complexes were amorphous and rapidly dissolved in water. Both the ¹H-NMR spectra and molecular modeling studies confirmed the penetration of the 2-(trifluoromethyl)benzonitrile ring of BCL within the cavity of both cyclodextrins (CyDs). Due to the consistent improvement of the water solubility of BCL, the inclusion complexes showed higher antiproliferative activity toward the human prostate androgen-independent cell lines, DU-145 and PC-3, with respect to free BCL. These results demonstrate the ability of HP-β-CyD and SBE-β-CyD to complex BCL, permitting the realization of liquid formulations with potentially high oral bioavailability and/or possible parenteral administration. Full article

(This article belongs to the Special Issue Chemopreventive and Therapeutic Potential of Phytochemicals and Their Analogs against Cancer)

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10 pages, 2224 KiB

Open AccessArticle

Combinational Growth Factor and Gas Delivery for Thrombosis Prevention

by Huan Cao, Xuejuan Xu, Fuyu Zhu and Yanhui Sheng

Biomolecules 2022, 12(11), 1715; https://doi.org/10.3390/biom12111715 - 19 Nov 2022

Viewed by 1427

Abstract

Cardiovascular stents enable the rapid re-endothelialization of endothelial cells (ECs), and the constant suppression of smooth muscle cell (SMC) proliferation has been proved to effectively prevent thrombosis. However, the development and application of such stents are still insufficient due the delayed re-endothelialization progress, [...] Read more.

Cardiovascular stents enable the rapid re-endothelialization of endothelial cells (ECs), and the constant suppression of smooth muscle cell (SMC) proliferation has been proved to effectively prevent thrombosis. However, the development and application of such stents are still insufficient due the delayed re-endothelialization progress, as well as the poor durability of the SMC inhibition. In this paper, we developed a mussel-inspired coating with the ability for the dual delivery of both growth factor (e.g., platelet-derived growth factor, PDGF) and therapeutic gas (e.g., nitric oxide, NO) for thrombosis prevention. We firstly synthesized the mussel-inspired co-polymer (DMHM) of dopamine methacrylamide (DMA) and hydroxyethyl methacrylate (HEMA) and then coated the DMHM on 316L SS stents combined with Cu^II. Afterwards, we immobilized the PDGF on the DMHM-coated stent and found that the PDGF could be released in the first 3 days to enhance the recruitment, proliferation, and migration of human umbilical vein endothelial cells (HUVECs) to promote re-endothelialization. The Cu^II could be “sealed” in the DMHM coating, with extended durability (2 months), with the capacity for catalyzed NO generation for up to 2 months to suppress the proliferation of SMCs. Such a stent surface modification strategy could enhance the development of the cardiovascular stents for thrombosis prevention. Full article

(This article belongs to the Special Issue Tissue Engineering Approaches for Reconstructing Biological Environment)

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15 pages, 3163 KiB

Open AccessArticle

Right Ventricle Remodelling in Left-Sided Heart Failure in Rats: The Role of Calcium Signalling

by Aleksandra Paterek, Marta Oknińska, Michał Mączewski and Urszula Mackiewicz

Biomolecules 2022, 12(11), 1714; https://doi.org/10.3390/biom12111714 - 19 Nov 2022

Viewed by 1384

Abstract

Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to [...] Read more.

Right ventricular dysfunction (RVD) can follow primary pulmonary diseases, but the most common cause of its development is left-sided heart failure (HF). RVD is associated with HF progression, increased risk of death and hospitalisation. The mechanism of right ventricle (RV) remodelling leading to RVD due to left-sided HF is not fully elucidated. Rats underwent LAD ligation to induce extensive left ventricle (LV) myocardial infarction (MI) and subsequent left-sided HF. Sham-operated animals served as controls. After 8 weeks of follow-up, the animals underwent LV and RV catheterisation, and systolic function and intracellular Ca²⁺ signalling were assessed in cardiomyocytes isolated from both ventricles. We demonstrated that rats with LV failure induced by extensive LV myocardial infarction also develop RV failure, leading to symptomatic biventricular HF, despite only mildly increased RV afterload. The contractility of RV cardiomyocytes was significantly increased, which could be related to increased amplitude of Ca²⁺ transient, preserved SERCA2a activity and reduced Ca²⁺ efflux via NCX1 and PMCA. Our study indicates that RV failure associated with post-MI LV failure in a rat model cannot be explained by a decline in cardiomyocyte function. This indicates that other factors may play a role here, pointing to the need for further research to better understand the biology of RV failure in order to ultimately develop therapies targeting the RV. Full article

(This article belongs to the Special Issue Calcium Regulation in the Cardiac Cells)

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13 pages, 596 KiB

Open AccessFeature PaperReview

Chelation Combination—A Strategy to Mitigate the Neurotoxicity of Manganese, Iron, and Copper?

by Jan O. Aaseth and Valeria M. Nurchi

Biomolecules 2022, 12(11), 1713; https://doi.org/10.3390/biom12111713 - 18 Nov 2022

Cited by 3 | Viewed by 2530

Abstract

The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to [...] Read more.

