Biomolecules

6 pages, 390 KiB

Open AccessEditorial

Bio-Based Formulations for Sustainable Applications in Agri-Food-Pharma

by Minaxi Sharma, Rajeev Bhat, Zeba Usmani, David Julian McClements, Pratyoosh Shukla, Vinay B. Raghavendra and Vijai Kumar Gupta

Biomolecules 2021, 11(5), 768; https://doi.org/10.3390/biom11050768 - 20 May 2021

Cited by 3 | Viewed by 2713

Abstract

Currently, there is a strong enduring interest towards obtaining high-value, sustainable bio-based bioactive compounds from natural resources, as there is great demand for these compounds in various market sectors such as agriculture, food, pharma, cosmeceuticals, and others [...] Full article

(This article belongs to the Special Issue Bioactive Formulations in Agri-Food-Pharma: Source and Applications)

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32 pages, 7848 KiB

Open AccessReview

Green Tea Epigallocatechin-3-gallate (EGCG) Targeting Protein Misfolding in Drug Discovery for Neurodegenerative Diseases

by Priscila Baltazar Gonçalves, Ana Carolina Rennó Sodero and Yraima Cordeiro

Biomolecules 2021, 11(5), 767; https://doi.org/10.3390/biom11050767 - 20 May 2021

Cited by 40 | Viewed by 8960

Abstract

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have [...] Read more.

The potential to treat neurodegenerative diseases (NDs) of the major bioactive compound of green tea, epigallocatechin-3-gallate (EGCG), is well documented. Numerous findings now suggest that EGCG targets protein misfolding and aggregation, a common cause and pathological mechanism in many NDs. Several studies have shown that EGCG interacts with misfolded proteins such as amyloid beta-peptide (Aβ), linked to Alzheimer’s disease (AD), and α-synuclein, linked to Parkinson’s disease (PD). To date, NDs constitute a serious public health problem, causing a financial burden for health care systems worldwide. Although current treatments provide symptomatic relief, they do not stop or even slow the progression of these devastating disorders. Therefore, there is an urgent need to develop effective drugs for these incurable ailments. It is expected that targeting protein misfolding can serve as a therapeutic strategy for many NDs since protein misfolding is a common cause of neurodegeneration. In this context, EGCG may offer great potential opportunities in drug discovery for NDs. Therefore, this review critically discusses the role of EGCG in NDs drug discovery and provides updated information on the scientific evidence that EGCG can potentially be used to treat many of these fatal brain disorders. Full article

(This article belongs to the Collection Natural and Synthetic Compounds in Neurodegenerative Disorders)

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12 pages, 493 KiB

Open AccessEditor’s ChoiceReview

Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?

by Courtney Griffiths, James Aikins, David Warshal and Olga Ostrovsky

Biomolecules 2021, 11(5), 766; https://doi.org/10.3390/biom11050766 - 20 May 2021

Cited by 13 | Viewed by 4549

Abstract

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. [...] Read more.

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound’s response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications. Full article

(This article belongs to the Special Issue Novel Indications of Epigenetic Therapy in Cancer)

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17 pages, 1325 KiB

Open AccessFeature PaperReview

Transient Receptor Potential (TRP) Channels in Haematological Malignancies: An Update

by Federica Maggi, Maria Beatrice Morelli, Massimo Nabissi, Oliviero Marinelli, Laura Zeppa, Cristina Aguzzi, Giorgio Santoni and Consuelo Amantini

Biomolecules 2021, 11(5), 765; https://doi.org/10.3390/biom11050765 - 20 May 2021

Cited by 7 | Viewed by 3232

Abstract

Transient receptor potential (TRP) channels are improving their importance in different cancers, becoming suitable as promising candidates for precision medicine. Their important contribution in calcium trafficking inside and outside cells is coming to light from many papers published so far. Encouraging results on [...] Read more.

Transient receptor potential (TRP) channels are improving their importance in different cancers, becoming suitable as promising candidates for precision medicine. Their important contribution in calcium trafficking inside and outside cells is coming to light from many papers published so far. Encouraging results on the correlation between TRP and overall survival (OS) and progression-free survival (PFS) in cancer patients are available, and there are as many promising data from in vitro studies. For what concerns haematological malignancy, the role of TRPs is still not elucidated, and data regarding TRP channel expression have demonstrated great variability throughout blood cancer so far. Thus, the aim of this review is to highlight the most recent findings on TRP channels in leukaemia and lymphoma, demonstrating their important contribution in the perspective of personalised therapies. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels: Markers and Therapeutic Targets for Cancer?)

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15 pages, 9207 KiB

Open AccessArticle

Lack of Conserved miRNA Deregulation in HPV-Induced Squamous Cell Carcinomas

by Jaroslav Nunvar, Lucie Pagacova, Zuzana Vojtechova, Nayara Trevisan Doimo de Azevedo, Jana Smahelova, Martina Salakova and Ruth Tachezy

Biomolecules 2021, 11(5), 764; https://doi.org/10.3390/biom11050764 - 20 May 2021

Cited by 5 | Viewed by 2480

Abstract

Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, [...] Read more.

Squamous cell carcinomas (SCCs) in the anogenital and head and neck regions are associated with high-risk types of human papillomaviruses (HR-HPV). Deregulation of miRNA expression is an important contributor to carcinogenesis. This study aimed to pinpoint commonly and uniquely deregulated miRNAs in cervical, anal, vulvar, and tonsillar tumors of viral or non-viral etiology, searching for a common set of deregulated miRNAs linked to HPV-induced carcinogenesis. RNA was extracted from tumors and nonmalignant tissues from the same locations. The miRNA expression level was determined by next-generation sequencing. Differential expression of miRNAs was calculated, and the patterns of miRNA deregulation were compared between tumors. The total of deregulated miRNAs varied between tumors of different locations by two orders of magnitude, ranging from 1 to 282. The deregulated miRNA pool was largely tumor-specific. In tumors of the same location, a low proportion of miRNAs were exclusively deregulated and no deregulated miRNA was shared by all four types of HPV-positive tumors. The most significant overlap of deregulated miRNAs was found between tumors which differed in location and HPV status (HPV-positive cervical tumors vs. HPV-negative vulvar tumors). Our results imply that HPV infection does not elicit a conserved miRNA deregulation in SCCs. Full article

(This article belongs to the Special Issue Non-coding RNAs in Cancer Diagnosis and Therapy)

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10 pages, 211 KiB

Open AccessArticle

Gene Polymorphisms of the Renin-Angiotensin-Aldosterone System as Risk Factors for the Development of In-Stent Restenosis in Patients with Stable Coronary Artery Disease

by Madina Azova, Kalima Timizheva, Amira Ait Aissa, Mikhail Blagonravov, Olga Gigani, Anna Aghajanyan and Leyla Tskhovrebova

Biomolecules 2021, 11(5), 763; https://doi.org/10.3390/biom11050763 - 20 May 2021

Cited by 13 | Viewed by 2540

Abstract

This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. [...] Read more.

