Biomolecules

13 pages, 1469 KiB

Open AccessEditor’s ChoiceReview

Oxidative Stress and Phototherapy in Atopic Dermatitis: Mechanisms, Role, and Future Perspectives

by Francesco Borgia, Federica Li Pomi, Mario Vaccaro, Clara Alessandrello, Vincenzo Papa and Sebastiano Gangemi

Biomolecules 2022, 12(12), 1904; https://doi.org/10.3390/biom12121904 - 19 Dec 2022

Cited by 23 | Viewed by 3593

Abstract

Atopic dermatitis is a chronic inflammatory skin disease in which the overproduction of reactive oxygen species plays a pivotal role in the pathogenesis and persistence of inflammatory lesions. Phototherapy represents one of the most used therapeutic options, with benefits in the clinical picture. [...] Read more.

Atopic dermatitis is a chronic inflammatory skin disease in which the overproduction of reactive oxygen species plays a pivotal role in the pathogenesis and persistence of inflammatory lesions. Phototherapy represents one of the most used therapeutic options, with benefits in the clinical picture. Studies have demonstrated the immunomodulatory effect of phototherapy and its role in reducing molecule hallmarks of oxidative stress. In this review, we report the data present in literature dealing with the main signaling molecular pathways involved in oxidative stress after phototherapy to target atopic dermatitis-affected cells. Since oxidative stress plays a pivotal role in the pathogenesis of atopic dermatitis and its flare-up, new research lines could be opened to study new drugs that act on this mechanism, perhaps in concert with phototherapy. Full article

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21 pages, 3034 KiB

Open AccessArticle

Novel Selective and Low-Toxic Inhibitor of LmCPB2.8ΔCTE (CPB) One Important Cysteine Protease for Leishmania Virulence

by Vitor Partite Moreira, Michele Ferreira da Silva Mela, Luana Ribeiro dos Anjos, Leonardo Figueiredo Saraiva, Angela M. Arenas Velásquez, Predrag Kalaba, Anna Fabisiková, Leandro da Costa Clementino, Mohammed Aufy, Christian Studenik, Natalie Gajic, Alexander Prado-Roller, Alvicler Magalhães, Martin Zehl, Ingrid Delbone Figueiredo, Amanda Martins Baviera, Eduardo Maffud Cilli, Marcia A. S. Graminha, Gert Lubec and Eduardo R. Perez Gonzalez

Biomolecules 2022, 12(12), 1903; https://doi.org/10.3390/biom12121903 - 19 Dec 2022

Cited by 7 | Viewed by 2233

Abstract

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed [...] Read more.

Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N′-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC_50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug. Full article

(This article belongs to the Section Chemical Biology)

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24 pages, 853 KiB

Open AccessFeature PaperEditor’s ChoiceReview

One-Carbon and Polyamine Metabolism as Cancer Therapy Targets

by Anowarul Islam, Zeeshan Shaukat, Rashid Hussain and Stephen L. Gregory

Biomolecules 2022, 12(12), 1902; https://doi.org/10.3390/biom12121902 - 19 Dec 2022

Cited by 10 | Viewed by 4247

Abstract

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key [...] Read more.

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key output of one-carbon metabolism with widespread effects on gene expression and signaling. As a result of these functions, one-carbon and polyamine metabolism have recently drawn a lot of interest for their part in cancer malignancy. Therapeutic inhibitors that target one-carbon and polyamine metabolism have thus been trialed as anticancer medications. The significance and future possibilities of one-carbon and polyamine metabolism as a target in cancer therapy are discussed in this review. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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14 pages, 1829 KiB

Open AccessArticle

Phenylbenzohydrazides Obtained from Isatoic Anhydride Present Anti-Inflammatory Activity In Vivo and In Vitro

by João Pedro Barros Paiva, Millena Santos Cordeiro, Patricia Ribeiro Carvalho França, Luiz Octavio Pereira Branco, Isabela Souza Santos, Nanashara Figueiredo Reis, Patrick Pedro Pimentel, Thais Biondino Sardella Giorno, Evanoel Crizanto Lima and Patricia Dias Fernandes

Biomolecules 2022, 12(12), 1901; https://doi.org/10.3390/biom12121901 - 19 Dec 2022

Cited by 2 | Viewed by 1766

Abstract

Background: Despite the existence of a wide variety of anti-inflammatory drugs, the vast majority are classified as steroidal or non-steroidal. Both classes present a variety of side effects that limit usage. Thus, the search for new molecules with anti-inflammatory potential is still important. [...] Read more.