The chelating thiol dimercaptosuccinate (DMSA) and the traditional agent D-penicillamine (PSH) are effective in enhancing the urinary excretion of copper (Cu) and lead (Pb) in poisoned individuals. However, DMSA, PSH, EDTA (ethylenediamine tetraacetate), and deferoxamine (DFOA) are water-soluble agents with limited access to the central nervous system (CNS). Strategies for mobilization of metals such as manganese (Mn), iron (Fe), and Cu from brain deposits may require the combined use of two agents: one water-soluble agent to remove circulating metal into urine, in addition to an adjuvant shuttler to facilitate the brain-to-blood mobilization. The present review discusses the chemical basis of metal chelation and the ligand exchange of metal ions. To obtain increased excretion of Mn, Cu, and Fe, early experiences showed promising results for CaEDTA, PSH, and DFOA, respectively. Recent experiments have indicated that p-amino salicylate (PAS) plus CaEDTA may be a useful combination to remove Mn from binding sites in CNS, while the deferasirox–DFOA and the tetrathiomolybdate–DMSA combinations may be preferable to promote mobilization of Fe and Cu, respectively, from the CNS. Further research is requested to explore benefits of chelator combinations. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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20 pages, 819 KiB

Open AccessReview

Receptor for Advanced Glycation End Product, Organ Crosstalk, and Pathomechanism Targets for Comprehensive Molecular Therapeutics in Diabetic Ischemic Stroke

by Nivedita L. Rao, Greeshma B. Kotian, Jeevan K. Shetty, Bhaskara P. Shelley, Mackwin Kenwood Dmello, Eric C. Lobo, Suchetha Padar Shankar, Shellette D. Almeida and Saiqa R. Shah

Biomolecules 2022, 12(11), 1712; https://doi.org/10.3390/biom12111712 - 18 Nov 2022

Cited by 4 | Viewed by 2709

Abstract

Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes–ischemic stroke [...] Read more.

Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes–ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain–kidney–muscle crosstalk, alternate pathomechanisms in neurodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitric oxide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation and oxidative stress. Experimental findings on a number of existing–emerging therapeutic agents and natural compounds against key targets are promising. The lack of large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE–RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory–antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation, are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients. Full article

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19 pages, 3438 KiB

Open AccessArticle

Biodefensive Based on Piper nigrum Essential Oil for Controlling of Anopheles aquasalis Larvae: Influence of Temperature (35 °C) and Preservatives

by Ayná Caroline Marcião Vieira, Sidney Gomes Azevedo, Ramon Andrade Linhares, Silvia Cássia Brandão Justiniano, Grafe Oliveira Pontes, Alessandra Ramos Lima, Pedro Henrique Campelo, Jaqueline de Araújo Bezerra, Camila da Costa Pinto, Henrique Duarte da Fonseca Filho, Robert Saraiva Matos, Ştefan Ţălu, Vanderlei Salvador Bagnato, Natalia Mayumi Inada and Edgar Aparecido Sanches

Biomolecules 2022, 12(11), 1711; https://doi.org/10.3390/biom12111711 - 18 Nov 2022

Viewed by 2023

Abstract

Considerable efforts have been spent on the development of biodefensives based on the encapsulation of essential oils for controlling of urban pests from their larval stage, especially as anopheline controlling agents. The larval source management of Anopheles aquasalis is important for malaria prevention. [...] Read more.

Considerable efforts have been spent on the development of biodefensives based on the encapsulation of essential oils for controlling of urban pests from their larval stage, especially as anopheline controlling agents. The larval source management of Anopheles aquasalis is important for malaria prevention. For this reason, this research proposes larvicidal biodefensives based on polymeric particles loaded with Piper nigrum essential oil, considering the influence of temperature (35 °C) and preservatives on the formulation stability. The biodefensive containing the preservative phenoxyethanol/methylisothiazolinone (PNE) resulted in 5 months of shelf-life storage with an Encapsulation Efficiency (EE%) of essential oil of 70%. The biodefensive PNE (containing 500 µg.mL⁻¹ of encapsulated essential oil) presented a polydisperse particle size distribution, ranging from D₁₀ = (127 ± 10) nm to D₉₀ = (472 ± 78) nm and a particle mean size of (236 ± 34) nm. The AFM images revealed a spherical morphology with an external surface almost regular and smooth. The controlled release of the essential oil was evaluated up to 72 h according to the Korsmeyer-Peppas mathematical model, confirming the anomalous transport (n = 0.64 in pH = 3 and pH = 10, and n = 0.65 in pH = 7). The total larvae mortality on the in loco bioassays was almost reached (92%) after 24 h. However, according to the in vitro bioassays applying the in natura essential oil alone, the concentration of 454 μg.mL⁻¹ resulted on the mortality of 70% of the larvae after 24 h. For this reason, the highest efficiency of the biodefensive PNE may be related to the encapsulation of essential oil, delivering the loaded particles more efficiently inside the larvae. From this perspective, the present study shows that a formulation based on P. nigrum essential oil may be taken into account in the integrated management of disease vector mosquitoes. Full article

(This article belongs to the Special Issue Bioactive Natural Compounds against Animal and Human Pathogens)

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18 pages, 2288 KiB

Open AccessReview

The Effects of TRPC6 Knockout in Animal Models of Kidney Disease

by Stuart E. Dryer and Eun Young Kim

Biomolecules 2022, 12(11), 1710; https://doi.org/10.3390/biom12111710 - 18 Nov 2022

Cited by 5 | Viewed by 2111

Abstract

Diseases that induce a loss of renal function affect a substantial portion of the world’s population and can range from a slight decline in the glomerular filtration rate or microalbuminuria to complete kidney failure. Kidney disorders can be acute or chronic, but any [...] Read more.

Diseases that induce a loss of renal function affect a substantial portion of the world’s population and can range from a slight decline in the glomerular filtration rate or microalbuminuria to complete kidney failure. Kidney disorders can be acute or chronic, but any significant reduction in renal function is associated with increased all-cause morbidity and mortality, especially when the conditions become chronic. There is an urgent need for new therapeutic approaches to slow or halt the progression of kidney disease. One potential target of considerable interest is the canonical transient receptor potential-6 (TRPC6) channel. TRCP6 is a cationic channel with a significant permeability to Ca²⁺. It is expressed in several tissues, including in multiple cell types of the kidney in glomeruli, microvasculature, and tubules. Here, we will describe TRPC6 channels and their roles in signal transduction, with an emphasis on renal cells, and the studies implicating TRPC6 channels in the progression of inherited and acquired kidney diseases. We then describe studies using TRPC6 knockout mice and rats subjected to treatments that model human diseases, including nephrotic syndromes, diabetic nephropathy, autoimmune glomerulonephritis, and acute kidney injuries induced by renal ischemia and by obstruction of the urinary tract. TRPC6 knockout has been shown to reduce glomerular manifestations of disease in several of these models and reduces renal fibrosis caused by urinary tract obstruction. TRPC6 knockout has proven to be less effective at reducing diabetic nephropathy in mouse and rat models. We also summarize the implications of these studies for drug development. Full article