This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. Patients were divided into two groups: with in-stent restenosis (ISR) and without it. The patients with ISR were classified into subgroups by the terms of the restenosis development and age. Real-time PCR and Restriction Fragment Length Polymorphism-PCR were used to genotype the study participants for RAAS gene polymorphisms. We found that the development of restenosis is generally associated with the minor A allele for renin (REN) rs2368564 and the major TT genotype for angiotensinogen (AGT) rs699. The heterozygous genotype for AGT rs4762 acts as a protective marker. A minor A allele for angiotensin II type 2 receptor (AGTR2) rs1403543 is associated with a risk of restenosis in people under 65 years old. Among patients with the early ISR, heterozygotes for angiotensin II type 1 receptor (AGTR1) rs5186 are more frequent, as well as A allele carriers for AGTR2 rs1403543. A minor homozygous genotype for REN rs41317140 and heterozygous genotype for aldosterone synthase (CYP11B2) rs1799998 are predisposed to the late restenosis. Thus, to choose the effective treatment tactics for patients with coronary artery disease, it is necessary to genotype patients for the RAAS polymorphisms, which, along with age and clinical characteristics, will allow a comprehensive assessment of the risk of the restenosis development after stenting. Full article

(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)

15 pages, 4183 KiB

Open AccessArticle

Thermal Properties and Structural Features of Multilayer Films Based on Chitosan and Anionic Polysaccharides

by Galina N. Gubanova, Valentina A. Petrova, Svetlana V. Kononova, Elena N. Popova, Valentina E. Smirnova, Alexander N. Bugrov, Vera V. Klechkovskaya and Yury A. Skorik

Biomolecules 2021, 11(5), 762; https://doi.org/10.3390/biom11050762 - 19 May 2021

Cited by 11 | Viewed by 2166

Abstract

This study investigates the thermal and structural properties of multilayer composites based on chitosan (CS) and polyanions with different functionalities, including sodium sulfoethyl cellulose (SEC), sodium alginate (ALG), and sodium hyaluronate (HA). Unlike polyelectrolyte complexes (PECs) obtained by polymer mixing, the formation of [...] Read more.

This study investigates the thermal and structural properties of multilayer composites based on chitosan (CS) and polyanions with different functionalities, including sodium sulfoethyl cellulose (SEC), sodium alginate (ALG), and sodium hyaluronate (HA). Unlike polyelectrolyte complexes (PECs) obtained by polymer mixing, the formation of a PEC layer by a process of layer-by-layer deposition of oppositely charged polymers is accompanied by the transformation of the CS polymorphic state, and this affects the relaxation and thermal properties of the resulting multilayer composite. X-ray diffraction analysis showed that the formation of the PEC layer in the CS/SEC multilayer film is accompanied by crystallization of the CS chains and the formation of a predominantly anhydrous CS modification. Thermogravimetric analysis of the CS/SEC film registers a high-temperature peak associated with the thermal decomposition of crystalline CS in the PEC composition. According to the dynamic mechanical analysis, the CS/SEC composite was characterized by a single glass transition temperature, indicating a strong interaction between the layers when using SEC (a strong acid salt) as the counterion to CS. For multilayer composites with weak polyacid salts (ALG and HA), the crystallization of CS in the PEC layer is weaker, as reflected in the thermal degradation of these films. A high-temperature peak is recorded in the thermal decomposition of CS/HA and is absent in the case of CS/ALG. Dynamic mechanical analysis of the CS/ALG composite showed two glass transition temperatures close to those of the original polymers, indicating weak PEC formation. The CS/HA composite showed an intermediate response. Thus, the effect of the PEC layer on the properties of the poly-layer composites decreases in the order CS/SEC > CS/HA > CS/ALG. Full article

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21 pages, 5637 KiB

Open AccessArticle

Potent Antimicrobial and Antibiofilm Activities of Feleucin-K3 Analogs Modified by α-(4-Pentenyl)-Ala against Multidrug-Resistant Bacteria

by Xiaomin Guo, Tiantian Yan, Jing Rao, Xin Yue, Xiong Pei, Jiahui Deng, Wangsheng Sun, Wenle Yang, Bangzhi Zhang and Junqiu Xie

Biomolecules 2021, 11(5), 761; https://doi.org/10.3390/biom11050761 - 19 May 2021

Cited by 7 | Viewed by 2365

Abstract

The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it [...] Read more.

The dramatic increase in antimicrobial resistance (AMR) highlights an urgent need to develop new antimicrobial therapies. Thus, antimicrobial peptides (AMPs) have emerged as promising novel antibiotic alternatives. Feleucin-K3 is an amphiphilic α-helical nonapeptide that has powerful antimicrobial activity. In our previous study, it was found that the fourth residue of Feleucin-K3 is important for antimicrobial activity. After α-(4-pentenyl)-Ala was introduced into this position, both the antimicrobial activity and stability were greatly improved. Herein, to improve the limitations of Feleucin-K3, this unnatural amino acid was further introduced into different positions of Feleucin-K3. Among these synthetic Feleucin-K3 analogs, the N-terminal-substituted analog Feleucin-K65 (K65) and C-terminal-substituted analog Feleucin-K70 (K70) had preferable antimicrobial activity. In particular, their antimicrobial activities against multidrug-resistant bacteria were more potent than that of antibiotics. The stabilities of these peptides in salt and serum environments were improved compared with those of Feleucin-K3. In addition, these analogs had low hemolytic activity and AMR. More importantly, they effectively inhibited biofilm formation and exhibited considerable efficacy compared with traditional antibiotics against biofilm infection caused by methicillin-resistant Staphylococcus aureus (MRSA). In antimicrobial mechanism studies, K65 and K70 mainly permeated the outer membrane and depolarized the cytoplasmic membrane, resulting in cellular component leakage and cell death. In summary, analogs K65 and K70 are potential antimicrobial alternatives to solve the antibiotic crisis. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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59 pages, 3408 KiB