Background: Despite the existence of a wide variety of anti-inflammatory drugs, the vast majority are classified as steroidal or non-steroidal. Both classes present a variety of side effects that limit usage. Thus, the search for new molecules with anti-inflammatory potential is still important. Methods: Five phenylbenzohydrazides were synthetized and evaluated in pre-clinical models of acute inflammation in vivo and in vitro. Results: The new substances (INL-06, -07, -10, and -11), as well as AISCT, significantly reduced cell migration induced by carrageenan. It was also observed that all INLs inhibited protein extravasation as well as cytokines (IL-6, IL-1β, and TNF-α) and nitric oxide (NO) production. The INL-11 was demonstrated to be the most potent, since the inhibition observed in several parameters was significant even when compared with dexamethasone. In vitro INLs also reduced cytokines and NO production and inducible nitric oxide (iNOS) enzyme activity. The INL-11 was the most effective in reducing cell migration in vitro. Conclusions: Our data suggest that these substances are suitable for further development into a new series of compounds that could lead to new hits and future drug prototypes for anti-inflammatory conditions. Full article

(This article belongs to the Topic Compounds with Medicinal Value (2nd Volume))

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14 pages, 2262 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Novel Selenopolysaccharide Isolated from Lentinula edodes Mycelium on Human T Lymphocytes Activation, Proliferation, and Cytokines Synthesis

by Aleksander Roszczyk, Michał Zych, Katarzyna Zielniok, Natalia Krata, Jadwiga Turło, Marzenna Klimaszewska, Radosław Zagożdżon and Beata Kaleta

Biomolecules 2022, 12(12), 1900; https://doi.org/10.3390/biom12121900 - 19 Dec 2022

Cited by 4 | Viewed by 2149

Abstract

Polysaccharides isolated from Lentinula edodes are bioactive compounds with immunomodulatory properties. In our previous studies from L. edodes mycelium, we have isolated a selenium(Se)-enriched fraction (named Se-Le-30), a mixture of linear 1,4-α-glucan and linear 1,3-β- and 1,6-β-glucans. In this study, we analyzed the [...] Read more.

Polysaccharides isolated from Lentinula edodes are bioactive compounds with immunomodulatory properties. In our previous studies from L. edodes mycelium, we have isolated a selenium(Se)-enriched fraction (named Se-Le-30), a mixture of linear 1,4-α-glucan and linear 1,3-β- and 1,6-β-glucans. In this study, we analyzed the effects of Se-Le-30 on the activation and proliferation of human T lymphocytes stimulated by anti-CD3 and anti-CD3/CD28 antibodies (Abs) and on the production of cytokines by peripheral blood mononuclear cells (PBMCs). Se-Le-30 had effects on T cell proliferation induced by Abs against CD3 and CD28. It significantly inhibited the proliferation of CD3-stimulated CD4⁺ and CD8⁺ T cells and enhanced the proliferation of CD4⁺ T cells stimulated with anti-CD3/CD28 Ab. Moreover, Se-Le-30 downregulated the number of CD3-stimulated CD4⁺CD69⁺ cells, CD4⁺CD25⁺ cells, as well as CD8⁺CD25⁺ cells, and upregulated the expression of CD25 marker on CD4+ and CD8+ T cells activated with anti-CD3/CD28 Abs. Furthermore, Se-Le-30 enhanced the synthesis of IFN-γ by the unstimulated and anti-CD3/CD28-stimulated PBMCs, inhibited synthesis of IL-2 and IL-4 by CD3-stimulated cells, and augmented the synthesis of IL-6 and IL-10 by unstimulated, CD3-stimulated, and CD3/CD28-stimulated PBMCs. Together, we demonstrated that Se-Le-30 exerts immunomodulatory effects on human T lymphocytes. These observations are of importance for the prospective use of Se-Le-30 in research or as a therapeutic compound. Full article

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10 pages, 1323 KiB

Open AccessArticle

Elevated Expression and Activation of GPR15 in Immune Cells in Graves’ Disease

by Jing Zhao, Xuerong Liu, Jianbin Xu, Yudie Fang, Peng Du, Chaoqun Gao, Tiantian Cai, Zhaohua Gu, Qiu Qin and Jin’an Zhang

Biomolecules 2022, 12(12), 1899; https://doi.org/10.3390/biom12121899 - 18 Dec 2022

Cited by 2 | Viewed by 2109

Abstract

GPR15 plays an important role in lymphocyte homing and is a key immune molecule to maintain organ immune homeostasis. Yet, no study on the association between GPR15 and Graves’ disease (GD) is available. In this study, we systematically investigated the expression of GPR15 [...] Read more.

