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Biomolecules
Volume 12
Issue 7
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Biomolecules, Volume 12, Issue 7 (July 2022) – 152 articles

Cover Story (view full-size image): Galactosemia is a rare autosomal recessive metabolic disease, potentially lethal, that affects the body’s ability to metabolize galactose, a sugar found mainly in milk. Several countries have recently introduced galactosemia into their newborn screening programs. There are four types of galactosemia, depending on which enzyme of the Leloir pathway does not work. In recent years, various therapeutic approaches have been studied to provide better treatment, such as gene-based therapies and small molecules. View this paper
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19 pages, 9530 KiB  
Article
Fewer Dimensions, More Structures for Improved Discrete Models of Dynamics of Free versus Antigen-Bound Antibody
by Kazi Lutful Kabir, Buyong Ma, Ruth Nussinov and Amarda Shehu
Biomolecules 2022, 12(7), 1011; https://doi.org/10.3390/biom12071011 - 21 Jul 2022
Cited by 3 | Viewed by 1692
Abstract
Over the past decade, Markov State Models (MSM) have emerged as powerful methodologies to build discrete models of dynamics over structures obtained from Molecular Dynamics trajectories. The identification of macrostates for the MSM is a central decision that impacts the quality of the [...] Read more.
Over the past decade, Markov State Models (MSM) have emerged as powerful methodologies to build discrete models of dynamics over structures obtained from Molecular Dynamics trajectories. The identification of macrostates for the MSM is a central decision that impacts the quality of the MSM but depends on both the selected representation of a structure and the clustering algorithm utilized over the featurized structures. Motivated by a large molecular system in its free and bound state, this paper investigates two directions of research, further reducing the representation dimensionality in a non-parametric, data-driven manner and including more structures in the computation. Rigorous evaluation of the quality of obtained MSMs via various statistical tests in a comparative setting firmly shows that fewer dimensions and more structures result in a better MSM. Many interesting findings emerge from the best MSM, advancing our understanding of the relationship between antibody dynamics and antibody–antigen recognition. Full article
(This article belongs to the Special Issue Protein Modeling and Simulation: Selected articles from the Computational Structural Bioinformatics Workshop 2021)
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13 pages, 703 KiB  
Review
The Role of Pyroptosis and Autophagy in Ischemia Reperfusion Injury
by Huijie Zhao, Yihan Yang, Xinya Si, Huiyang Liu and Honggang Wang
Biomolecules 2022, 12(7), 1010; https://doi.org/10.3390/biom12071010 - 21 Jul 2022
Cited by 11 | Viewed by 3543
Abstract
Pyroptosis is a process of programmed cell death mediated by gasdermin (GSDM) found in recent years. In the process of pyroptosis, caspase-1 or caspase-11/4/5 is activated, which cleaves gasdermin D and separates its N-terminal pore-forming domain (PFD). The oligomers of PFD bind to [...] Read more.
Pyroptosis is a process of programmed cell death mediated by gasdermin (GSDM) found in recent years. In the process of pyroptosis, caspase-1 or caspase-11/4/5 is activated, which cleaves gasdermin D and separates its N-terminal pore-forming domain (PFD). The oligomers of PFD bind to the cell membrane and form macropores on the membrane, resulting in cell swelling and membrane rupture. Increasing evidence indicates that pyroptosis is involved in many diseases, including ischemia reperfusion injury. Autophagy is a highly conserved catabolic process in eukaryotic cells. It plays an important role in the survival and maintenance of cells by degrading organelles, proteins, and macromolecules in the cytoplasm and recycling degradation products. Increasing evidence shows that dysfunctional autophagy participates in many diseases. Recently, autophagy and pyroptosis have been reported to play a vital role in the process of ischemia/reperfusion injury, but the related mechanisms are not completely clear. Therefore, this article reviews the role of autophagy and pyroptosis in ischemia–reperfusion injury and analyzes the related mechanisms to provide a basis for future research. Full article
(This article belongs to the Section Molecular Biology)
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28 pages, 4278 KiB  
Review
Molecular Basis of Rare Diseases Associated to the Maturation of Mitochondrial [4Fe-4S]-Containing Proteins
by Francesca Camponeschi, Simone Ciofi-Baffoni, Vito Calderone and Lucia Banci
Biomolecules 2022, 12(7), 1009; https://doi.org/10.3390/biom12071009 - 21 Jul 2022
Cited by 8 | Viewed by 2177
Abstract
The importance of mitochondria in mammalian cells is widely known. Several biochemical reactions and pathways take place within mitochondria: among them, there are those involving the biogenesis of the iron–sulfur (Fe-S) clusters. The latter are evolutionarily conserved, ubiquitous inorganic cofactors, performing a variety [...] Read more.
The importance of mitochondria in mammalian cells is widely known. Several biochemical reactions and pathways take place within mitochondria: among them, there are those involving the biogenesis of the iron–sulfur (Fe-S) clusters. The latter are evolutionarily conserved, ubiquitous inorganic cofactors, performing a variety of functions, such as electron transport, enzymatic catalysis, DNA maintenance, and gene expression regulation. The synthesis and distribution of Fe-S clusters are strictly controlled cellular processes that involve several mitochondrial proteins that specifically interact each other to form a complex machinery (Iron Sulfur Cluster assembly machinery, ISC machinery hereafter). This machinery ensures the correct assembly of both [2Fe-2S] and [4Fe-4S] clusters and their insertion in the mitochondrial target proteins. The present review provides a structural and molecular overview of the rare diseases associated with the genes encoding for the accessory proteins of the ISC machinery (i.e., GLRX5, ISCA1, ISCA2, IBA57, FDX2, BOLA3, IND1 and NFU1) involved in the assembly and insertion of [4Fe-4S] clusters in mitochondrial proteins. The disease-related missense mutations were mapped on the 3D structures of these accessory proteins or of their protein complexes, and the possible impact that these mutations have on their specific activity/function in the frame of the mitochondrial [4Fe-4S] protein biogenesis is described. Full article
(This article belongs to the Special Issue Insights in the Structure and Functions of Mitochondrial Proteins and Metalloproteins)
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16 pages, 2609 KiB  
Article
Mitochondria Transfer from Adipose Stem Cells Improves the Developmental Potential of Cryopreserved Oocytes
by Udayanga Sanath Kankanam Gamage, Shu Hashimoto, Yuki Miyamoto, Tatsuya Nakano, Masaya Yamanaka, Akiko Koike, Manabu Satoh and Yoshiharu Morimoto
Biomolecules 2022, 12(7), 1008; https://doi.org/10.3390/biom12071008 - 21 Jul 2022
Cited by 4 | Viewed by 2349
Abstract
Although it is not a well-established technology, oocyte cryopreservation is becoming prevalent in assisted reproductive technologies in response to the growing demands of patients’ sociological and pathological conditions. Oocyte cryopreservation can adversely affect the developmental potential of oocytes by causing an increase in [...] Read more.