Open AccessSystematic Review

A Systematic Review and Meta-Analyses of Interventional Clinical Trial Studies for Gene Therapies for the Inherited Retinal Degenerations (IRDs)

by Gearóid P. Tuohy and Roly Megaw

Biomolecules 2021, 11(5), 760; https://doi.org/10.3390/biom11050760 - 19 May 2021

Cited by 15 | Viewed by 4563

Abstract

IRDs are one of the leading causes of visual loss in children and young adults. Mutations in over 271 genes lead to retinal dysfunction, degeneration and sight loss. Though no cure exists, gene augmentation therapy has brought hope to the field. This systematic [...] Read more.

IRDs are one of the leading causes of visual loss in children and young adults. Mutations in over 271 genes lead to retinal dysfunction, degeneration and sight loss. Though no cure exists, gene augmentation therapy has brought hope to the field. This systematic review sought to assess the efficacy of available gene therapy treatments for IRDs. Databases and public resources were searched for randomised controlled trials (RCTs) and non-randomised studies of interventions (NRSIs). Standard methodological procedures were used, including a risk-of-bias assessment. One RCT and five NRSIs were assessed, all for adeno-associated virus two (AAV2)-mediated treatment of RPE-specific 65 kDa (RPE65)-associated LCA (Leber congenital amaurosis). Five outcomes were reported for meta-analyses. Modest improvements in visual acuity, ambulatory navigation/mobility testing or central retinal thickness was observed. There was significant improvement in red and blue light full-field stimulus testing (FST) (red light risk ratio of 1.89, treated v control, p = 0.04; and blue light risk ratio of 2.01, treated v control, p = 0.001). Study design assessment using a ROBIN-I tool (Cochrane Library) showed risk-of-bias judgement to be “low/moderate”, whilst there were “some concerns” for the RCT using a RoB-2 tool (Cochrane Library). Although comparison by meta-analysis is compromised by, amongst other issues, a variable amount of vector delivered in each trial, FST improvements demonstrate a proof-of-principle for treating IRDs with gene therapy. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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16 pages, 6840 KiB

Open AccessArticle

Mechanical Sensing Element PDLIM5 Promotes Osteogenesis of Human Fibroblasts by Affecting the Activity of Microfilaments

by Xiaolan Huang, Rongmei Qu, Yan Peng, Yuchao Yang, Tingyu Fan, Bing Sun, Asmat Ullah Khan, Shutong Wu, Kuanhai Wei, Chujiang Xu, Jingxing Dai, Jun Ouyang and Shizhen Zhong

Biomolecules 2021, 11(5), 759; https://doi.org/10.3390/biom11050759 - 19 May 2021

Cited by 4 | Viewed by 2300

Abstract

Human skin fibroblasts (HSFs) approximate the multidirectional differentiation potential of mesenchymal stem cells, so they are often used in differentiation, cell cultures, and injury repair. They are an important seed source in the field of bone tissue engineering. However, there are a few [...] Read more.

Human skin fibroblasts (HSFs) approximate the multidirectional differentiation potential of mesenchymal stem cells, so they are often used in differentiation, cell cultures, and injury repair. They are an important seed source in the field of bone tissue engineering. However, there are a few studies describing the mechanism of osteogenic differentiation of HSFs. Here, osteogenic induction medium was used to induce fibroblasts to differentiate into osteoblasts, and the role of the mechanical sensitive element PDLIM5 in microfilament-mediated osteogenic differentiation of human fibroblasts was evaluated. The depolymerization of microfilaments inhibited the expression of osteogenesis-related proteins and alkaline phosphatase activity of HSFs, while the polymerization of microfilaments enhanced the osteogenic differentiation of HSFs. The evaluation of potential protein molecules affecting changes in microfilaments showed that during the osteogenic differentiation of HSFs, the expression of PDLIM5 increased with increasing induction time, and decreased under the state of microfilament depolymerization. Lentivirus-mediated PDLIM5 knockdown by shRNA weakened the osteogenic differentiation ability of HSFs and inhibited the expression and morphological changes of microfilament protein. The inhibitory effect of knocking down PDLIM5 on HSF osteogenic differentiation was reversed by a microfilament stabilizer. Taken together, these data suggest that PDLIM5 can mediate the osteogenic differentiation of fibroblasts by affecting the formation and polymerization of microfilaments. Full article

(This article belongs to the Special Issue Stem Cell Applications in Tissue Repairing for Metabolic Disorders and Diseases Modeling, Drug Screening)

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11 pages, 640 KiB

Open AccessArticle

Age-Specific Excretion of Calcium, Oxalate, Citrate, and Glycosaminoglycans and Their Ratios in Healthy Children and Children with Urolithiasis

by Daniel Turudic, Anja Tea Golubic, Mila Lovric, Marko Bilic and Danko Milosevic

Biomolecules 2021, 11(5), 758; https://doi.org/10.3390/biom11050758 - 19 May 2021

Cited by 3 | Viewed by 1971

Abstract

We analyzed children with urolithiasis with age- and gender-matched healthy children. Calcium (mmol/mmol creatinine) and the calcium/citrate ratio (mol/mmol) are the only variables that differentiate children before puberty from healthy children (ROC analysis confirmed only calcium/citrate as a significant variable with cut-off value [...] Read more.