GPR15 plays an important role in lymphocyte homing and is a key immune molecule to maintain organ immune homeostasis. Yet, no study on the association between GPR15 and Graves’ disease (GD) is available. In this study, we systematically investigated the expression of GPR15 in different types of immune cells and different tissues of GD patients. We found that the expressions of GPR15 and GPR15L in peripheral blood of GD patients were increased compared with those in healthy controls. A flow cytometry analysis showed that GPR15 positive cells were mainly CD14+ monocytes and CD56+ natural killer cells (NK cells) of innate immunity, T helper cells and cytotoxic T cells of adaptive immunity. We also found that the expressions of GPR15 and GPR15L in the PBMC of GD patients were positively correlated with the Tfh-specific cytokines IL21 and IL4. In addition, immunohistochemistry showed that the level of GPR15 in thyroid tissue of GD patients was higher than that of the control group. Our results demonstrate for the first time that GPR15 is highly expressed in various immune cells in GD patients, suggesting that GPR15-GPR15L is associated with the activation and infiltration of proinflammatory immune cells in the thyroid tissue of GD patients. Full article

(This article belongs to the Special Issue The Role of CD4⁺ Th Cells and Regulatory T Cells in Autoimmune Diseases)

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17 pages, 2775 KiB

Open AccessArticle

Genetic Ablation of Ankrd1 Mitigates Cardiac Damage during Experimental Autoimmune Myocarditis in Mice

by Ieva Rinkūnaitė, Egidijus Šimoliūnas, Milda Alksnė, Gabrielė Bartkutė, Siegfried Labeit, Virginija Bukelskienė and Julius Bogomolovas

Biomolecules 2022, 12(12), 1898; https://doi.org/10.3390/biom12121898 - 18 Dec 2022

Cited by 1 | Viewed by 2606

Abstract

Myocarditis (MC) is an inflammatory disease of the myocardium that can cause sudden death in the acute phase, and dilated cardiomyopathy (DCM) with chronic heart failure as its major long-term outcome. However, the molecular mechanisms beyond the acute MC phase remain poorly understood. [...] Read more.

Myocarditis (MC) is an inflammatory disease of the myocardium that can cause sudden death in the acute phase, and dilated cardiomyopathy (DCM) with chronic heart failure as its major long-term outcome. However, the molecular mechanisms beyond the acute MC phase remain poorly understood. The ankyrin repeat domain 1 (ANKRD1) is a functionally pleiotropic stress/stretch-inducible protein, which can modulate cardiac stress response during various forms of pathological stimuli; however, its involvement in post-MC cardiac remodeling leading to DCM is not known. To address this, we induced experimental autoimmune myocarditis (EAM) in ANKRD1-deficient mice, and evaluated post-MC consequences at the DCM stage mice hearts. We demonstrated that ANKRD1 does not significantly modulate heart failure; nevertheless, the genetic ablation of Ankrd1 blunted the cardiac damage/remodeling and preserved heart function during post-MC DCM. Full article

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

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19 pages, 1215 KiB

Open AccessReview

Phenolipids, Amphipilic Phenolic Antioxidants with Modified Properties and Their Spectrum of Applications in Development: A Review

by Silvia Ivonne Arzola-Rodríguez, Laila-Nayzzel Muñoz-Castellanos, César López-Camarillo and Erika Salas

Biomolecules 2022, 12(12), 1897; https://doi.org/10.3390/biom12121897 - 17 Dec 2022

Cited by 15 | Viewed by 3065

Abstract

Polyphenols, as secondary metabolites from plants, possess a natural antioxidant capacity and biological activities attributed to their chemical and structural characteristics. Due to their mostly polar character, polyphenols present a low solubility in less polar environments or hydrophobic matrices. However, in order to [...] Read more.