Although it is not a well-established technology, oocyte cryopreservation is becoming prevalent in assisted reproductive technologies in response to the growing demands of patients’ sociological and pathological conditions. Oocyte cryopreservation can adversely affect the developmental potential of oocytes by causing an increase in intracellular oxidative stresses and damage to the mitochondrial structure. In this study, we studied whether autologous adipose stem cell (ASC) mitochondria supplementation with vitrified and warmed oocytes could restore post-fertilization development that decreased due to mitochondrial damage following cryopreservation. ASC mitochondria showed similar morphology to oocytes’ mitochondria and had a higher ATP production capacity. The vitrified-warmed oocytes from juvenile mice were supplemented with ASC mitochondria at the same time as intracellular sperm injection (ICSI), after which we compared their developmental capacity and the mitochondria quality of 2-cell embryos. We found that, compared to their counterpart, mitochondria supplementation significantly improved development from 2-cell embryos to blastocysts (56.8% vs. 38.2%) and ATP production in 2-cell embryos (905.6 & 561.1 pmol), while reactive oxygen species levels were comparable. With these results, we propose that ASC mitochondria supplementation could restore the quality of cryopreserved oocytes and enhance the embryo developmental capacity, signifying another possible approach for mitochondrial transplantation therapy. Full article
(This article belongs to the Special Issue State-of-the-Art Molecular Reproduction in Japan)
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16 pages, 3480 KiB  
Review
Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy
by Fan Yang, Zhigang Hu and Zhigang Guo
Biomolecules 2022, 12(7), 1007; https://doi.org/10.3390/biom12071007 - 20 Jul 2022
Cited by 15 | Viewed by 3927
Abstract
DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in [...] Read more.
DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in the regulation of other DNA repair pathways, including homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Abnormal expression or mutation of FEN1 in cells can cause a series of pathological responses, leading to various diseases, including cancers. Moreover, overexpression of FEN1 contributes to drug resistance in several types of cancers. All this supports the hypothesis that FEN1 could be a therapeutic target for cancer treatment. Targeting FEN1 has been verified as an effective strategy in mono or combined treatment of cancer. Small-molecule compounds targeting FEN1 have also been developed and detected in cancer regression. In this review, we summarize the recent development of small-molecule inhibitors targeting FEN1 in recent years, thereby expanding their therapeutic potential and application. Full article
(This article belongs to the Special Issue Pharmacokinetics, Pharmacodynamics, and Toxicology of Small-Molecule Drugs and Nanomedicine)
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17 pages, 27079 KiB  
Article
Immunohistochemical Demonstration of the pGlu79 α-Synuclein Fragment in Alzheimer’s Disease and Its Tg2576 Mouse Model
by Alexandra Bluhm, Sarah Schrempel, Stephan Schilling, Stephan von Hörsten, Anja Schulze, Steffen Roßner and Maike Hartlage-Rübsamen
Biomolecules 2022, 12(7), 1006; https://doi.org/10.3390/biom12071006 - 20 Jul 2022
Cited by 2 | Viewed by 2322
Abstract
The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead [...] Read more.
The deposition of β-amyloid peptides and of α-synuclein proteins is a neuropathological hallmark in the brains of Alzheimer’s disease (AD) and Parkinson’s disease (PD) subjects, respectively. However, there is accumulative evidence that both proteins are not exclusive for their clinical entity but instead co-exist and interact with each other. Here, we investigated the presence of a newly identified, pyroglutamate79-modified α-synuclein variant (pGlu79-aSyn)—along with the enzyme matrix metalloproteinase-3 (MMP-3) and glutaminyl cyclase (QC) implicated in its formation—in AD and in the transgenic Tg2576 AD mouse model. In the human brain, pGlu79-aSyn was detected in cortical pyramidal neurons, with more distinct labeling in AD compared to control brain tissue. Using immunohistochemical double and triple labelings and confocal laser scanning microscopy, we demonstrate an association of pGlu79-aSyn, MMP-3 and QC with β-amyloid plaques. In addition, pGlu79-aSyn and QC were present in amyloid plaque-associated reactive astrocytes that were also immunoreactive for the chaperone heat shock protein 27 (HSP27). Our data are consistent for the transgenic mouse model and the human clinical condition. We conclude that pGlu79-aSyn can be generated extracellularly or within reactive astrocytes, accumulates in proximity to β-amyloid plaques and induces an astrocytic protein unfolding mechanism involving HSP27. Full article
(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)
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25 pages, 3082 KiB  
Review
Activation and Pharmacological Regulation of Inflammasomes
by Chen Chen and Pinglong Xu
Biomolecules 2022, 12(7), 1005; https://doi.org/10.3390/biom12071005 - 20 Jul 2022
Cited by 19 | Viewed by 4620
Abstract
Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues [...] Read more.
Inflammasomes are intracellular signaling complexes of the innate immune system, which is part of the response to exogenous pathogens or physiological aberration. The multiprotein complexes mainly consist of sensor proteins, adaptors, and pro-caspase-1. The assembly of the inflammasome upon extracellular and intracellular cues drives the activation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18 to maturation and gasdermin-D for pore formation, leading to pyroptosis and cytokine release. Inflammasome signaling functions in numerous infectious or sterile inflammatory diseases, including inherited autoinflammatory diseases, metabolic disorders, cardiovascular diseases, cancers, neurodegenerative disorders, and COVID-19. In this review, we summarized current ideas on the organization and activation of inflammasomes, with details on the molecular mechanisms, regulations, and interventions. The recent developments of pharmacological strategies targeting inflammasomes as disease therapeutics were also covered. Full article
(This article belongs to the Collection Molecular Biology: Feature Papers)
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16 pages, 1682 KiB  
Article
Calpain-Independent Intracellular Protease Activity Is Elevated in Excitotoxic Cortical Neurons Prior to Delayed Calcium Deregulation and Mitochondrial Dysfunction
by Brian M. Polster, Karla A. Mark, Rafael Arze and Derek Hudson
Biomolecules 2022, 12(7), 1004; https://doi.org/10.3390/biom12071004 - 20 Jul 2022
Cited by 1 | Viewed by 2077
Abstract
Glutamate excitotoxicity contributes to many neurodegenerative diseases. Excessive glutamate receptor-mediated calcium entry causes delayed calcium deregulation (DCD) that coincides with abrupt mitochondrial depolarization. We developed cA-TAT, a live-cell protease activity reporter based on a vimentin calpain cleavage site, to test whether glutamate increases [...] Read more.