We analyzed children with urolithiasis with age- and gender-matched healthy children. Calcium (mmol/mmol creatinine) and the calcium/citrate ratio (mol/mmol) are the only variables that differentiate children before puberty from healthy children (ROC analysis confirmed only calcium/citrate as a significant variable with cut-off value > 0.84). Peri-pubertal children are distinguished from age- and gender-matched healthy children by the following variables: citrate (mmol/mol creatinine), calcium/citrate (mol/mmol), oxalate/glycosaminoglycans (mmol/g), oxalate/citrate ratios (mmol/mmol) and oxalate/(citrate × glycosaminoglycans) (mol oxalate × mol creatinine)/(mol citrate × g glycosaminoglycans). All variables were confirmed by ROC analysis with cut-off values ≤ 327.87, >1.02, >11.24, >0.12 and >0.03, respectively. These results indicate a different risk of urinary stones development before puberty vs. pubertal/postpubertal children and increasing importance (deficiency) of citrate and glycosaminoglycans in such children. J48 classifier confirmed the importance of the oxalate/(citrate × glycosaminoglycans) and the calcium/citrate ratios (Ox/Cit × GAG 0.22 and Cit/GAG 0.612) with the practically applicable classification tree for distinguishing between pubertal/postpubertal children with urolithiasis with age- and gender-matched healthy children. Full article

(This article belongs to the Special Issue Biomolecules in Development and Diseases of Urogenital System)

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10 pages, 919 KiB

Open AccessArticle

Protein–Protein Connections—Oligomer, Amyloid and Protein Complex—By Wide Line ¹H NMR

by Mónika Bokor and Ágnes Tantos

Biomolecules 2021, 11(5), 757; https://doi.org/10.3390/biom11050757 - 18 May 2021

Cited by 1 | Viewed by 2062

Abstract

The amount of bonds between constituting parts of a protein aggregate were determined in wild type (WT) and A53T α-synuclein (αS) oligomers, amyloids and in the complex of thymosin-β₄–cytoplasmic domain of stabilin-2 (Tβ₄-stabilin CTD). A53T αS aggregates have more [...] Read more.

The amount of bonds between constituting parts of a protein aggregate were determined in wild type (WT) and A53T α-synuclein (αS) oligomers, amyloids and in the complex of thymosin-β₄–cytoplasmic domain of stabilin-2 (Tβ₄-stabilin CTD). A53T αS aggregates have more extensive βsheet contents reflected by constant regions at low potential barriers in difference (to monomers) melting diagrams (MDs). Energies of the intermolecular interactions and of secondary structures bonds, formed during polymerization, fall into the 5.41 kJ mol⁻¹ ≤ E_a ≤ 5.77 kJ mol⁻¹ range for αS aggregates. Monomers lose more mobile hydration water while forming amyloids than oligomers. Part of the strong mobile hydration water–protein bonds break off and these bonding sites of the protein form intermolecular bonds in the aggregates. The new bonds connect the constituting proteins into aggregates. Amyloid–oligomer difference MD showed an overall more homogeneous solvent accessible surface of A53T αS amyloids. From the comparison of the nominal sum of the MDs of the constituting proteins to the measured MD of the Tβ₄-stabilin CTD complex, the number of intermolecular bonds connecting constituent proteins into complex is 20(1) H₂O/complex. The energies of these bonds are in the 5.40(3) kJ mol⁻¹ ≤ E_a ≤ 5.70(5) kJ mol⁻¹ range. Full article

(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases II)

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56 pages, 8166 KiB

Open AccessFeature PaperReview

Sweet Modifications Modulate Plant Development

by Tibo De Coninck, Koen Gistelinck, Henry C. Janse van Rensburg, Wim Van den Ende and Els J. M. Van Damme

Biomolecules 2021, 11(5), 756; https://doi.org/10.3390/biom11050756 - 18 May 2021

Cited by 13 | Viewed by 6558

Abstract

Plant development represents a continuous process in which the plant undergoes morphological, (epi)genetic and metabolic changes. Starting from pollination, seed maturation and germination, the plant continues to grow and develops specialized organs to survive, thrive and generate offspring. The development of plants and [...] Read more.

Plant development represents a continuous process in which the plant undergoes morphological, (epi)genetic and metabolic changes. Starting from pollination, seed maturation and germination, the plant continues to grow and develops specialized organs to survive, thrive and generate offspring. The development of plants and the interplay with its environment are highly linked to glycosylation of proteins and lipids as well as metabolism and signaling of sugars. Although the involvement of these protein modifications and sugars is well-studied, there is still a long road ahead to profoundly comprehend their nature, significance, importance for plant development and the interplay with stress responses. This review, approached from the plants’ perspective, aims to focus on some key findings highlighting the importance of glycosylation and sugar signaling for plant development. Full article

(This article belongs to the Section Cellular Biochemistry)

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20 pages, 1776 KiB

Open AccessReview

Epigenetic Insights and Potential Modifiers as Therapeutic Targets in β–Thalassemia

by Nur Atikah Zakaria, Md Asiful Islam, Wan Zaidah Abdullah, Rosnah Bahar, Abdul Aziz Mohamed Yusoff, Ridhwan Abdul Wahab, Shaharum Shamsuddin and Muhammad Farid Johan

Biomolecules 2021, 11(5), 755; https://doi.org/10.3390/biom11050755 - 18 May 2021

Cited by 13 | Viewed by 7185

Abstract

Thalassemia, an inherited quantitative globin disorder, consists of two types, α– and β–thalassemia. β–thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation [...] Read more.

Thalassemia, an inherited quantitative globin disorder, consists of two types, α– and β–thalassemia. β–thalassemia is a heterogeneous disease that can be asymptomatic, mild, or even severe. Considerable research has focused on investigating its underlying etiology. These studies found that DNA hypomethylation in the β–globin gene cluster is significantly related to fetal hemoglobin (HbF) elevation. Histone modification reactivates γ-globin gene expression in adults and increases β–globin expression. Down-regulation of γ–globin suppressor genes, i.e., BCL11A, KLF1, HBG-XMN1, HBS1L-MYB, and SOX6, elevates the HbF level. β–thalassemia severity is predictable through FLT1, ARG2, NOS2A, and MAP3K5 gene expression. NOS2A and MAP3K5 may predict the β–thalassemia patient’s response to hydroxyurea, a HbF-inducing drug. The transcription factors NRF2 and BACH1 work with antioxidant enzymes, i.e., PRDX1, PRDX2, TRX1, and SOD1, to protect erythrocytes from oxidative damage, thus increasing their lifespan. A single β–thalassemia-causing mutation can result in different phenotypes, and these are predictable by IGSF4 and LARP2 methylation as well as long non-coding RNA expression levels. Finally, the coinheritance of β–thalassemia with α–thalassemia ameliorates the β–thalassemia clinical presentation. In conclusion, the management of β–thalassemia is currently limited to genetic and epigenetic approaches, and numerous factors should be further explored in the future. Full article