Polyphenols, as secondary metabolites from plants, possess a natural antioxidant capacity and biological activities attributed to their chemical and structural characteristics. Due to their mostly polar character, polyphenols present a low solubility in less polar environments or hydrophobic matrices. However, in order to make polyphenols able to incorporate in oils and fats, a transformation strategy is necessary. For the above, the functionalization of polyphenols through chemical or enzymatic lipophilization has allowed the synthesis of phenolipids. These are amphipilic molecules that preserve the natural phenolic core to which an aliphatic motif is attached by esterification or transesterification reactions. The length of the aliphatic chain in phenolipids allows them to interact with different systems (such as emulsions, oily molecules, micelles and cellular membranes), which would favor their use in processed foods, as vehicles for drugs, antimicrobial agents, antioxidants in the cosmetic industry and even in the treatment of degenerative diseases related to oxidative stress Full article

(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Phenolic Compounds Derivatives)

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16 pages, 2158 KiB

Open AccessArticle

Concomitant Administration of Red Ginseng Extract with Lactic Acid Bacteria Increases the Plasma Concentration of Deglycosylated Ginsenosides in Healthy Human Subjects

by Ji-Hyeon Jeon, Jin-Hyang Park, So Yeon Jeon, Minyeong Pang, Min-Koo Choi and Im-Sook Song

Biomolecules 2022, 12(12), 1896; https://doi.org/10.3390/biom12121896 - 17 Dec 2022

Cited by 7 | Viewed by 2031

Abstract

With the increased frequency of red ginseng extract (RGE) and lactic acid bacteria (LAB) co-administration, we aimed to investigate the interactions between RGE and LAB with regard to in vitro and in vivo deglycosylation metabolism and the pharmacokinetics of ginsenosides. As a proof-of-concept [...] Read more.

With the increased frequency of red ginseng extract (RGE) and lactic acid bacteria (LAB) co-administration, we aimed to investigate the interactions between RGE and LAB with regard to in vitro and in vivo deglycosylation metabolism and the pharmacokinetics of ginsenosides. As a proof-of-concept study, five healthy humans were administered RGE (104.1 mg of total ginsenosides/day) with or without co-administration of LAB (2 g, 1 billion CFU/day) for 2 weeks, and the plasma concentrations of ginsenosides in human plasma were monitored. The plasma exposure to compound K (CK), ginsenoside Rh2 (GRh2), protopanaxadiol (PPD), and protopanaxatriol (PPT) in the concomitant administration RGE and LAB groups increased by 2.7-, 2.1-, 1.6-, and 3.5-fold, respectively, compared to those in the RGE administration group, without a significant change in T_max. The plasma concentrations of GRb1, GRb2, and GRc remained unchanged, whereas the AUC values of GRd and GRg3 significantly decreased in the concomitant administration RGE and LAB groups. To understand the underlying mechanism, the in vitro metabolic activity of ginsenosides was measured during the fermentation of RGE or individual ginsenosides in the presence of LAB for 1 week. Consistent with the in vivo results, co-incubation with RGE and LAB significantly increased the formation rate of GRh2, CK, PPD, and PPT. These results may be attributed to the facilitated deglycosylation of GRd and GRg3 and the increased production of GRh2, CK, PPD, and PPT by the co-administration of LAB and RGE. In conclusion, LAB supplementation increased the plasma concentrations of deglycosylated ginsenosides, such as GRh2, CK, PPD, and PPT, through facilitated deglycosylation metabolism of ginsenosides in the intestine. Full article

(This article belongs to the Special Issue Advances in Ginsenosides 2.0)

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12 pages, 2742 KiB

Open AccessEditor’s ChoiceArticle

Effects of the Myokine Irisin on Stromal Cells from Swine Adipose Tissue

by Giuseppina Basini, Simona Bussolati, Stefano Grolli, Priscilla Berni, Rosanna Di Lecce and Francesca Grasselli

Biomolecules 2022, 12(12), 1895; https://doi.org/10.3390/biom12121895 - 17 Dec 2022

Cited by 5 | Viewed by 1675

Abstract

Irisin is a hormone able to reproduce some of the positive effects of physical activity and diet. Recently, we demonstrated the presence of Irisin at the ovarian level as a potential physiological regulator of follicular function. Adipose tissue is crucial for reproductive function [...] Read more.