Glutamate excitotoxicity contributes to many neurodegenerative diseases. Excessive glutamate receptor-mediated calcium entry causes delayed calcium deregulation (DCD) that coincides with abrupt mitochondrial depolarization. We developed cA-TAT, a live-cell protease activity reporter based on a vimentin calpain cleavage site, to test whether glutamate increases protease activity in neuronal cell bodies prior to DCD. Treatment of rat cortical neurons with excitotoxic (100 µM) glutamate increased the low baseline rate of intracellular cA-TAT proteolysis by approximately three-fold prior to DCD and by approximately seven-fold upon calcium deregulation. The glutamate-induced rate enhancement prior to DCD was suppressed by glutamate receptor antagonists, but not by calpain or proteasome inhibitors, whereas DCD-stimulated proteolysis was partly attenuated by the proteasome inhibitor MG132. Further suggesting that cA-TAT cleavage is calpain-independent, cA-TAT fluorescence was observed in immortalized Capn4 knockout fibroblasts lacking the regulatory calpain subunit. About half of the neurons lost calcium homeostasis within two hours of a transient, 20 min glutamate receptor stimulation. These neurons had a significantly (49%) higher mean baseline cA-TAT proteolysis rate than those maintaining calcium homeostasis, suggesting that the unknown protease(s) cleaving cA-TAT may influence DCD susceptibility. Overall, the results indicate that excitotoxic glutamate triggers the activation of calpain-independent neuronal protease activity prior to the simultaneous loss of calcium homeostasis and mitochondrial bioenergetic function. Full article
(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders)
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22 pages, 3957 KiB  
Article
Kallikrein-Related Peptidase 6 (KLK6) as a Contributor toward an Aggressive Cancer Cell Phenotype: A Potential Role in Colon Cancer Peritoneal Metastasis
by Hayet Bouzid, Feryel Soualmia, Katerina Oikonomopoulou, Antoninus Soosaipillai, Francine Walker, Khaoula Louati, Rea Lo Dico, Marc Pocard, Chahrazade El Amri, Natalia A. Ignatenko and Dalila Darmoul
Biomolecules 2022, 12(7), 1003; https://doi.org/10.3390/biom12071003 - 19 Jul 2022
Cited by 9 | Viewed by 2407
Abstract
Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one of the 15 KLK family members, is a promising biomarker for diagnosis of many cancers and has been associated with poor prognosis of colorectal cancer (CRC) patients. Herein, we evaluated the expression [...] Read more.
Kallikrein-related peptidases (KLKs) are implicated in many cancer-related processes. KLK6, one of the 15 KLK family members, is a promising biomarker for diagnosis of many cancers and has been associated with poor prognosis of colorectal cancer (CRC) patients. Herein, we evaluated the expression and cellular functions of KLK6 in colon cancer-derived cell lines and in clinical samples from CRC patients. We showed that, although many KLKs transcripts are upregulated in colon cancer-derived cell lines, KLK6, KLK10, and KLK11 are the most highly secreted proteins. KLK6 induced calcium flux in HT29 cells by activation and internalization of protease-activated receptor 2 (PAR2). Furthermore, KLK6 induced extracellular signal–regulated kinases 1 and 2 (ERK1/2) phosphorylation. KLK6 suppression in HCT-116 colon cancer cells decreased the colony formation, increased cell adhesion to extracellular matrix proteins, and reduced spheroid formation and compaction. Immunohistochemistry (IHC) analysis demonstrated ectopic expression of KLK6 in human colon adenocarcinomas but not in normal epithelia. Importantly, high levels of KLK6 protein were detected in the ascites of CRC patients with peritoneal metastasis, but not in benign ascites. These data indicate that KLK6 overexpression is associated with aggressive CRC, and may be applied to differentiate between benign and malignant ascites. Full article
(This article belongs to the Special Issue Role of Proteases in Cancer)
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13 pages, 4288 KiB  
Article
High-Throughput Proteomic Analysis of Human Dermal Fibroblast Response to Different Blood Derivatives: Autologous Topical Serum Derived from Plasma Rich in Growth Factors (PRGF) versus Leukocyte- and Platelet-Rich Plasma (L-PRP)
by Eduardo Anitua, Ander Pino, Mikel Azkargorta, Felix Elortza and Roberto Prado
Biomolecules 2022, 12(7), 1002; https://doi.org/10.3390/biom12071002 - 19 Jul 2022
Cited by 2 | Viewed by 1880
Abstract
Platelet-rich plasma (PRP) is nowadays used in the treatment of different types of cutaneous lesions. However, different compositions can influence clinical outcomes. Among them, the inclusion of leukocytes is controversial. High-throughput proteomics techniques were used to analyze the proteins that are differentially expressed [...] Read more.
Platelet-rich plasma (PRP) is nowadays used in the treatment of different types of cutaneous lesions. However, different compositions can influence clinical outcomes. Among them, the inclusion of leukocytes is controversial. High-throughput proteomics techniques were used to analyze the proteins that are differentially expressed in human dermal fibroblasts (HDFs) after treatment for 24 h with two PRP types, autologous topical serum (Endoret serum—ES) derived from plasma rich in growth factors (PRGF) and leukocyte- and platelet-rich plasma (L-PRP). The identified proteins were then classified by both Gene Ontology and Ingenuity Pathway Analysis. The obtained results show that the compositions of ES and L-PRP differ in such a way that they induce different responses in HDFs. ES-treated HDFs overexpress growth factor-related proteins, leading to protein synthesis, cell proliferation and migration. By contrast, L-PRP treatment induces a response similar to that caused by proinflammatory molecules. These data could explain the contradictory clinical results obtained for the different types of PRP, especially with respect to their leukocyte contents. Full article
(This article belongs to the Special Issue Novel Materials for Biomedical Applications)
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18 pages, 4581 KiB  
Article
Modifying Thermostability and Reusability of Hyperthermophilic Mannanase by Immobilization on Glutaraldehyde Cross-Linked Chitosan Beads
by Beenish Sadaqat, Chong Sha, Mudasir Ahmad Dar, Maruti J. Dhanavade, Kailas D. Sonawane, Hassan Mohamed, Weilan Shao and Yuanda Song
Biomolecules 2022, 12(7), 999; https://doi.org/10.3390/biom12070999 - 18 Jul 2022
Cited by 7 | Viewed by 1841
Abstract
In the current study, the purified β-mannanase (Man/Cel5B) from Thermotoga maritima was immobilized on glutaraldehyde cross-linked chitosan beads. The immobilization of Man/Cel5B on chitosan beads was confirmed by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis. After immobilization, the protein loading efficiency [...] Read more.
In the current study, the purified β-mannanase (Man/Cel5B) from Thermotoga maritima was immobilized on glutaraldehyde cross-linked chitosan beads. The immobilization of Man/Cel5B on chitosan beads was confirmed by Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis. After immobilization, the protein loading efficiency and immobilization yield were found to be 73.3% and 71.8%, respectively. The optimum pH for both free and immobilized enzymes was found to be pH 5.5. However, the optimum temperature of immobilized Man/Cel5B increased by 10 °C, from 85 °C (free Man/Cel5B) to 95 °C (Immobilized). The half-life of free and immobilized enzymes was found to be 7 h and 9 h, respectively, at 85 °C owing to the higher thermostability of immobilized Man/Cel5B. The increase in thermostability was also demonstrated by an increase in the energy of deactivation (209 kJmol−1) for immobilized enzyme compared to its native form (92 kJmol−1), at 85 °C. Furthermore, the immobilized Man/Cel5B displayed good operational stability as it retained 54% of its original activity after 15 repeated catalytic reactions concerning its free form. Full article
(This article belongs to the Section Biomacromolecules: Proteins)
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13 pages, 951 KiB  
Review
The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases
by Knut Hestad, Jan Alexander, Helge Rootwelt and Jan O. Aaseth
Biomolecules 2022, 12(7), 998; https://doi.org/10.3390/biom12070998 - 18 Jul 2022
Cited by 42 | Viewed by 4916
Abstract
Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan [...] Read more.
Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands. Full article
(This article belongs to the Special Issue Biochemistry in Medicine—Honorary Special Issue Commemorating Research and Work of Professors Jan O. Aaseth and Jan Alexander)
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13 pages, 3573 KiB  
Article
Programmable Polyproteams of Tyrosine Ammonia Lyases as Cross-Linked Enzymes for Synthesizing p-Coumaric Acid
by Mingyu Jia, Zhiyuan Luo, Haomin Chen, Bianqin Ma, Li Qiao, Qinjie Xiao, Pengfei Zhang and Anming Wang
Biomolecules 2022, 12(7), 997; https://doi.org/10.3390/biom12070997 - 18 Jul 2022
Cited by 2 | Viewed by 1898
Abstract
Ideal immobilization with enhanced biocatalyst activity and thermostability enables natural enzymes to serve as a powerful tool to yield synthetically useful chemicals in industry. Such an enzymatic method strategy becomes easier and more convenient with the use of genetic and protein engineering. Here, [...] Read more.
Ideal immobilization with enhanced biocatalyst activity and thermostability enables natural enzymes to serve as a powerful tool to yield synthetically useful chemicals in industry. Such an enzymatic method strategy becomes easier and more convenient with the use of genetic and protein engineering. Here, we developed a covalent programmable polyproteam of tyrosine ammonia lyases (TAL-CLEs) by fusing SpyTag and SpyCatcher peptides into the N-terminal and C-terminal of the TAL, respectively. The resulting circular enzymes were clear after the spontaneous isopeptide bonds formed between the SpyTag and SpyCatcher. Furthermore, the catalytic performance of the TAL-CLEs was measured via a synthesis sample of p-Coumaric acid. Our TAL-CLEs showed excellent catalytic efficiency, with 98.31 ± 1.14% yield of the target product—which is 4.15 ± 0.08 times higher than that of traditional glutaraldehyde-mediated enzyme aggregates. They also showed over four times as much enzyme-activity as wild-type TAL does and demonstrated good reusability, and so may become a good candidate for industrial enzymes. Full article
(This article belongs to the Section Enzymology)
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15 pages, 1892 KiB  
Review
Comparison of Tau and Amyloid-β Targeted Immunotherapy Nanoparticles for Alzheimer’s Disease
by Yara Mashal, Hosam Abdelhady and Arun K. Iyer
Biomolecules 2022, 12(7), 1001; https://doi.org/10.3390/biom12071001 - 18 Jul 2022
Cited by 6 | Viewed by 2963
Abstract
Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, [...] Read more.
Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, and brain damage is irreversible. Several therapeutic targets have been defined mainly related to two hypotheses of AD: the tau hypothesis and the amyloid-β hypothesis. Here, we intend to investigate and to compare different therapeutic approaches for AD, mainly based on nanoparticles (NPs) targeted at the brain and at the pathological hallmarks of the disease. We analyzed preclinical trials that have successfully improved drug bioavailability in the brain by using targeted nanocarriers towards either tau, amyloid-β, or both. We then compared these trials to find out which protein is more efficient in therapeutic targeting. We found that the search for a cure was mostly based on the amyloid-β hypothesis, with Aβ dysplasia emerging as the most confirmed and convincing therapeutic target. Targeted NPs have proven useful to enhance both the bioavailability and the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted NPs for combined therapies. Full article
(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)
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31 pages, 1039 KiB  
Review
Zinc in Cognitive Impairment and Aging
by Ruize Sun, Jue Wang, Juan Feng and Bin Cao
Biomolecules 2022, 12(7), 1000; https://doi.org/10.3390/biom12071000 - 18 Jul 2022
Cited by 15 | Viewed by 4212
Abstract
Zinc, an essential micronutrient for life, was first discovered in 1869 and later found to be indispensable for the normal development of plants and for the normal growth of rats and birds. Zinc plays an important role in many physiological and pathological processes [...] Read more.
Zinc, an essential micronutrient for life, was first discovered in 1869 and later found to be indispensable for the normal development of plants and for the normal growth of rats and birds. Zinc plays an important role in many physiological and pathological processes in normal mammalian brain development, especially in the development of the central nervous system. Zinc deficiency can lead to neurodegenerative diseases, mental abnormalities, sleep disorders, tumors, vascular diseases, and other pathological conditions, which can cause cognitive impairment and premature aging. This study aimed to review the important effects of zinc and zinc-associated proteins in cognitive impairment and aging, to reveal its molecular mechanism, and to highlight potential interventions for zinc-associated aging and cognitive impairments. Full article
(This article belongs to the Special Issue Zinc in Health and Disease Conditions)
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19 pages, 688 KiB  
Review
Amylin and Secretases in the Pathology and Treatment of Alzheimer’s Disease
by Som Singh, Felix Yang, Andy Sivils, Victoria Cegielski and Xiang-Ping Chu
Biomolecules 2022, 12(7), 996; https://doi.org/10.3390/biom12070996 - 17 Jul 2022
Cited by 5 | Viewed by 3063
Abstract
Alzheimer’s disease remains a prevailing neurodegenerative condition which has an array physical, emotional, and financial consequences to patients and society. In the past decade, there has been a greater degree of investigation on therapeutic small peptides. This group of biomolecules have a profile [...] Read more.
Alzheimer’s disease remains a prevailing neurodegenerative condition which has an array physical, emotional, and financial consequences to patients and society. In the past decade, there has been a greater degree of investigation on therapeutic small peptides. This group of biomolecules have a profile of fundamentally sound characteristics which make them an intriguing area for drug development. Among these biomolecules, there are four modulatory mechanisms of interest in this review: alpha-, beta-, gamma-secretases, and amylin. These protease-based biomolecules all have a contributory role in the amyloid cascade hypothesis. Moreover, the involvement of various biochemical pathways intertwines these peptides to have shared regulators (i.e., retinoids). Further clinical and translational investigation must occur to gain a greater understanding of its potential application in patient care. The aim of this narrative review is to evaluate the contemporary literature on these protease biomolecule modulators and determine its utility in the treatment of Alzheimer’s disease. Full article
(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)
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18 pages, 2826 KiB  
Article
Enhancer-LSTMAtt: A Bi-LSTM and Attention-Based Deep Learning Method for Enhancer Recognition
by Guohua Huang, Wei Luo, Guiyang Zhang, Peijie Zheng, Yuhua Yao, Jianyi Lyu, Yuewu Liu and Dong-Qing Wei
Biomolecules 2022, 12(7), 995; https://doi.org/10.3390/biom12070995 - 17 Jul 2022
Cited by 5 | Viewed by 2266
Abstract
Enhancers are short DNA segments that play a key role in biological processes, such as accelerating transcription of target genes. Since the enhancer resides anywhere in a genome sequence, it is difficult to precisely identify enhancers. We presented a bi-directional long-short term memory [...] Read more.