(This article belongs to the Collection DNA Methylation Dynamics in Health and Disease)

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18 pages, 1678 KiB

Open AccessReview

Synthetic Biology towards Improved Flavonoid Pharmacokinetics

by Moon Sajid, Chaitanya N. Channakesavula, Shane R. Stone and Parwinder Kaur

Biomolecules 2021, 11(5), 754; https://doi.org/10.3390/biom11050754 - 18 May 2021

Cited by 26 | Viewed by 4789

Abstract

Flavonoids are a structurally diverse class of natural products that have been found to have a range of beneficial activities in humans. However, the clinical utilisation of these molecules has been limited due to their low solubility, chemical stability, bioavailability and extensive intestinal [...] Read more.

Flavonoids are a structurally diverse class of natural products that have been found to have a range of beneficial activities in humans. However, the clinical utilisation of these molecules has been limited due to their low solubility, chemical stability, bioavailability and extensive intestinal metabolism in vivo. Recently, the view has been formed that site-specific modification of flavonoids by methylation and/or glycosylation, processes that occur in plants endogenously, can be used to improve and adapt their biophysical and pharmacokinetic properties. The traditional source of flavonoids and their modified forms is from plants and is limited due to the low amounts present in biomass, intrinsic to the nature of secondary metabolite biosynthesis. Access to greater amounts of flavonoids, and understanding of the impact of modifications, requires a rethink in terms of production, more specifically towards the adoption of plant biosynthetic pathways into ex planta synthesis approaches. Advances in synthetic biology and metabolic engineering, aided by protein engineering and machine learning methods, offer attractive and exciting avenues for ex planta flavonoid synthesis. This review seeks to explore the applications of synthetic biology towards the ex planta biosynthesis of flavonoids, and how the natural plant methylation and glycosylation pathways can be harnessed to produce modified flavonoids with more favourable biophysical and pharmacokinetic properties for clinical use. It is envisaged that the development of viable alternative production systems for the synthesis of flavonoids and their methylated and glycosylated forms will help facilitate their greater clinical application. Full article

(This article belongs to the Special Issue Nucleic Acids: Applications in the Fields of Diagnostics, Therapeutics, Synthetic Biology, and Beyond)

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11 pages, 1541 KiB

Open AccessFeature PaperArticle

Povidone-Iodine Attenuates Viral Replication in Ocular Cells: Implications for Ocular Transmission of RNA Viruses

by Sneha Singh, Onkar B. Sawant, Shahzad I. Mian and Ashok Kumar

Biomolecules 2021, 11(5), 753; https://doi.org/10.3390/biom11050753 - 18 May 2021

Cited by 8 | Viewed by 3290

Abstract

Several RNA viruses, including SARS-CoV-2, can infect or use the eye as an entry portal to cause ocular or systemic diseases. Povidone-Iodine (PVP-I) is routinely used during ocular surgeries and eye banking as a cost-effective disinfectant due to its broad-spectrum antimicrobial activity, including against [...] Read more.

Several RNA viruses, including SARS-CoV-2, can infect or use the eye as an entry portal to cause ocular or systemic diseases. Povidone-Iodine (PVP-I) is routinely used during ocular surgeries and eye banking as a cost-effective disinfectant due to its broad-spectrum antimicrobial activity, including against viruses. However, whether PVP-I can exert antiviral activities in virus-infected cells remains elusive. In this study, using Zika (ZIKV) and Chikungunya (CHIKV) virus infection of human corneal and retinal pigment epithelial cells, we report antiviral mechanisms of PVP-I. Our data showed that PVP-I, even at the lowest concentration (0.01%), drastically reduced viral replication in corneal and retinal cells without causing cellular toxicity. Antiviral effects of PVP-I against ZIKV and CHIKV were mediated by direct viral inactivation, thus attenuating the ability of the virus to infect host cells. Moreover, one-minute PVP-I exposure of infected ocular cells drastically reduced viral replication and the production of infectious progeny virions. Furthermore, viral-induced (CHIKV) expression of inflammatory genes (TNF-α, IL-6, IL-8, and IL1β) were markedly reduced in PVP-I treated corneal epithelial cells. Together, our results demonstrate potent antiviral effects of PVP-I against ZIKV and CHIKV infection of ocular cells. Thus, a low dose of PVP-I can be used during tissue harvesting for corneal transplants to prevent potential transmission of RNA viruses via infected cells. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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18 pages, 3807 KiB

Open AccessEditor’s ChoiceArticle

Proton Detected Solid-State NMR of Membrane Proteins at 28 Tesla (1.2 GHz) and 100 kHz Magic-Angle Spinning

by Evgeny Nimerovsky, Kumar Tekwani Movellan, Xizhou Cecily Zhang, Marcel C. Forster, Eszter Najbauer, Kai Xue, Rıza Dervişoǧlu, Karin Giller, Christian Griesinger, Stefan Becker and Loren B. Andreas

Biomolecules 2021, 11(5), 752; https://doi.org/10.3390/biom11050752 - 18 May 2021

Cited by 37 | Viewed by 4676

Abstract

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided [...] Read more.

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided the sample preparation results in homogeneous broadening. We compare two-dimensional (2D) proton detected MAS NMR spectra of four membrane proteins at 950 and 1200 MHz. We find a consistent improvement in resolution that scales superlinearly with the increase in magnetic field for three of the four examples. In 3D and 4D spectra, which are now routinely acquired, this improvement indicates the ability to resolve at least 2 and 2.5 times as many signals, respectively. Full article

(This article belongs to the Special Issue Advances in Membrane Proteins 2021)

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20 pages, 3876 KiB

Open AccessFeature PaperArticle

Paternal High-Protein Diet Programs Offspring Insulin Sensitivity in a Sex-Specific Manner

by Pengfei Gong, Danielle Bailbé, Lola Bianchi, Gaëlle Pommier, Junjun Liu, Stefania Tolu, Maria G. Stathopoulou, Bernard Portha, Valérie Grandjean and Jamileh Movassat

Biomolecules 2021, 11(5), 751; https://doi.org/10.3390/biom11050751 - 18 May 2021

Cited by 7 | Viewed by 2654

Abstract

The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas [...] Read more.