(This article belongs to the Special Issue Featured Papers in Ion Channels Diseases)

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19 pages, 1505 KiB

Open AccessArticle

GOProFormer: A Multi-Modal Transformer Method for Gene Ontology Protein Function Prediction

by Anowarul Kabir and Amarda Shehu

Biomolecules 2022, 12(11), 1709; https://doi.org/10.3390/biom12111709 - 18 Nov 2022

Cited by 4 | Viewed by 2593

Abstract

Protein Language Models (PLMs) are shown to be capable of learning sequence representations useful for various prediction tasks, from subcellular localization, evolutionary relationships, family membership, and more. They have yet to be demonstrated useful for protein function prediction. In particular, the problem of [...] Read more.

Protein Language Models (PLMs) are shown to be capable of learning sequence representations useful for various prediction tasks, from subcellular localization, evolutionary relationships, family membership, and more. They have yet to be demonstrated useful for protein function prediction. In particular, the problem of automatic annotation of proteins under the Gene Ontology (GO) framework remains open. This paper makes two key contributions. It debuts a novel method that leverages the transformer architecture in two ways. A sequence transformer encodes protein sequences in a task-agnostic feature space. A graph transformer learns a representation of GO terms while respecting their hierarchical relationships. The learned sequence and GO terms representations are combined and utilized for multi-label classification, with the labels corresponding to GO terms. The method is shown superior over recent representative GO prediction methods. The second major contribution in this paper is a deep investigation of different ways of constructing training and testing datasets. The paper shows that existing approaches under- or over-estimate the generalization power of a model. A novel approach is proposed to address these issues, resulting in a new benchmark dataset to rigorously evaluate and compare methods and advance the state-of-the-art. Full article

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17 pages, 1322 KiB

Open AccessReview

The Role of Macrophage Iron Overload and Ferroptosis in Atherosclerosis

by Jiedong Ma, Hongqi Zhang, Yufei Chen, Xiaojin Liu, Jiamin Tian and Wei Shen

Biomolecules 2022, 12(11), 1702; https://doi.org/10.3390/biom12111702 - 18 Nov 2022

Cited by 16 | Viewed by 3515

Abstract

Ferroptosis is a new type of cell death caused by iron-dependent lipid peroxidation. In recent years, it has been found that ferroptosis can promote the progression of atherosclerosis (AS). Macrophages have been proven to play multiple roles in the occurrence and development of [...] Read more.

Ferroptosis is a new type of cell death caused by iron-dependent lipid peroxidation. In recent years, it has been found that ferroptosis can promote the progression of atherosclerosis (AS). Macrophages have been proven to play multiple roles in the occurrence and development of AS. Iron is a necessary mineral that participates in different functions of macrophages under physiological conditions. But iron overload and ferroptosis in macrophages may promote the progression of AS. Herein, we summarize the role of iron overload and ferroptosis in macrophages in AS from the perspective of iron metabolism, and iron overload and ferroptosis are significant contributors to AS development. Full article

(This article belongs to the Topic Molecular and Cellular Mechanisms of Diseases: Heart Disease)

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20 pages, 1466 KiB

Open AccessReview

Extracellular Hemoglobin: Modulation of Cellular Functions and Pathophysiological Effects

by Ivana T. Drvenica, Ana Z. Stančić, Irina S. Maslovarić, Drenka I. Trivanović and Vesna Lj. Ilić

Biomolecules 2022, 12(11), 1708; https://doi.org/10.3390/biom12111708 - 17 Nov 2022

Cited by 8 | Viewed by 3670

Abstract

Hemoglobin is essential for maintaining cellular bioenergetic homeostasis through its ability to bind and transport oxygen to the tissues. Besides its ability to transport oxygen, hemoglobin within erythrocytes plays an important role in cellular signaling and modulation of the inflammatory response either directly [...] Read more.

Hemoglobin is essential for maintaining cellular bioenergetic homeostasis through its ability to bind and transport oxygen to the tissues. Besides its ability to transport oxygen, hemoglobin within erythrocytes plays an important role in cellular signaling and modulation of the inflammatory response either directly by binding gas molecules (NO, CO, and CO₂) or indirectly by acting as their source. Once hemoglobin reaches the extracellular environment, it acquires several secondary functions affecting surrounding cells and tissues. By modulating the cell functions, this macromolecule becomes involved in the etiology and pathophysiology of various diseases. The up-to-date results disclose the impact of extracellular hemoglobin on (i) redox status, (ii) inflammatory state of cells, (iii) proliferation and chemotaxis, (iv) mitochondrial dynamic, (v) chemoresistance and (vi) differentiation. This review pays special attention to applied biomedical research and the use of non-vertebrate and vertebrate extracellular hemoglobin as a promising candidate for hemoglobin-based oxygen carriers, as well as cell culture medium additive. Although recent experimental settings have some limitations, they provide additional insight into the modulatory activity of extracellular hemoglobin in various cellular microenvironments, such as stem or tumor cells niches. Full article

(This article belongs to the Special Issue Extracellular Factors of Connective Tissues: Regulation of Cell Fate and Disease Modelling Perspectives)

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12 pages, 2577 KiB

Open AccessArticle

Phosphatidic Acid Accumulates at Areas of Curvature in Tubulated Lipid Bilayers and Liposomes

by Broderick L. Bills and Michelle K. Knowles

Biomolecules 2022, 12(11), 1707; https://doi.org/10.3390/biom12111707 - 17 Nov 2022

Cited by 3 | Viewed by 1795

Abstract

Phosphatidic acid (PA) is a signaling lipid that is produced enzymatically from phosphatidylcholine (PC), lysophosphatidic acid, or diacylglycerol. Compared to PC, PA lacks a choline moiety on the headgroup, making the headgroup smaller than that of PC and PA, and PA has a [...] Read more.