Irisin is a hormone able to reproduce some of the positive effects of physical activity and diet. Recently, we demonstrated the presence of Irisin at the ovarian level as a potential physiological regulator of follicular function. Adipose tissue is crucial for reproductive function through its metabolic activity and the production of adipokines. At present, the exact nature of adipocyte precursors is still under debate, but an important role has been assigned to the population of adipose tissue mesenchymal stromal cells (ASCs) of perivascular origin. It should be noted that, when appropriately stimulated, ASCs can differentiate into preadipocytes and, subsequently, adipocytes. Therefore, this present study was undertaken to explore the potential effect of Irisin on ASCs, known for their high differentiative potential. Since Irisin expression in ASCs was confirmed by PCR, we tested its potential effects on the main functional activities of these cells, including proliferation (BrdU uptake); metabolic activity (ATP production); redox status, evaluated as the generation of free molecules such as superoxide anion and nitric oxide; and scavenger activities, assessed as both enzymatic (superoxide dismutase) and non-enzymatic antioxidant power. Moreover, we tested the effect of Irisin on ASCs adipogenic differentiation. BrdU uptake was significantly (p < 0.001) inhibited by Irisin, while ATP production was significantly (p < 0.05) increased. Both superoxide anion and nitric oxide generation were significantly increased (p < 0.001) by Irisin, while scavenger activity was significantly reduced (p < 0.05). Irisin was found to significantly (p < 0.05) inhibit ASCs adipogenic differentiation. Taken together, the present results suggest a potential local role of Irisin in the regulation of adipose tissue function. Full article

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13 pages, 1422 KiB

Open AccessArticle

Modulation of Anionic Lipid Bilayers by Specific Interplay of Protons and Calcium Ions

by Abhinav, Piotr Jurkiewicz, Martin Hof, Christoph Allolio and Jan Sýkora

Biomolecules 2022, 12(12), 1894; https://doi.org/10.3390/biom12121894 - 17 Dec 2022

Cited by 1 | Viewed by 2084

Abstract

Biomembranes, important building blocks of living organisms, are often exposed to large local fluctuations of pH and ionic strength. To capture changes in the membrane organization under such harsh conditions, we investigated the mobility and hydration of zwitterionic and anionic lipid bilayers upon [...] Read more.

Biomembranes, important building blocks of living organisms, are often exposed to large local fluctuations of pH and ionic strength. To capture changes in the membrane organization under such harsh conditions, we investigated the mobility and hydration of zwitterionic and anionic lipid bilayers upon elevated H₃O⁺ and Ca²⁺ content by the time-dependent fluorescence shift (TDFS) technique. While the zwitterionic bilayers remain inert to lower pH and increased calcium concentrations, anionic membranes are responsive. Specifically, both bilayers enriched in phosphatidylserine (PS) and phosphatidylglycerol (PG) become dehydrated and rigidified at pH 4.0 compared to at pH 7.0. However, their reaction to the gradual Ca²⁺ increase in the acidic environment differs. While the PG bilayers exhibit strong rehydration and mild loosening of the carbonyl region, restoring membrane properties to those observed at pH 7.0, the PS bilayers remain dehydrated with minor bilayer stiffening. Molecular dynamics (MD) simulations support the strong binding of H₃O⁺ to both PS and PG. Compared to PS, PG exhibits a weaker binding of Ca²⁺ also at a low pH. Full article

(This article belongs to the Special Issue Proton and Proton-Coupled Transport)

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18 pages, 4708 KiB

Open AccessArticle

Influence of Diets Enriched with Flavonoids (Cocoa and Hesperidin) on the Systemic Immunity of Intensively Trained and Exhausted Rats

by Patricia Ruiz-Iglesias, Malén Massot-Cladera, Francisco J. Pérez-Cano and Margarida Castell

Biomolecules 2022, 12(12), 1893; https://doi.org/10.3390/biom12121893 - 17 Dec 2022

Cited by 3 | Viewed by 2098

Abstract

The aim of this study was to establish the influence of flavonoid-enriched diets on the immune alterations induced by an intensive training and a final exhaustion test in rats. A flavanol-enriched diet (with 10% cocoa, C10 diet) and a flavanol and flavanone-enriched diet [...] Read more.