Enhancers are short DNA segments that play a key role in biological processes, such as accelerating transcription of target genes. Since the enhancer resides anywhere in a genome sequence, it is difficult to precisely identify enhancers. We presented a bi-directional long-short term memory (Bi-LSTM) and attention-based deep learning method (Enhancer-LSTMAtt) for enhancer recognition. Enhancer-LSTMAtt is an end-to-end deep learning model that consists mainly of deep residual neural network, Bi-LSTM, and feed-forward attention. We extensively compared the Enhancer-LSTMAtt with 19 state-of-the-art methods by 5-fold cross validation, 10-fold cross validation and independent test. Enhancer-LSTMAtt achieved competitive performances, especially in the independent test. We realized Enhancer-LSTMAtt into a user-friendly web application. Enhancer-LSTMAtt is applicable not only to recognizing enhancers, but also to distinguishing strong enhancer from weak enhancers. Enhancer-LSTMAtt is believed to become a promising tool for identifying enhancers. Full article
(This article belongs to the Special Issue Applications of Systems Biology Approaches in Biomedicine)
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18 pages, 1447 KiB  
Review
α-Synuclein Conformational Plasticity: Physiologic States, Pathologic Strains, and Biotechnological Applications
by Amanda Li, Cyrus Rastegar and Xiaobo Mao
Biomolecules 2022, 12(7), 994; https://doi.org/10.3390/biom12070994 - 17 Jul 2022
Cited by 6 | Viewed by 2711
Abstract
α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is [...] Read more.
α-Synuclein (αS) is remarkable for both its extensive conformational plasticity and pathologic prion-like properties. Physiologically, αS may populate disordered monomeric, helically folded tetrameric, or membrane-bound oligomeric states. Pathologically, αS may assemble into toxic oligomers and subsequently fibrils, the prion-like transmission of which is implicated in a class of neurodegenerative disorders collectively termed α-synucleinopathies. Notably, αS does not adopt a single “amyloid fold”, but rather exists as structurally distinct amyloid-like conformations referred to as “strains”. The inoculation of animal models with different strains induces distinct pathologies, and emerging evidence suggests that the propagation of disease-specific strains underlies the differential pathologies observed in patients with different α-synucleinopathies. The characterization of αS strains has provided insight into the structural basis for the overlapping, yet distinct, symptoms of Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. In this review, we first explore the physiological and pathological differences between conformational states of αS. We then discuss recent studies on the influence of micro-environmental factors on αS species formation, propagation, and the resultant pathological characteristics. Lastly, we review how an understanding of αS conformational properties has been translated to emerging strain amplification technologies, which have provided further insight into the role of specific strains in distinct α-synucleinopathies, and show promise for the early diagnosis of disease. Full article
(This article belongs to the Special Issue Synuclein Proteins)
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21 pages, 2847 KiB  
Article
Analysis of Alternative mRNA Splicing in Vemurafenib-Resistant Melanoma Cells
by Honey Bokharaie, Walter Kolch and Aleksandar Krstic
Biomolecules 2022, 12(7), 993; https://doi.org/10.3390/biom12070993 - 17 Jul 2022
Cited by 5 | Viewed by 3008
Abstract
Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS [...] Read more.
Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS in SK-MEL-239 melanoma cells and a BRAF inhibitor (vemurafenib)-resistant derivative that expresses an AS, shortened BRAF V600E transcript. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. As there is no consensus approach to analysing AS events, we used and compared four common AS softwares based on different principles, DEXSeq, rMATS, ASpli, and LeafCutter. Two of them correctly identified the BRAF V600E AS in the vemurafenib-resistant cells. Only 12 AS events were identified by all four softwares. Testing the AS predictions experimentally showed that these overlapping predictions are highly accurate. Interestingly, they identified AS caused alterations in the expression of melanin synthesis and cell migration genes in the vemurafenib-resistant cells. This analysis shows that combining different AS analysis approaches produces reliable results and meaningful, biologically testable hypotheses. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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22 pages, 5889 KiB  
Article
Development of a Multi-Enzymatic Approach for the Modification of Biopolymers with Ferulic Acid
by Archontoula Giannakopoulou, Georgia Tsapara, Anastassios N. Troganis, Panagiota Koralli, Christos L. Chochos, Angeliki C. Polydera, Petros Katapodis, Nektaria-Marianthi Barkoula and Haralambos Stamatis
Biomolecules 2022, 12(7), 992; https://doi.org/10.3390/biom12070992 - 17 Jul 2022
Cited by 2 | Viewed by 2797
Abstract
A series of polymers, including chitosan (CS), carboxymethylcellulose (CMC) and a chitosan–gelatin (CS–GEL) hybrid polymer, were functionalized with ferulic acid (FA) derived from the enzymatic treatment of arabinoxylan through the synergistic action of two enzymes, namely, xylanase and feruloyl esterase. Subsequently, the ferulic [...] Read more.
A series of polymers, including chitosan (CS), carboxymethylcellulose (CMC) and a chitosan–gelatin (CS–GEL) hybrid polymer, were functionalized with ferulic acid (FA) derived from the enzymatic treatment of arabinoxylan through the synergistic action of two enzymes, namely, xylanase and feruloyl esterase. Subsequently, the ferulic acid served as the substrate for laccase from Agaricus bisporus (AbL) in order to enzymatically functionalize the above-mentioned polymers. The successful grafting of the oxidized ferulic acid products onto the different polymers was confirmed through ultraviolet–visible (UV–Vis) spectroscopy, attenuated total reflectance (ATR) spectroscopy, scanning electron microscopy (SEM) and nuclear magnetic resonance (NMR) spectroscopy. Additionally, an enhancement of the antioxidant properties of the functionalized polymers was observed according to the DDPH and ABTS protocols. Finally, the modified polymers exhibited strong antimicrobial activity against bacterial populations of Escherichia coli BL21DE3 strain, suggesting their potential application in pharmaceutical, cosmeceutical and food industries. Full article
(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Phenolic Compounds Derivatives)
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24 pages, 5103 KiB  
Article
Cloning and Characterization of Drosophila melanogaster Juvenile Hormone Epoxide Hydrolases (JHEH) and Their Promoters
by Dov Borovsky, Hilde Breyssens, Esther Buytaert, Tom Peeters, Carole Laroye, Karolien Stoffels and Pierre Rougé
Biomolecules 2022, 12(7), 991; https://doi.org/10.3390/biom12070991 - 16 Jul 2022
Cited by 3 | Viewed by 2291
Abstract
Juvenile hormone epoxide hydrolase (JHEH) plays an important role in the metabolism of JH III in insects. To study the control of JHEH in female Drosophila melanogaster, JHEH 1, 2 and 3 cDNAs were cloned and sequenced. Northern blot analyses showed that [...] Read more.