Phosphatidic acid (PA) is a signaling lipid that is produced enzymatically from phosphatidylcholine (PC), lysophosphatidic acid, or diacylglycerol. Compared to PC, PA lacks a choline moiety on the headgroup, making the headgroup smaller than that of PC and PA, and PA has a net negative charge. Unlike the cylindrical geometry of PC, PA, with its small headgroup relative to the two fatty acid tails, is proposed to support negatively curved membranes. Thus, PA is thought to play a role in a variety of biological processes that involve bending membranes, such as the formation of intraluminal vesicles in multivesicular bodies and membrane fusion. Using supported tubulated lipid bilayers (STuBs), the extent to which PA localizes to curved membranes was determined. STuBs were created via liposome deposition with varying concentrations of NaCl (500 mM to 1 M) on glass to form supported bilayers with connected tubules. The location of fluorescently labeled lipids relative to tubules was determined by imaging with total internal reflection or confocal fluorescence microscopy. The accumulation of various forms of PA (with acyl chains of 16:0-6:0, 16:0-12:0, 18:1-12:0) were compared to PC and the headgroup labeled phosphatidylethanolamine (PE), a lipid that has been shown to accumulate at regions of curvature. PA and PE accumulated more at tubules and led to the formation of more tubules than PC. Using large unilamellar liposomes in a dye-quenching assay, the location of the headgroup labeled PE was determined to be mostly on the outer, positively curved leaflet, whereas the tail labeled PA was located more on the inner, negatively curved leaflet. This study demonstrates that PA localizes to regions of negative curvature in liposomes and supports the formation of curved, tubulated membranes. This is one way that PA could be involved with curvature formation during a variety of cell processes. Full article

(This article belongs to the Special Issue Recent Developments in Biophysical Studies of Cell Membranes)

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17 pages, 6664 KiB

Open AccessArticle

E-Cadherin Expression Distinguishes Mouse from Human Hematopoiesis in the Basophil and Erythroid Lineages

by Rosa A. Krimpenfort, Felix M. Behr, Marja Nieuwland, Iris de Rink, Ron Kerkhoven, Marieke von Lindern and Micha Nethe

Biomolecules 2022, 12(11), 1706; https://doi.org/10.3390/biom12111706 - 17 Nov 2022

Cited by 2 | Viewed by 1987

Abstract

E-cadherin is a key regulator of epithelial cell–cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive. In this study, we explored [...] Read more.

E-cadherin is a key regulator of epithelial cell–cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive. In this study, we explored the validity of mouse models to functionally investigate the role of hematopoietic E-cadherin in human hematopoiesis. We generated a hematopoietic-specific E-cadherin knockout mouse model. In mice, hematopoietic E-cadherin is predominantly expressed within the basophil lineage, the expression of which is dispensable for the generation of basophils. However, neither E-cadherin mRNA nor protein were detected in human basophils. In contrast, human hematopoietic E-cadherin marks the erythroid lineage. E-cadherin expression in hematopoiesis thereby revealed striking evolutionary differences between the basophil and erythroid cell lineage in humans and mice. This is remarkable as E-cadherin expression in epithelia is highly conserved among vertebrates including humans and mice. Our study therefore revealed that the mouse does not represent a suitable model to study the function of E-cadherin in human hematopoiesis and an alternative means to study the role of E-cadherin in human erythropoiesis needs to be developed. Full article

(This article belongs to the Topic Advances in Red Blood Cells Research)

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16 pages, 4196 KiB

Open AccessCommunication

First Anti-Inflammatory Peptide AnmTX Sco 9a-1 from the Swimming Sea Anemone Stomphia coccinea

by Rimma S. Kalina, Irina N. Gladkikh, Anna A. Klimovich, Yulia V. Kozhevnikova, Aleksandra N. Kvetkina, Eugene A. Rogozhin, Sergey G. Koshelev, Sergey A. Kozlov and Elena V. Leychenko

Biomolecules 2022, 12(11), 1705; https://doi.org/10.3390/biom12111705 - 17 Nov 2022

Viewed by 1389

Abstract

A novel peptide AnmTX Sco 9a-1 with the β-hairpin fold was isolated from the swimming sea anemone Stomphia coccinea (Actinostolidae family). The peptide consists of 28 amino acid residues, including modified hydroxyproline residue, and its measured molecular mass is 2960 Da. The peptide [...] Read more.

A novel peptide AnmTX Sco 9a-1 with the β-hairpin fold was isolated from the swimming sea anemone Stomphia coccinea (Actinostolidae family). The peptide consists of 28 amino acid residues, including modified hydroxyproline residue, and its measured molecular mass is 2960 Da. The peptide was not toxic on mice; however, it stimulated their exploratory motivation and active search behavior, and demonstrated an anti-anxiety effect. AnmTX Sco 9a-1 at doses of 0.1 and 1 mg/kg reduced the volume of edema during 24 h better than the nonsteroidal anti-inflammatory drug, Diclofenac, at dose of 1 mg/kg in a model of acute local λ-carrageenan-induced inflammation. ELISA analysis of the animal’s blood showed that peptide at a dose of 1 mg/kg reduced the content of tumor necrosis factor-α (TNF-α), a pro-inflammatory mediator responsible in the edema development, up to the level of TNF-α in the intact group. Besides, AnmTX Sco 9a-1 demonstrated a significant analgesic effect on acute pain sensitivity in the carrageenan-induced thermal hyperalgesia model at doses of 0.1 and 1 mg/kg. Activity of AnmTX Sco 9a-1 was shown not to be associated with modulation of nociceptive ASIC channels. Full article