The impact of maternal nutrition on offspring is well documented. However, the implication of pre-conceptional paternal nutrition on the metabolic health of the progeny remains underexplored. Here, we investigated the impact of paternal high-protein diet (HPD, 43.2% protein) consumption on the endocrine pancreas and the metabolic phenotype of offspring. Male Wistar rats were given HPD or standard diet (SD, 18.9% protein) for two months. The progenies (F1) were studied at fetal stage and in adulthood. Body weight, glycemia, glucose tolerance (GT), glucose-induced insulin secretion in vivo (GIIS) and whole-body insulin sensitivity were assessed in male and female F1 offspring. Insulin sensitivity, GT and GIIS were similar between F1 females from HPD (HPD/F1) and SD fathers (SD/F1). Conversely, male HPD/F1 exhibited increased insulin sensitivity (p < 0.05) and decreased GIIS (p < 0.05) compared to male SD/F1. The improvement of insulin sensitivity in HPD/F1 was sustained even after 2 months of high-fat feeding. In male HPD/F1, the β cell mass was preserved and the β cell plasticity, following metabolic challenge, was enhanced compared to SD/F1. In conclusion, we provide the first evidence of a sex-specific impact of paternal HPD on the insulin sensitivity and GIIS of their descendants, demonstrating that changes in paternal nutrition alter the metabolic status of their progeny in adulthood. Full article

(This article belongs to the Special Issue Early-Life Programming of Metabolic Diseases)

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14 pages, 571 KiB

Open AccessReview

Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

by Kiyohiro Ando and Akira Nakagawara

Biomolecules 2021, 11(5), 750; https://doi.org/10.3390/biom11050750 - 18 May 2021

Cited by 9 | Viewed by 2894

Abstract

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to [...] Read more.

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas. Full article

(This article belongs to the Special Issue Molecular and Biological Enigma of Neuroblastoma: How to Solve It?)

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16 pages, 9809 KiB

Open AccessFeature PaperArticle

Magnetic Field Alignment, a Perspective in the Engineering of Collagen-Silica Composite Biomaterials

by Nicolas Debons, Kenta Matsumoto, Noriyuki Hirota, Thibaud Coradin, Toshiyuki Ikoma and Carole Aimé

Biomolecules 2021, 11(5), 749; https://doi.org/10.3390/biom11050749 - 18 May 2021

Cited by 6 | Viewed by 2617

Abstract

Major progress in the field of regenerative medicine is expected from the design of artificial scaffolds that mimic both the structural and functional properties of the ECM. The bionanocomposites approach is particularly well fitted to meet this challenge as it can combine ECM-based [...] Read more.

Major progress in the field of regenerative medicine is expected from the design of artificial scaffolds that mimic both the structural and functional properties of the ECM. The bionanocomposites approach is particularly well fitted to meet this challenge as it can combine ECM-based matrices and colloidal carriers of biological cues that regulate cell behavior. Here we have prepared bionanocomposites under high magnetic field from tilapia fish scale collagen and multifunctional silica nanoparticles (SiNPs). We show that scaffolding cues (collagen), multiple display of signaling peptides (SiNPs) and control over the global structuration (magnetic field) can be combined into a unique bionanocomposite for the engineering of biomaterials with improved cell performances. Full article

(This article belongs to the Special Issue Bionanocomposites)

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12 pages, 1233 KiB

Open AccessArticle

Impact of Venoarterial Extracorporeal Membrane Oxygenation on Alkaline Phosphatase Metabolism after Cardiac Surgery

by Thomas Poschner, Anne-Kristin Schaefer, Doris Hutschala, Georg Goliasch, Julia Riebandt, Klaus Distelmaier, Martin H. Bernardi, Martin Andreas, Ruud Brands, Tandis Aref, Günther Laufer and Dominik Wiedemann

Biomolecules 2021, 11(5), 748; https://doi.org/10.3390/biom11050748 - 17 May 2021

Cited by 1 | Viewed by 1929

Abstract

(1) Alkaline phosphatase (AP) is consumed during cardiopulmonary bypass (CPB). A high AP depletion leads to an impaired outcome after cardiac surgery. However, data is scarce on the postoperative course of AP under venoarterial ECMO (VA-ECMO) support. (2) A total of 239 patients [...] Read more.

(1) Alkaline phosphatase (AP) is consumed during cardiopulmonary bypass (CPB). A high AP depletion leads to an impaired outcome after cardiac surgery. However, data is scarce on the postoperative course of AP under venoarterial ECMO (VA-ECMO) support. (2) A total of 239 patients with VA-ECMO support between 2000 and 2019 at the Department of Cardiac Surgery (Vienna General Hospital, Austria) were included in this retrospective analysis. Blood samples were collected at several timepoints (baseline, postoperative day (POD) 1–7, POD 14 and 30). Patients were categorized according to the relative AP drop (<60% vs. ≥60%) and ECMO duration (<5 days vs. ≥5 days). (3) Overall, 44.4% reached the baseline AP values within 5 days—this was only the case for 28.6% with a higher AP drop (compared to 62.7% with a lower drop; p = 0.000). A greater AP drop was associated with a significantly higher need for renal replacement therapy (40.9% vs. 61.9%; p = 0.002) and an impaired 1-year survival (51.4% vs. 66.0%; p = 0.031). (4) CPB exceeds the negative impact of VA-ECMO; still, ECMO seems to delay alkaline phosphatase recovery. A greater initial AP drop bears the risk of higher morbidity and mortality. Full article

(This article belongs to the Special Issue Exogenous and Endogenous Alkaline Phosphatase in Health and Disease)

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15 pages, 1145 KiB

Open AccessReview

Role of Biomolecules in Osteoclasts and Their Therapeutic Potential for Osteoporosis

by Xin Zhao, Suryaji Patil, Fang Xu, Xiao Lin and Airong Qian

Biomolecules 2021, 11(5), 747; https://doi.org/10.3390/biom11050747 - 17 May 2021

Cited by 16 | Viewed by 3371

Abstract

Osteoclasts (OCs) are important cells that are involved in the regulation of bone metabolism and are mainly responsible for coordinating bone resorption with bone formation to regulate bone remodeling. The imbalance between bone resorption and formation significantly affects bone metabolism. When the activity [...] Read more.