Juvenile hormone epoxide hydrolase (JHEH) plays an important role in the metabolism of JH III in insects. To study the control of JHEH in female Drosophila melanogaster, JHEH 1, 2 and 3 cDNAs were cloned and sequenced. Northern blot analyses showed that the three transcripts are expressed in the head thorax, the gut, the ovaries and the fat body of females. Molecular modeling shows that the enzyme is a homodimer that binds juvenile hormone III acid (JH IIIA) at the catalytic groove better than JH III. Analyses of the three JHEH promoters and expressing short promoter sequences behind a reporter gene (lacZ) in D. melanogaster cell culture identified a JHEH 3 promoter sequence (626 bp) that is 10- and 25-fold more active than the most active promoter sequences of JHEH 2 and JHEH 1, respectively. A transcription factor (TF) Sp1 that is involved in the activation of JHEH 3 promoter sequence was identified. Knocking down Sp1 using dsRNA inhibited the transcriptional activity of this promoter in transfected D. melanogaster cells and JH III and 20HE downregulated the JHEH 3 promoter. On the other hand, JH IIIA and farnesoic acid did not affect the promoter, indicating that JH IIIA is JHEH’s preferred substrate. A transgenic D. melanogaster expressing a highly activated JHEH 3 promoter behind a lacZ reporter gene showed promoter transcriptional activity in many D. melanogaster tissues. Full article
(This article belongs to the Special Issue Contributions of Promoters to the Physiology, Biochemistry and Molecular Biology Processes of Insects)
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22 pages, 3755 KiB  
Article
Impact of Primary RPE Cells in a Porcine Organotypic Co-Cultivation Model
by Natalie Wagner, Armin Safaei, José Hurst, Pia A. Vogt, H. Burkhard Dick, Stephanie C. Joachim and Sven Schnichels
Biomolecules 2022, 12(7), 990; https://doi.org/10.3390/biom12070990 - 16 Jul 2022
Cited by 2 | Viewed by 2181
Abstract
The pathological events of age-related macular degeneration are characterized by degenerative processes involving the photoreceptor cells, retinal pigment epithelium (RPE), and the Bruch’s membrane as well as choroidal alterations. To mimic in vivo interactions between photoreceptor cells and RPE cells ex vivo, complex [...] Read more.
The pathological events of age-related macular degeneration are characterized by degenerative processes involving the photoreceptor cells, retinal pigment epithelium (RPE), and the Bruch’s membrane as well as choroidal alterations. To mimic in vivo interactions between photoreceptor cells and RPE cells ex vivo, complex models are required. Hence, the aim of this study was to establish a porcine organotypic co-cultivation model and enlighten the interactions of photoreceptor and RPE cells, with a special emphasis on potential neuroprotective effects. Porcine neuroretina explants were cultured with primary porcine RPE cells (ppRPE) or medium derived from these cells (=conditioned medium). Neuroretina explants cultured alone served as controls. After eight days, RT-qPCR and immunohistology were performed to analyze photoreceptors, synapses, macroglia, microglia, complement factors, and pro-inflammatory cytokines (e.g., IL1B, IL6, TNF) in the neuroretina samples. The presence of ppRPE cells preserved photoreceptors, whereas synaptical density was unaltered. Interestingly, on an immunohistological as well as on an mRNA level, microglia and complement factors were comparable in all groups. Increased IL6 levels were noted in ppRPE and conditioned medium samples, while TNF was only upregulated in the ppRPE group. IL1B was elevated in conditioned medium samples. In conclusion, a co-cultivation of ppRPE cells and neuroretina seem to have beneficial effects on the neuroretina, preserving photoreceptors and maintaining synaptic vesicles in vitro. This organotypic co-cultivation model can be used to investigate the complex interactions between the retina and RPE cells, gain further insight into neurodegenerative pathomechanisms occurring in retinal diseases, and evaluate potential therapeutics. Full article
(This article belongs to the Special Issue Cell and Organ Cultures for Studying Retinal Diseases)
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17 pages, 3301 KiB  
Article
Concurrent Change in Serum Cholinesterase Activity and Midregional-Proadrennomedullin Level Could Predict Patient Outcome following Liver Transplantation
by Sebastian O. Decker, Albert Krüger, Henryk Wilk, Florian Uhle, Thomas Bruckner, Stefan Hofer, Markus A. Weigand, Thorsten Brenner and Aleksandar R. Zivkovic
Biomolecules 2022, 12(7), 989; https://doi.org/10.3390/biom12070989 - 15 Jul 2022
Cited by 1 | Viewed by 1388
Abstract
Background: After liver transplantation (LTX), patients are susceptible to opportunistic infections resulting in reduced outcomes within the early post-transplantation period. The postoperative monitoring of LTX patients has gained much importance in recent years. However, reliable plasmatic markers predicting 90-day outcomes are still lacking. [...] Read more.
Background: After liver transplantation (LTX), patients are susceptible to opportunistic infections resulting in reduced outcomes within the early post-transplantation period. The postoperative monitoring of LTX patients has gained much importance in recent years. However, reliable plasmatic markers predicting 90-day outcomes are still lacking. Methods: In the post hoc analysis of a prospective, observational study, butyrylcholinesterase (BChE), mid-regional proadrenomedullin (MR-proADM), as well as conventional inflammatory markers (procalcitonin, C-reactive protein) were evaluated in 93 patients at seven consecutive timepoints within the first 28 days following LTX. Results: Persistently reduced activity of BChE and elevated MR-proADM levels indicated reduced 90-day survival following LTX. Furthermore, reduced BChE and increased MR-proADM activity could indicate early post-transplantation bacterial infections, whereas conventional inflammatory biomarkers showed no diagnostic efficacy within the observation period. Conclusion: Concurrent assessment of BChE and MR-proADM activity might serve as a bedside diagnostic tool for early bacterial infections following liver transplantation. Thus, a combined utilization of the two biomarkers may be a useful tool in the risk evaluation of patients following liver transplantation. Full article
(This article belongs to the Special Issue New Biomarkers in Solid Organ Transplantation)
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17 pages, 3979 KiB  
Article
Molecular Characterization of Kunitz-Type Protease Inhibitors from Blister Beetles (Coleoptera, Meloidae)
by Emiliano Fratini, Marianna Nicoletta Rossi, Lucrezia Spagoni, Alessandra Riccieri, Emiliano Mancini, Fabio Polticelli, Marco Alberto Bologna, Paolo Mariottini and Manuela Cervelli
Biomolecules 2022, 12(7), 988; https://doi.org/10.3390/biom12070988 - 15 Jul 2022
Cited by 1 | Viewed by 1940
Abstract
Protease inhibitors are widely studied since the unrestricted activity of proteases can cause extensive organ lesions. In particular, elastase activity is involved in the pathophysiology of acute lung injury, for example during SARS-CoV-2 infection, while serine proteases and thrombin-like proteases are involved in [...] Read more.