(This article belongs to the Special Issue Marine Natural Compounds with Biomedical Potential 2.0)

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19 pages, 2297 KiB

Open AccessArticle

Potential Application of Recombinant Snake Prothrombin Activator Ecarin in Blood Diagnostics

by Kong-Nan Zhao, Paul Masci, Goce Dimeski, Lambro Johnson, Michael Grant, John de Jersey and Martin F. Lavin

Biomolecules 2022, 12(11), 1704; https://doi.org/10.3390/biom12111704 - 17 Nov 2022

Cited by 1 | Viewed by 2054

Abstract

We describe here the purification and cloning of a codon-optimized form of the snake prothrombin activator ecarin from the saw scaled viper (Echis carinatus) expressed in mammalian cells. Expression of recombinant ecarin (rEcarin) was carried out in human embryonic kidney cells [...] Read more.

We describe here the purification and cloning of a codon-optimized form of the snake prothrombin activator ecarin from the saw scaled viper (Echis carinatus) expressed in mammalian cells. Expression of recombinant ecarin (rEcarin) was carried out in human embryonic kidney cells (HEK) cells under conditions for the development and performance of a novel and scalable recombinant snake ecarin to industry standards. Clotting performance of the rEcarin was established in recalcified citrated whole blood, plasma, and fresh whole blood and found to be comparable to native ecarin (N-Ecarin). Furthermore, hemolysis was observed with N-Ecarin at relatively high doses in both recalcified citrated and fresh whole blood, while clotting was not observed with rEcarin, providing an important advantage for the recombinant form. In addition, rEcarin effectively clotted both recalcified citrated whole blood and fresh whole blood containing different anticoagulants including heparin, warfarin, dabigatran, Fondaparinux, rivaroxaban and apixaban, forming firm clots in the blood collection tubes. These results demonstrate that rEcarin efficiently clots normal blood as well as blood spiked with high concentrations of anticoagulants and has great potential as an additive to blood collection tubes to produce high quality serum for analyte analysis in diagnostic medicine. Full article

(This article belongs to the Topic Biomedical Applications of Enzymes)

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24 pages, 2034 KiB

Open AccessArticle

Inter-Site Cooperativity of Calmodulin N-Terminal Domain and Phosphorylation Synergistically Improve the Affinity and Selectivity for Uranyl

by Maria Rosa Beccia, Sandrine Sauge-Merle, Nicolas Brémond, David Lemaire, Pierre Henri, Christine Battesti, Philippe Guilbaud, Serge Crouzy and Catherine Berthomieu

Biomolecules 2022, 12(11), 1703; https://doi.org/10.3390/biom12111703 - 17 Nov 2022

Cited by 2 | Viewed by 1319

Abstract

Uranyl–protein interactions participate in uranyl trafficking or toxicity to cells. In addition to their qualitative identification, thermodynamic data are needed to predict predominant mechanisms that they mediate in vivo. We previously showed that uranyl can substitute calcium at the canonical EF-hand binding motif [...] Read more.

Uranyl–protein interactions participate in uranyl trafficking or toxicity to cells. In addition to their qualitative identification, thermodynamic data are needed to predict predominant mechanisms that they mediate in vivo. We previously showed that uranyl can substitute calcium at the canonical EF-hand binding motif of calmodulin (CaM) site I. Here, we investigate thermodynamic properties of uranyl interaction with site II and with the whole CaM N-terminal domain by spectrofluorimetry and ITC. Site II has an affinity for uranyl about 10 times lower than site I. Uranyl binding at site I is exothermic with a large enthalpic contribution, while for site II, the enthalpic contribution to the Gibbs free energy of binding is about 10 times lower than the entropic term. For the N–terminal domain, macroscopic binding constants for uranyl are two to three orders of magnitude higher than for calcium. A positive cooperative process driven by entropy increases the second uranyl-binding event as compared with the first one, with ΔΔG = −2.0 ± 0.4 kJ mol⁻¹, vs. ΔΔG = −6.1 ± 0.1 kJ mol⁻¹ for calcium. Site I phosphorylation largely increases both site I and site II affinity for uranyl and uranyl-binding cooperativity. Combining site I phosphorylation and site II Thr7Trp mutation leads to picomolar dissociation constants Kd₁ = 1.7 ± 0.3 pM and Kd₂ = 196 ± 21 pM at pH 7. A structural model obtained by MD simulations suggests a structural role of site I phosphorylation in the affinity modulation. Full article

(This article belongs to the Special Issue Biomolecule-Metal Ion Interaction)

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9 pages, 3149 KiB

Open AccessFeature PaperArticle

Prevalence of Spotted Fever Group Rickettsia and Candidatus Lariskella in Multiple Tick Species from Guizhou Province, China

by Miao Lu, Chao Meng, Bing Zhang, Xiao Wang, Junhua Tian, Guangpeng Tang, Wen Wang, Na Li, Mengyao Li, Xiaoyu Xu, Yue Sun, Chengyu Duan, Xincheng Qin and Kun Li

Biomolecules 2022, 12(11), 1701; https://doi.org/10.3390/biom12111701 - 17 Nov 2022

Cited by 1 | Viewed by 1397

Abstract

Rickettsiales (Rickettsia spp., Ehrlichia spp., and Anaplasma spp., etc.) are generally recognized as potentially emerging tick-borne pathogens. However, some bacteria and areas in China remain uninvestigated. In this study, we collected 113 ticks from mammals in Guizhou Province, Southwest China, and screened [...] Read more.