Osteoclasts (OCs) are important cells that are involved in the regulation of bone metabolism and are mainly responsible for coordinating bone resorption with bone formation to regulate bone remodeling. The imbalance between bone resorption and formation significantly affects bone metabolism. When the activity of osteoclasts exceeds the osteoblasts, it results in a condition called osteoporosis, which is characterized by reduced bone microarchitecture, decreased bone mass, and increased occurrences of fracture. Molecules, including transcription factors, proteins, hormones, nucleic acids, such as non-coding RNAs, play an important role in osteoclast proliferation, differentiation, and function. In this review, we have highlighted the role of these molecules in osteoclasts regulation and osteoporosis. The developed therapeutics targeting these molecules for the treatment of osteoporosis in recent years have also been discussed with challenges faced in clinical application. Full article

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20 pages, 4523 KiB

Open AccessEditor’s ChoiceArticle

Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumatic Tripterygium wilfordii Glycosides

by Kehong Zhang, Simona Pace, Paul M. Jordan, Lukas K. Peltner, Alexander Weber, Dagmar Fischer, Robert K. Hofstetter, Xinchun Chen and Oliver Werz

Biomolecules 2021, 11(5), 746; https://doi.org/10.3390/biom11050746 - 17 May 2021

Cited by 9 | Viewed by 2901

Abstract

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation [...] Read more.

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC₅₀ = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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14 pages, 1319 KiB

Open AccessArticle

Antimicrobial Activity of Cyclic-Monomeric and Dimeric Derivatives of the Snail-Derived Peptide Cm-p5 against Viral and Multidrug-Resistant Bacterial Strains

by Melaine González-García, Fidel Morales-Vicente, Erbio Díaz Pico, Hilda Garay, Daniel G. Rivera, Mark Grieshober, Lia Raluca Olari, Rüdiger Groß, Carina Conzelmann, Franziska Krüger, Fabian Zech, Caterina Prelli Bozzo, Janis A. Müller, Alexander Zelikin, Heinz Raber, Dennis Kubiczek, Frank Rosenau, Jan Münch, Steffen Stenger, Barbara Spellerberg, Octavio L. Franco, Armando A. Rodriguez Alfonso, Ludger Ständker and Anselmo J. Otero-Gonzalez Show full author list Hide full author list

Biomolecules 2021, 11(5), 745; https://doi.org/10.3390/biom11050745 - 17 May 2021

Cited by 7 | Viewed by 2902

Abstract

Cm-p5 is a snail-derived antimicrobial peptide, which demonstrated antifungal activity against the pathogenic strains of Candida albicans. Previously we synthetized a cyclic monomer as well as a parallel and an antiparallel dimer of Cm-p5 with improved antifungal activity. Considering the alarming increase [...] Read more.

Cm-p5 is a snail-derived antimicrobial peptide, which demonstrated antifungal activity against the pathogenic strains of Candida albicans. Previously we synthetized a cyclic monomer as well as a parallel and an antiparallel dimer of Cm-p5 with improved antifungal activity. Considering the alarming increase of microbial resistance to conventional antibiotics, here we evaluated the antimicrobial activity of these derivatives against multiresistant and problematic bacteria and against important viral agents. The three peptides showed a moderate activity against Pseudomonas aeruginosa, Klebsiella pneumoniae Extended Spectrum β-Lactamase (ESBL), and Streptococcus agalactiae, with MIC values > 100 µg/mL. They exerted a considerable activity with MIC values between 25–50 µg/mL against Acinetobacter baumanii and Enterococcus faecium. In addition, the two dimers showed a moderate activity against Pseudomonas aeruginosa PA14. The three Cm-p5 derivatives inhibited a virulent extracellular strain of Mycobacterium tuberculosis, in a dose-dependent manner. Moreover, they inhibited Herpes Simplex Virus 2 (HSV-2) infection in a concentration-dependent manner, but had no effect on infection by the Zika Virus (ZIKV) or pseudoparticles of Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2). At concentrations of >100 µg/mL, the three new Cm-p5 derivatives showed toxicity on different eukaryotic cells tested. Considering a certain cell toxicity but a potential interesting activity against the multiresistant strains of bacteria and HSV-2, our compounds require future structural optimization. Full article

(This article belongs to the Section Natural and Bio-inspired Molecules)

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10 pages, 999 KiB

Open AccessEditor’s ChoiceArticle

Plasma Extracellular Vesicle α-Synuclein Level in Patients with Parkinson’s Disease

by Chen-Chih Chung, Lung Chan, Jia-Hung Chen, Yi-Chieh Hung and Chien-Tai Hong

Biomolecules 2021, 11(5), 744; https://doi.org/10.3390/biom11050744 - 17 May 2021

Cited by 13 | Viewed by 2790

Abstract

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) [...] Read more.

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood–brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Methods: Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction–based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Results: Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson’s Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Conclusion: Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein’s clinical relevance and feasibility as a PD biomarker. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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14 pages, 2903 KiB

Open AccessArticle

Characterising the Response of Human Breast Cancer Cells to Polyamine Modulation

by Oluwaseun Akinyele and Heather M. Wallace

Biomolecules 2021, 11(5), 743; https://doi.org/10.3390/biom11050743 - 17 May 2021

Cited by 10 | Viewed by 2994

Abstract

Breast cancer is a complex heterogeneous disease with multiple underlying causes. The polyamines putrescine, spermidine, and spermine are polycationic molecules essential for cell proliferation. Their biosynthesis is upregulated in breast cancer and they contribute to disease progression. While elevated polyamines are linked to [...] Read more.