The aim of this study was to establish the influence of flavonoid-enriched diets on the immune alterations induced by an intensive training and a final exhaustion test in rats. A flavanol-enriched diet (with 10% cocoa, C10 diet) and a flavanol and flavanone-enriched diet (C10 plus 0.5% hesperidin, CH diet) were used. Lewis rats were fed either a standard diet, C10 diet or CH diet while they were submitted to an intensive running training on a treadmill. After 6 weeks, samples were obtained 24 h after performing a regular training (T groups) and after carrying out a final exhaustion test (TE groups). The C10 diet attenuated the increase in plasma cortisol induced by exhaustion, while both the C10 and the CH diets prevented the alterations in the spleen Th cell proportion. The experimental diets also induced an increase in serum immunoglobulin concentration and an enhancement of spleen natural killer cytotoxicity, which may be beneficial in situations with a weakened immunity. Most of the effects observed in the CH groups seem to be due to the cocoa content. Overall, a dietary intervention with flavonoids enhances immune function, partially attenuating the alterations in systemic immunity induced by intensive training or exhausting exercise. Full article

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

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14 pages, 629 KiB

Open AccessArticle

IL-1 Superfamily Member (IL-1A, IL-1B and IL-18) Genetic Variants Influence Susceptibility and Clinical Course of Mediterranean Spotter Fever

by Letizia Scola, Giovanni Pilato, Rosa Maria Giarratana, Giuseppa Luisa Sanfilippo, Domenico Lio, Claudia Colomba and Giovanni Maurizio Giammanco

Biomolecules 2022, 12(12), 1892; https://doi.org/10.3390/biom12121892 - 17 Dec 2022

Cited by 2 | Viewed by 2063

Abstract

Mediterranean Spotted Fever (MSF) is one of the most common spotted fever Rickettsioses. Most cases of MSF follow a benign course, with a minority of cases being fatal. The severity of the infection depends on bacterial virulence, dose and host factors such as [...] Read more.

Mediterranean Spotted Fever (MSF) is one of the most common spotted fever Rickettsioses. Most cases of MSF follow a benign course, with a minority of cases being fatal. The severity of the infection depends on bacterial virulence, dose and host factors such as effective immune response and genetic background. Herein, we reported data on typing by competitive allele-specific PCR of functionally relevant polymorphisms of genes coding for MyD88 adapter-like (Mal/TIRAP) protein (rs8177374), interleukin(IL)-1 cluster (IL-1A rs1800587, IL-1B rs16944 and rs1143634) and IL-18 (rs187238), which might be crucial for an efficient immune response. The results enlighten the role that IL-1 gene cluster variants might play in susceptibility against Rickettsia conorii infection. In particular, the IL-1A rs1800587TT genotype was significantly increased in patients alone and combined in a haplotype composed by minor alleles rs1800587T, rs16944A and rs1143634A. This result was confirmed using the decision tree heuristic approach. Using this methodology, IL-1A rs1800587TT genotype was the better discrimination key among MSF patients and controls. In addition, the IL-1 gene cluster SNP genotypes containing minor alleles and IL-18 rs187238G positive genotypes were found as associated with risk of severe complications such as sepsis, septic shock, acute respiratory distress syndrome and coma. In conclusion, these data suggest that the evaluation of IL-1A, IL-1B and IL-18 gene SNPs can add useful information on the clinical course of patients affected by Mediterranean Spotted Fever, even if further confirmatory studies will be necessary. Full article

(This article belongs to the Special Issue Advances in Immunogenetic Markers of Human Multifactorial Diseases)

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13 pages, 2282 KiB

Open AccessEditor’s ChoiceReview

Calcium Overload and Mitochondrial Metabolism

by Lauren L. Walkon, Jasiel O. Strubbe-Rivera and Jason N. Bazil

Biomolecules 2022, 12(12), 1891; https://doi.org/10.3390/biom12121891 - 17 Dec 2022

Cited by 52 | Viewed by 5430

Abstract

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates [...] Read more.