Rickettsiales (Rickettsia spp., Ehrlichia spp., and Anaplasma spp., etc.) are generally recognized as potentially emerging tick-borne pathogens. However, some bacteria and areas in China remain uninvestigated. In this study, we collected 113 ticks from mammals in Guizhou Province, Southwest China, and screened for the Rickettsiales bacteria. Subsequently, two spotted fever group Rickettsia species and one Candidatus Lariskella sp. were detected and characterized. “Candidatus Rickettsia jingxinensis” was detected in Rhipicephalus microplus (1/1), Haemaphysalis flava (1/3, 33.33%), Haemaphysalis kitaokai (1/3), and Ixodes sinensis (4/101, 3.96%), whereas Rickettsia monacensis was positive in H. flava (1/3), H. kitaokai (2/3), and I. sinensis ticks (74/101, 73.27%). At least two variants/sub-genotypes were identified in the R. monacensis isolates, and the strikingly high prevalence of R. monacensis may suggest a risk of human infection. Unexpectedly, a Candidatus Lariskella sp. belonging to the family Candidatus Midichloriaceae was detected from Ixodes ovatus (1/4) and I. sinensis (10/101, 9.90%). The gltA and groEL gene sequences were successfully obtained, and they show the highest (74.63–74.89% and 73.31%) similarities to “Candidatus Midichloria mitochondrii”, respectively. Herein, we name the species “Candidatus Lariskella guizhouensis”. These may be the first recovered gltA and groEL sequences of the genus Candidatus Lariskella. Full article

(This article belongs to the Special Issue New Insight into Vector Borne Diseases)

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25 pages, 13769 KiB

Open AccessArticle

Screening for Lipid-Metabolism-Related Genes and Identifying the Diagnostic Potential of ANGPTL6 for HBV-Related Early-Stage Hepatocellular Carcinoma

by Duo Zuo, Jiawei Xiao, Haohua An, Yongzi Chen, Jianhua Li, Xiaohui Yang, Xia Wang and Li Ren

Biomolecules 2022, 12(11), 1700; https://doi.org/10.3390/biom12111700 - 17 Nov 2022

Cited by 1 | Viewed by 2018

Abstract

Lipid metabolic reprogramming is one of the hallmarks of hepatocarcinogenesis and development. Therefore, lipid-metabolism-related genes may be used as potential biomarkers for hepatocellular carcinoma (HCC). This study aimed to screen for genes with dysregulated expression related to lipid metabolism in HCC and explored [...] Read more.

Lipid metabolic reprogramming is one of the hallmarks of hepatocarcinogenesis and development. Therefore, lipid-metabolism-related genes may be used as potential biomarkers for hepatocellular carcinoma (HCC). This study aimed to screen for genes with dysregulated expression related to lipid metabolism in HCC and explored the clinical value of these genes. We screened differentially expressed proteins between tumorous and adjacent nontumorous tissues of hepatitis B virus (HBV)-related HCC patients using a Nanoscale Liquid Chromatography–Tandem Mass Spectrometry platform and combined it with transcriptomic data of lipid-metabolism-related genes from the GEO and HPA databases to identify dysregulated genes that may be involved in lipid metabolic processes. The potential clinical values of these genes were explored by bioinformatics online analysis tools (GEPIA, cBioPortal, SurvivalMeth, and TIMER). The expression levels of the secreted protein (angiopoietin-like protein 6, ANGPTL6) in serum were analyzed by ELISA. The ability of serum ANGPTL6 to diagnose early HCC was assessed by ROC curves. The results showed that serum ANGPTL6 could effectively differentiate between HBV-related early HCC patients with normal serum alpha-fetoprotein (AFP) levels and the noncancer group (healthy participants and chronic hepatitis B patients) (AUC = 0.717, 95% CI: from 0.614 to 0.805). Serum ANGPTL6 can be used as a potential second-line biomarker to supplement serum AFP in the early diagnosis of HBV-related HCC. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease)

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18 pages, 3621 KiB

Open AccessArticle

Knockdown of Two Trehalase Genes by RNA Interference Is Lethal to the White-Backed Planthopper Sogatella furcifera (Horváth) (Hemiptera: Delphacidae)

by Zhao Wang, Gui-Yun Long, Dao-Chao Jin, Hong Yang, Cao Zhou and Xi-Bin Yang

Biomolecules 2022, 12(11), 1699; https://doi.org/10.3390/biom12111699 - 17 Nov 2022

Cited by 3 | Viewed by 1792

Abstract

Trehalase (Tre) is a crucial enzyme involved in trehalose metabolism, and it plays pivotal roles in insect development and metamorphosis. However, the biological function of Tre genes in Sogatella furcifera remains unclear. In the present study, two Tre genes—SfTre1 and SfTre2—were [...] Read more.

Trehalase (Tre) is a crucial enzyme involved in trehalose metabolism, and it plays pivotal roles in insect development and metamorphosis. However, the biological function of Tre genes in Sogatella furcifera remains unclear. In the present study, two Tre genes—SfTre1 and SfTre2—were cloned and identified based on the S. furcifera transcriptome data. Bioinformatic analysis revealed that the full-length complementary DNA of SfTre1 and SfTre2 genes were 3700 and 2757 bp long, with 1728- and 1902-bp open reading frame encoding 575 and 633 amino acid residues, respectively. Expression analysis indicated that SfTre1 and SfTre2 were expressed at all developmental stages, with the highest expression in day two adults. Furthermore, the highest expression levels of SfTre1 and SfTre2 were observed in the ovary; enriched expression was also noted in head tissues. The knockdown of SfTre1 and SfTre2 via injecting double-stranded RNAs decreased the transcription levels of the corresponding mRNAs and led to various malformed phenotypes and high lethality rates. The results of our present study indicate that SfTre1 and SfTre2 play crucial roles in S. furcifera growth and development, which can provide referable information for Tre genes as a potential target for planthopper control. Full article