Breast cancer is a complex heterogeneous disease with multiple underlying causes. The polyamines putrescine, spermidine, and spermine are polycationic molecules essential for cell proliferation. Their biosynthesis is upregulated in breast cancer and they contribute to disease progression. While elevated polyamines are linked to breast cancer cell proliferation, there is little evidence to suggest breast cancer cells of different hormone receptor status are equally dependent on polyamines. In this study, we characterized the responses of two breast cancer cells, ER+ (oestrogen receptor positive) MCF-7 and ER- MDA-MB-231 cell lines, to polyamine modulation and determined the requirement of each polyamine for cancer cell growth. The cells were exposed to DFMO (a polyamine pathway inhibitor) at various concentrations under different conditions, after which several growth parameters were determined. Exposure of both cell lines to DFMO induced differential growth responses, MCF-7 cells showed greater sensitivity to polyamine pathway inhibition at various DFMO concentrations than the MDA-MB-231 cells. Analysis of intracellular DFMO after withdrawal from growth medium showed residual DFMO in the cells with concomitant decreases in polyamine content, ODC protein level, and cell growth. Addition of exogenous polyamines reversed the cell growth inhibition, and this growth recovery appears to be partly dependent on the spermidine content of the cell. Similarly, DFMO exposure inhibits the global translation state of the cells, with spermidine addition reversing the inhibition of translation in the breast cancer cells. Taken together, these data suggest that breast cancer cells are differentially sensitive to the antitumour effects of polyamine depletion, thus, targeting polyamine metabolism might be therapeutically beneficial in breast cancer management based on their subtype. Full article

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11 pages, 1187 KiB

Open AccessArticle

L-Proline Activates Mammalian Target of Rapamycin Complex 1 and Modulates Redox Environment in Porcine Trophectoderm Cells

by Ning Liu, Ying Yang, Xuemeng Si, Hai Jia, Yunchang Zhang, Da Jiang, Zhaolai Dai and Zhenlong Wu

Biomolecules 2021, 11(5), 742; https://doi.org/10.3390/biom11050742 - 17 May 2021

Cited by 9 | Viewed by 2602

Abstract

L-proline (proline) is a key regulator of embryogenesis, placental development, and fetal growth. However, the underlying mechanisms that support the beneficial effects of proline are largely unknown. This study used porcine trophectoderm cell line 2 (pTr2) to investigate the underlying mechanisms of proline [...] Read more.

L-proline (proline) is a key regulator of embryogenesis, placental development, and fetal growth. However, the underlying mechanisms that support the beneficial effects of proline are largely unknown. This study used porcine trophectoderm cell line 2 (pTr2) to investigate the underlying mechanisms of proline in cell proliferation and redox homeostasis. Cells were cultured in the presence of 0, 0.25, 0.50, or 1.0 mmol/L proline for an indicated time. The results showed that 0.5 and 1.0 mmol/L proline enhanced cell viability. These effects of proline (0.5 mmol/L) were accompanied by the enhanced protein abundance of p-mTORC1, p-p70S6K, p-S6, and p-4E-BP1. Additionally, proline dose-dependently enhanced the mRNA expression of proline transporters [solute carrier family (SLC) 6A20, SLC36A1, SLC36A2, SLC38A1, and SLC38A2], elevated proline concentration, and protein abundance of proline dehydrogenase (PRODH). Furthermore, proline addition (0.25 or 0.5 mmol/L) resulted in lower abundance of p-AMPKα when compared with a control. Of note, proline resulted in lower reactive oxygen species (ROS) level, upregulated mRNA expression of the catalytic subunit of glutamate–cysteine ligase (GCLC) and glutathione synthetase (GSS), as well as enhanced total (T)-GSH and GSH concentration when compared with a control. These data indicated that proline activates themTORC1 signaling and modulates the intracellular redox environment via enhancing proline transport. Full article

(This article belongs to the Section Molecular Biology)

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3 pages, 180 KiB

Open AccessEditorial

Recent Advances in the Bacterial Flagellar Motor Study

by Tohru Minamino and Keiichi Namba

Biomolecules 2021, 11(5), 741; https://doi.org/10.3390/biom11050741 - 17 May 2021

Viewed by 2236

Abstract

The bacterial flagellum is a supramolecular motility machine that allows bacterial cells to swim in liquid environments [...] Full article

(This article belongs to the Special Issue Perspectives on Bacterial Flagellar Motor)

10 pages, 2731 KiB

Open AccessArticle

Evaluating Mechanisms of IDH1 Regulation through Site-Specific Acetylation Mimics

by Joi Weeks, Alexandra I. Strom, Vinnie Widjaja, Sati Alexander, Dahra K. Pucher and Christal D. Sohl

Biomolecules 2021, 11(5), 740; https://doi.org/10.3390/biom11050740 - 16 May 2021

Cited by 3 | Viewed by 2355

Abstract

Isocitrate dehydrogenase (IDH1) catalyzes the reversible NADP⁺-dependent oxidation of isocitrate to α-ketoglutarate (αKG). IDH1 mutations, primarily R132H, drive > 80% of low-grade gliomas and secondary glioblastomas and facilitate the NADPH-dependent reduction of αKG to the oncometabolite D-2-hydroxyglutarate (D2HG). While the biochemical [...] Read more.

Isocitrate dehydrogenase (IDH1) catalyzes the reversible NADP⁺-dependent oxidation of isocitrate to α-ketoglutarate (αKG). IDH1 mutations, primarily R132H, drive > 80% of low-grade gliomas and secondary glioblastomas and facilitate the NADPH-dependent reduction of αKG to the oncometabolite D-2-hydroxyglutarate (D2HG). While the biochemical features of human WT and mutant IDH1 catalysis have been well-established, considerably less is known about mechanisms of regulation. Proteomics studies have identified lysine acetylation in WT IDH1, indicating post-translational regulation. Here, we generated lysine to glutamine acetylation mimic mutants in IDH1 to evaluate the effects on activity. We show that mimicking lysine acetylation decreased the catalytic efficiency of WT IDH1, with less severe catalytic consequences for R132H IDH1. Full article

(This article belongs to the Section Cellular Biochemistry)

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22 pages, 5131 KiB

Open AccessEditor’s ChoiceReview

A Bittersweet Computational Journey among Glycosaminoglycans

by Giulia Paiardi, Maria Milanesi, Rebecca C. Wade, Pasqualina D’Ursi and Marco Rusnati

Biomolecules 2021, 11(5), 739; https://doi.org/10.3390/biom11050739 - 15 May 2021

Cited by 10 | Viewed by 3687

Abstract

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of [...] Read more.

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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