Protease inhibitors are widely studied since the unrestricted activity of proteases can cause extensive organ lesions. In particular, elastase activity is involved in the pathophysiology of acute lung injury, for example during SARS-CoV-2 infection, while serine proteases and thrombin-like proteases are involved in the development and/or pathology of the nervous system. Natural protease inhibitors have the advantage to be reversible and with few side effects and thus are increasingly considered as new drugs. Kunitz-type protease inhibitors (KTPIs), reported in the venom of various organisms, such as wasps, spiders, scorpions, and snakes, have been studied for their potent anticoagulant activity and widespread protease inhibitor activity. Putative KTPI anticoagulants have been identified in transcriptomic resources obtained for two blister beetle species, Lydus trimaculatus and Mylabris variabilis. The KTPIs of L. trimaculatus and M. variabilis were characterized by combined transcriptomic and bioinformatics methodologies. The full-length mRNA sequences were divided on the base of the sequence of the active sites of the putative proteins. In silico protein structure analyses of each group of translational products show the biochemical features of the active sites and the potential protease targets. Validation of these genes is the first step for considering these molecules as new drugs for use in medicine. Full article
(This article belongs to the Special Issue Functional Peptides and Their Interactions: From Molecules to Systems)
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13 pages, 1013 KiB  
Article
Infection Rate of Respiratory Viruses in the Pandemic SARS-CoV-2 Period Considering Symptomatic Patients: Two Years of Ongoing Observations
by Gaetana Costanza, Pierpaolo Paba, Marco Ciotti, Domenico Ombres, Stefano Di Carlo, Fabbio Marcuccilli, Ada Bertoli, Loide Di Traglia, Marcello Mozzani, Lucia Piredda, Vita Petrone, Marialaura Fanelli, Carla Paganelli, Barbara Cortese, Emanuela Balestrieri, Sergio Bernardini, Massimo Andreoni, Claudia Matteucci, Antonella Minutolo and Sandro Grelli
Biomolecules 2022, 12(7), 987; https://doi.org/10.3390/biom12070987 - 15 Jul 2022
Cited by 5 | Viewed by 2405
Abstract
Background: In the last two years, the SARS-CoV-2 pandemic has determined radical changes in human behaviors and lifestyles, with a drastic reduction in socialization due to physical distancing and self-isolation. These changes have also been reflected in the epidemiological patterns of common respiratory [...] Read more.
Background: In the last two years, the SARS-CoV-2 pandemic has determined radical changes in human behaviors and lifestyles, with a drastic reduction in socialization due to physical distancing and self-isolation. These changes have also been reflected in the epidemiological patterns of common respiratory viruses. For this reason, early discrimination of respiratory viruses is important as new variants emerge. Methods: Nasopharyngeal swabs of 2554 patients, with clinically suspected Acute Respiratory Infections (ARIs) from October 2019 to November 2021, were collected to detect 1 or more of the 23 common respiratory pathogens, especially viruses, via BioFilmArray RP2.1plus, including SARS-CoV-2. Demographical characteristics and epidemiological analyses were performed as well as a laboratory features profile of positive patients. Results: An observational study on 2300 patients (254 patients were excluded because of missing data) including 1560 men and 760 women, median age of 64.5 years, was carried out. Considering the respiratory virus research request, most of the patients were admitted to the Emergency Medicine Department (41.2%, of patients), whereas 29.5% were admitted to the Infectious Diseases Department. The most frequently detected pathogens included SARS-CoV-2 (31.06%, 707/2300, from March 2020 to November 2021), InfA-B (1.86%, 43/2300), HCoV (2.17% 50/2300), and HSRV (1.65%, 38/2300). Interestingly, coinfection rates decreased dramatically in the SARS-CoV-2 pandemic period. The significative decrease in positive rate of SARS-CoV-2 was associated with the massive vaccination. Conclusion: This study represents a dynamic picture of the epidemiological curve of common respiratory viruses during the two years of pandemic, with a disregarded trend for additional viruses. Our results showed that SARS-CoV-2 had a preferential tropism for the respiratory tract without co-existing with other viruses. The possible causes were attributable either to the use of masks, social isolation, or to specific respiratory receptors mostly available for this virus, external and internal lifestyle factors, vaccination campaigns, and emergence of new SARS-CoV-2 variants. Full article
(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)
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14 pages, 1564 KiB  
Article
Metabolomic Analysis of Human Astrocytes in Lipotoxic Condition: Potential Biomarker Identification by Machine Learning Modeling
by Daniel Báez Castellanos, Cynthia A. Martín-Jiménez, Andrés Pinzón, George E. Barreto, Guillermo Federico Padilla-González, Andrés Aristizábal, Martha Zuluaga and Janneth González Santos
Biomolecules 2022, 12(7), 986; https://doi.org/10.3390/biom12070986 - 15 Jul 2022
Cited by 1 | Viewed by 2768
Abstract
The association between neurodegenerative diseases (NDs) and obesity has been well studied in recent years. Obesity is a syndrome of multifactorial etiology characterized by an excessive accumulation and release of fatty acids (FA) in adipose and non-adipose tissue. An excess of FA generates [...] Read more.
The association between neurodegenerative diseases (NDs) and obesity has been well studied in recent years. Obesity is a syndrome of multifactorial etiology characterized by an excessive accumulation and release of fatty acids (FA) in adipose and non-adipose tissue. An excess of FA generates a metabolic condition known as lipotoxicity, which triggers pathological cellular and molecular responses, causing dysregulation of homeostasis and a decrease in cell viability. This condition is a hallmark of NDs, and astrocytes are particularly sensitive to it, given their crucial role in energy production and oxidative stress management in the brain. However, analyzing cellular mechanisms associated with these conditions represents a challenge. In this regard, metabolomics is an approach that allows biochemical analysis from the comprehensive perspective of cell physiology. This technique allows cellular metabolic profiles to be determined in different biological contexts, such as those of NDs and specific metabolic insults, including lipotoxicity. Since data provided by metabolomics can be complex and difficult to interpret, alternative data analysis techniques such as machine learning (ML) have grown exponentially in areas related to omics data. Here, we developed an ML model yielding a 93% area under the receiving operating characteristic (ROC) curve, with sensibility and specificity values of 80% and 93%, respectively. This study aimed to analyze the metabolomic profiles of human astrocytes under lipotoxic conditions to provide powerful insights, such as potential biomarkers for scenarios of lipotoxicity induced by palmitic acid (PA). In this work, we propose that dysregulation in seleno-amino acid metabolism, urea cycle, and glutamate metabolism pathways are major triggers in astrocyte lipotoxic scenarios, while increased metabolites such as alanine, adenosine, and glutamate are suggested as potential biomarkers, which, to our knowledge, have not been identified in human astrocytes and are proposed as candidates for further research and validation. Full article
(This article belongs to the Collection Metabolomics and Integrated Multi-Omics in Health and Disease)
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11 pages, 4149 KiB  
Article
Benchmarking the Accuracy of AlphaFold 2 in Loop Structure Prediction
by Amy O. Stevens and Yi He
Biomolecules 2022, 12(7), 985; https://doi.org/10.3390/biom12070985 - 14 Jul 2022
Cited by 24 | Viewed by 3928
Abstract
The inhibition of protein–protein interactions is a growing strategy in drug development. In addition to structured regions, many protein loop regions are involved in protein–protein interactions and thus have been identified as potential drug targets. To effectively target such regions, protein structure is [...] Read more.