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20 pages, 2697 KiB

Open AccessArticle

Redox Regulation of Signaling Complex between Caveolin-1 and Neuronal Calcium Sensor Recoverin

by Vasiliy I. Vladimirov, Margarita P. Shchannikova, Alexey V. Baldin, Alexey S. Kazakov, Marina P. Shevelyova, Aliya A. Nazipova, Viktoriia E. Baksheeva, Ekaterina L. Nemashkalova, Anastasia S. Frolova, Natalia K. Tikhomirova, Pavel P. Philippov, Andrey A. Zamyatnin, Jr., Sergei E. Permyakov, Dmitry V. Zinchenko and Evgeni Yu. Zernii

Biomolecules 2022, 12(11), 1698; https://doi.org/10.3390/biom12111698 - 16 Nov 2022

Cited by 1 | Viewed by 1786

Abstract

Caveolin-1 is a cholesterol-binding scaffold protein, which is localized in detergent-resistant membrane (DRM) rafts and interacts with components of signal transduction systems, including visual cascade. Among these components are neuronal calcium sensors (NCSs), some of which are redox-sensitive proteins that respond to calcium [...] Read more.

Caveolin-1 is a cholesterol-binding scaffold protein, which is localized in detergent-resistant membrane (DRM) rafts and interacts with components of signal transduction systems, including visual cascade. Among these components are neuronal calcium sensors (NCSs), some of which are redox-sensitive proteins that respond to calcium signals by modulating the activity of multiple intracellular targets. Here, we report that the formation of the caveolin-1 complex with recoverin, a photoreceptor NCS serving as the membrane-binding regulator of rhodopsin kinase (GRK1), is a redox-dependent process. Biochemical and biophysical in vitro experiments revealed a two-fold decreased affinity of recoverin to caveolin-1 mutant Y14E mimicking its oxidative stress-induced phosphorylation of the scaffold protein. At the same time, wild-type caveolin-1 demonstrated a 5–10-fold increased affinity to disulfide dimer of recoverin (dRec) or its thiol oxidation mimicking the C39D mutant. The formation of dRec in vitro was not affected by caveolin-1 but was significantly potentiated by zinc, the well-known mediator of redox homeostasis. In the MDCK cell model, oxidative stress indeed triggered Y14 phosphorylation of caveolin-1 and disulfide dimerization of recoverin. Notably, oxidative conditions promoted the accumulation of phosphorylated caveolin-1 in the plasma membrane and the recruitment of recoverin to the same sites. Co-localization of these proteins was preserved upon depletion of intracellular calcium, i.e., under conditions reducing membrane affinity of recoverin but favoring its interaction with caveolin-1. Taken together, these data suggest redox regulation of the signaling complex between recoverin and caveolin-1. During oxidative stress, the high-affinity interaction of thiol-oxidized recoverin with caveolin-1/DRMs may disturb the light-induced translocation of the former within photoreceptors and affect rhodopsin desensitization. Full article

(This article belongs to the Special Issue Redox Regulation of Protein Functioning)

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21 pages, 5284 KiB

Open AccessArticle

Evaluating the Potential of Marine Invertebrate and Insect Protein Hydrolysates to Reduce Fetal Bovine Serum in Cell Culture Media for Cultivated Fish Production

by Inayat Batish, Mohammad Zarei, Nitin Nitin and Reza Ovissipour

Biomolecules 2022, 12(11), 1697; https://doi.org/10.3390/biom12111697 - 16 Nov 2022

Cited by 3 | Viewed by 2225

Abstract

The use of fetal bovine serum (FBS) and the price of cell culture media are the key constraints for developing serum-free cost-effective media. This study aims to replace or reduce the typical 10% serum application in fish cell culture media by applying protein [...] Read more.

The use of fetal bovine serum (FBS) and the price of cell culture media are the key constraints for developing serum-free cost-effective media. This study aims to replace or reduce the typical 10% serum application in fish cell culture media by applying protein hydrolysates from insects and marine invertebrate species for the growth of Zebrafish embryonic stem cells (ESC) as the model organism. Protein hydrolysates were produced from black soldier flies (BSF), crickets, oysters, mussels, and lugworms with a high protein content, suitable functional properties, and adequate amino-acid composition, with the degree of hydrolysis from 18.24 to 33.52%. Protein hydrolysates at low concentrations from 0.001 to 0.1 mg/mL in combination with 1 and 2.5% serums significantly increased cell growth compared to the control groups (5 and 10% serums) (p < 0.05). All protein hydrolysates with concentrations of 1 and 10 mg/mL were found to be toxic to cells and significantly reduced cell growth and performance (p < 0.05). However, except for crickets, all the hydrolysates were able to restore or significantly increase cell growth and viability with 50% less serum at concentrations of 0.001, 0.01, and 0.1 mg/mL. Although cell growth was enhanced at lower concentrations of protein hydrolysates, the cell morphology was altered due to the lack of serum. The lactate dehydrogenase (LDH) activity results indicated that BSF and lugworm hydrolysates did not alter the cell membrane. In addition, light and fluorescence imaging revealed that the cell morphological features were comparable to those of the 10% serum control group. Overall, lugworm and BSF hydrolysates reduced the serum by up to 90% while preserving excellent cell health. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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23 pages, 58767 KiB

Open AccessArticle

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

by Atteeque Ahmed, Mubashir Aziz, Syeda Abida Ejaz, Pervaiz Ali Channar, Aamer Saeed, Seema Zargar, Tanveer A. Wani, Asad Hamad, Qamar Abbas, Hussain Raza and Song Ja Kim

Biomolecules 2022, 12(11), 1696; https://doi.org/10.3390/biom12111696 - 16 Nov 2022

Cited by 7 | Viewed by 2036

Abstract

Carbonic anhydrases (CA), having Zn²⁺ metal atoms, are responsible for the catalysis of CO₂ and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including [...] Read more.