The inhibition of protein–protein interactions is a growing strategy in drug development. In addition to structured regions, many protein loop regions are involved in protein–protein interactions and thus have been identified as potential drug targets. To effectively target such regions, protein structure is critical. Loop structure prediction is a challenging subgroup in the field of protein structure prediction because of the reduced level of conservation in protein sequences compared to the secondary structure elements. AlphaFold 2 has been suggested to be one of the greatest achievements in the field of protein structure prediction. The AlphaFold 2 predicted protein structures near the X-ray resolution in the Critical Assessment of protein Structure Prediction (CASP 14) competition in 2020. The purpose of this work is to survey the performance of AlphaFold 2 in specifically predicting protein loop regions. We have constructed an independent dataset of 31,650 loop regions from 2613 proteins (deposited after the AlphaFold 2 was trained) with both experimentally determined structures and AlphaFold 2 predicted structures. With extensive evaluation using our dataset, the results indicate that AlphaFold 2 is a good predictor of the structure of loop regions, especially for short loop regions. Loops less than 10 residues in length have an average Root Mean Square Deviation (RMSD) of 0.33 Å and an average the Template Modeling score (TM-score) of 0.82. However, we see that as the number of residues in a given loop increases, the accuracy of AlphaFold 2’s prediction decreases. Loops more than 20 residues in length have an average RMSD of 2.04 Å and an average TM-score of 0.55. Such a correlation between accuracy and length of the loop is directly linked to the increase in flexibility. Moreover, AlphaFold 2 does slightly over-predict α-helices and β-strands in proteins. Full article
(This article belongs to the Special Issue Unveiling Protein Functions, Dynamics and Interactions in Health and Disease Using Experimental and Theoretical Approaches)
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19 pages, 2084 KiB  
Review
Src Family Kinases: A Potential Therapeutic Target for Acute Kidney Injury
by Nannan Li, Guoxin Lin, Hao Zhang, Jian Sun, Ming Gui, Yan Liu, Wei Li, Jishi Liu and Juan Tang
Biomolecules 2022, 12(7), 984; https://doi.org/10.3390/biom12070984 - 14 Jul 2022
Cited by 10 | Viewed by 3164
Abstract
Src family kinases (SFKs) are non-receptor tyrosine kinases and play a key role in regulating signal transduction. The mechanism of SFKs in various tumors has been widely studied, and there are more and more studies on its role in the kidney. Acute kidney [...] Read more.
Src family kinases (SFKs) are non-receptor tyrosine kinases and play a key role in regulating signal transduction. The mechanism of SFKs in various tumors has been widely studied, and there are more and more studies on its role in the kidney. Acute kidney injury (AKI) is a disease with complex pathogenesis, including oxidative stress (OS), inflammation, endoplasmic reticulum (ER) stress, autophagy, and apoptosis. In addition, fibrosis has a significant impact on the progression of AKI to developing chronic kidney disease (CKD). The mortality rate of this disease is very high, and there is no effective treatment drug at present. In recent years, some studies have found that SFKs, especially Src, Fyn, and Lyn, are involved in the pathogenesis of AKI. In this paper, the structure, function, and role of SFKs in AKI are discussed. SFKs play a crucial role in the occurrence and development of AKI, making them promising molecular targets for the treatment of AKI. Full article
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20 pages, 2336 KiB  
Review
P2 Receptors: Novel Disease Markers and Metabolic Checkpoints in Immune Cells
by Valentina Vultaggio-Poma and Francesco Di Virgilio
Biomolecules 2022, 12(7), 983; https://doi.org/10.3390/biom12070983 - 14 Jul 2022
Cited by 6 | Viewed by 2741
Abstract
Extracellular ATP (eATP) and P2 receptors are novel emerging regulators of T-lymphocyte responses. Cellular ATP is released via multiple pathways and accumulates at sites of tissue damage and inflammation. P2 receptor expression and function are affected by numerous single nucleotide polymorphisms (SNPs) associated [...] Read more.
Extracellular ATP (eATP) and P2 receptors are novel emerging regulators of T-lymphocyte responses. Cellular ATP is released via multiple pathways and accumulates at sites of tissue damage and inflammation. P2 receptor expression and function are affected by numerous single nucleotide polymorphisms (SNPs) associated with diverse disease conditions. Stimulation by released nucleotides (purinergic signalling) modulates several T-lymphocyte functions, among which energy metabolism. Energy metabolism, whether oxidative or glycolytic, in turn deeply affects T-cell activation, differentiation and effector responses. Specific P2R subtypes, among which the P2X7 receptor (P2X7R), are either up- or down-regulated during T-cell activation and differentiation; thus, they can be considered indexes of activation/quiescence, reporters of T-cell metabolic status and, in principle, markers of immune-mediated disease conditions. Full article
(This article belongs to the Special Issue Advances in Immunogenetic Markers of Human Multifactorial Diseases)
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20 pages, 1173 KiB  
Review
Epigenetic Reprogramming of the Inflammatory Response in Obesity and Type 2 Diabetes
by Federica Zatterale, Gregory Alexander Raciti, Immacolata Prevenzano, Alessia Leone, Michele Campitelli, Veronica De Rosa, Francesco Beguinot and Luca Parrillo
Biomolecules 2022, 12(7), 982; https://doi.org/10.3390/biom12070982 - 14 Jul 2022
Cited by 11 | Viewed by 2618
Abstract
For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these [...] Read more.
For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these conditions are accompanied by major abnormalities in fuel metabolism, evidence indicates that altered immune cell functions also play an important role in shaping of obesity and T2D phenotypes. Interestingly, these events have been shown to be determined by epigenetic mechanisms. Consistently, recent epigenome-wide association studies have demonstrated that immune cells from obese and T2D individuals feature specific epigenetic profiles when compared to those from healthy subjects. In this work, we have reviewed recent literature reporting epigenetic changes affecting the immune cell phenotype and function in obesity and T2D. We will further discuss therapeutic strategies targeting epigenetic marks for treating obesity and T2D-associated inflammation. Full article
(This article belongs to the Special Issue Advances in Immunogenetic Markers of Human Multifactorial Diseases)
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