Carbonic anhydrases (CA), having Zn²⁺ metal atoms, are responsible for the catalysis of CO₂ and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (¹H, ¹³C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC₅₀ value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of −6.12, −6.99, and −6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged. Full article

(This article belongs to the Special Issue Redox Regulation of Protein Functioning)

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16 pages, 633 KiB

Open AccessArticle

Fatty Acids Profile and Antioxidant Properties of Raw Fermented Sausages with the Addition of Tomato Pomace

by Patrycja Skwarek and Małgorzata Karwowska

Biomolecules 2022, 12(11), 1695; https://doi.org/10.3390/biom12111695 - 16 Nov 2022

Cited by 4 | Viewed by 1763

Abstract

The aim of the study was to evaluate the effect of tomato pomace (TP) on physicochemical parameters and fatty acid profile as well as antioxidant properties of dry fermented sausages with a reduced content of nitrites. Four different sausage formulations were prepared: control [...] Read more.

The aim of the study was to evaluate the effect of tomato pomace (TP) on physicochemical parameters and fatty acid profile as well as antioxidant properties of dry fermented sausages with a reduced content of nitrites. Four different sausage formulations were prepared: control sample, and samples with 0.5%, 1% and 1.5% addition of freeze-dried TP. The sausages were analyzed for: chemical composition, pH and water activity, fatty acid profile, color parameters, biogenic content, and number of lactic acid bacteria and Enterobacteriacea. The antioxidant properties were also assessed depending on the amount of TP used. The products were characterized by similar water activity and pH in the range of 0.877–0.895 and 4.55–4.81, respectively. The effect of the addition of freeze-dried TP on an increase in antioxidant activity along with an increase in the concentration of the additive was observed. This phenomenon was most likely due to the strong antioxidant properties of tomato as well as the high content of lycopene. The antimicrobial properties of TP in raw fermented sausages were also noted as the product with the highest concentration of pomace had the lowest number of Enterobacteriaceae. In addition, sausages with reduced levels of nitrites to which TP was added were characterized by a higher redness, which will probably have a positive impact on the assessment consumers make of them. The most promising results were obtained for the dry fermented sausage with 1.5% addition of TP. Full article

(This article belongs to the Special Issue Lipids, Proteins and Bioactive Peptides in Food: A Themed Issue Dedicated to Dr. José M. Lorenzo)

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15 pages, 1544 KiB

Open AccessEditor’s ChoiceReview

Essential Components of Synthetic Infectious Prion Formation De Novo

by Kezia Jack, Graham S. Jackson and Jan Bieschke

Biomolecules 2022, 12(11), 1694; https://doi.org/10.3390/biom12111694 - 16 Nov 2022

Cited by 1 | Viewed by 2407

Abstract

Prion diseases are a class of neurodegenerative diseases that are uniquely infectious. Whilst their general replication mechanism is well understood, the components required for the formation and propagation of highly infectious prions are poorly characterized. The protein-only hypothesis posits that the prion protein [...] Read more.

Prion diseases are a class of neurodegenerative diseases that are uniquely infectious. Whilst their general replication mechanism is well understood, the components required for the formation and propagation of highly infectious prions are poorly characterized. The protein-only hypothesis posits that the prion protein (PrP) is the only component of the prion; however, additional co-factors are required for its assembly into infectious prions. These can be provided by brain homogenate, but synthetic lipids and non-coding RNA have also been used in vitro. Here, we review a range of experimental approaches, which generate PrP amyloid assemblies de novo. These synthetic PrP assemblies share some, but not necessarily all, properties of genuine infectious prions. We will discuss the different experimental approaches, how a prion is defined, the non-protein requirements of a prion, and provide an overview of the current state of prion amplification and generation in vitro. Full article

(This article belongs to the Special Issue Prions and Prion-Like Mechanisms in Disease and Biological Function)

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28 pages, 7143 KiB

Open AccessArticle

Genome-Wide RNA Sequencing of Human Trabecular Meshwork Cells Treated with TGF-β1: Relevance to Pseudoexfoliation Glaucoma

by Anton W. Roodnat, Breedge Callaghan, Chelsey Doyle, Megan Henry, Katarzyna Goljanek-Whysall, David A. Simpson, Carl Sheridan, Sarah D. Atkinson and Colin E. Willoughby

Biomolecules 2022, 12(11), 1693; https://doi.org/10.3390/biom12111693 - 15 Nov 2022

Cited by 7 | Viewed by 2635

Abstract

Pseudoexfoliation glaucoma (XFG) is an aggressive form of secondary open angle glaucoma, characterised by the production of exfoliation material and is estimated to affect 30 million people worldwide. Activation of the TGF-β pathway by TGF-β1 has been implicated in the pathogenesis of pseudoexfoliation [...] Read more.

Pseudoexfoliation glaucoma (XFG) is an aggressive form of secondary open angle glaucoma, characterised by the production of exfoliation material and is estimated to affect 30 million people worldwide. Activation of the TGF-β pathway by TGF-β1 has been implicated in the pathogenesis of pseudoexfoliation glaucoma. To further investigate the role of TGF-β1 in glaucomatous changes in the trabecular meshwork (TM), we used RNA-Seq to determine TGF-β1 induced changes in the transcriptome of normal human trabecular meshwork (HTM) cells. The main purpose of this study was to perform a hypothesis-independent RNA sequencing analysis to investigate genome-wide alterations in the transcriptome of normal HTMs stimulated with TGF-β1 and investigate possible pathophysiological mechanisms driving XFG. Our results identified multiple differentially expressed genes including several genes known to be present in exfoliation material. Significantly altered pathways, biological processes and molecular functions included extracellular matrix remodelling, Hippo and Wnt pathways, the unfolded protein response, oxidative stress, and the antioxidant system. This cellular model of pseudoexfoliation glaucoma can provide insight into disease pathogenesis and support the development of novel therapeutic interventions. Full article

(This article belongs to the Section Molecular Biology)

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Biomolecules, Volume 12, Issue 11 (November 2022) – 180 articles

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