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo–electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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19 pages, 6685 KiB

Open AccessArticle

Identification and Validation of Cuproptosis-Related LncRNA Signatures in the Prognosis and Immunotherapy of Clear Cell Renal Cell Carcinoma Using Machine Learning

by Zhixun Bai, Jing Lu, Anjian Chen, Xiang Zheng, Mingsong Wu, Zhouke Tan and Jian Xie

Biomolecules 2022, 12(12), 1890; https://doi.org/10.3390/biom12121890 - 16 Dec 2022

Cited by 9 | Viewed by 2868

Abstract

(1) Objective: We aimed to mine cuproptosis-related LncRNAs with prognostic value and construct a corresponding prognostic model using machine learning. External validation of the model was performed in the ICGC database and in multiple renal cancer cell lines via qPCR. (2) Methods: TCGA [...] Read more.

(1) Objective: We aimed to mine cuproptosis-related LncRNAs with prognostic value and construct a corresponding prognostic model using machine learning. External validation of the model was performed in the ICGC database and in multiple renal cancer cell lines via qPCR. (2) Methods: TCGA and ICGC cohorts related to renal clear cell carcinoma were included. GO and KEGG analyses were conducted to determine the biological significance of differentially expressed cuproptosis-related LncRNAs (CRLRs). Machine learning (LASSO), Kaplan–Meier, and Cox analyses were conducted to determine the prognostic genes. The tumor microenvironment and tumor mutation load were further studied. TIDE and IC50 were used to evaluate the response to immunotherapy, a risk model of LncRNAs related to the cuproptosis genes was established, and the ability of this model was verified in an external independent ICGC cohort. LncRNAs were identified in normal HK-2 cells and verified in four renal cell lines via qPCR. (3) Results: We obtained 280 CRLRs and identified 66 LncRNAs included in the TCGA-KIRC cohort. Then, three hub LncRNAs (AC026401.3, FOXD2−AS1, and LASTR), which were over-expressed in the four ccRCC cell lines compared with the human renal cortex proximal tubule epithelial cell line HK-2, were identified. In the ICGC database, the expression of FOXD2-AS1 and LASTR was consistent with the qPCR and TCGA-KIRC. The results also indicated that patients with low-risk ccRCC—stratified by tumor-node metastasis stage, sex, and tumor grade—had significantly better overall survival than those with high-risk ccRCC. The predictive algorithm showed that, according to the three CRLR models, the low-risk group was more sensitive to nine target drugs (A.443654, A.770041, ABT.888, AG.014699, AMG.706, ATRA, AP.24534, axitinib, and AZ628), based on the estimated half-maximal inhibitory concentrations. In contrast, the high-risk group was more sensitive to ABT.263 and AKT inhibitors VIII and AS601245. Using the CRLR models, the correlation between the tumor immune microenvironment and cancer immunotherapy response revealed that high-risk patients are more likely to respond to immunotherapy than low-risk patients. In terms of immune marker levels, there were significant differences between the high- and low-risk groups. A high TMB score in the high-risk CRLR group was associated with worse survival, which could be a prognostic factor for KIRC. (4) Conclusions: This study elucidates the core cuproptosis-related LncRNAs, FOXD2−AS1, AC026401.3, and LASTR, in terms of potential predictive value, immunotherapeutic strategy, and outcome of ccRCC. Full article

(This article belongs to the Special Issue Identification of Important Biomolecules of Chronic Diseases from Multi-Omics Data by Using Machine Learning and Deep Learning)

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14 pages, 1020 KiB

Open AccessFeature PaperReview

Unconventional Myosins from Caenorhabditis elegans as a Probe to Study Human Orthologues

by Chloe A Johnson, Ranya Behbehani and Folma Buss

Biomolecules 2022, 12(12), 1889; https://doi.org/10.3390/biom12121889 - 16 Dec 2022

Cited by 2 | Viewed by 2290

Abstract

Unconventional myosins are a superfamily of actin-based motor proteins that perform a number of roles in fundamental cellular processes, including (but not limited to) intracellular trafficking, cell motility, endocytosis, exocytosis and cytokinesis. 40 myosins genes have been identified in humans, which belong to [...] Read more.

Unconventional myosins are a superfamily of actin-based motor proteins that perform a number of roles in fundamental cellular processes, including (but not limited to) intracellular trafficking, cell motility, endocytosis, exocytosis and cytokinesis. 40 myosins genes have been identified in humans, which belong to different 12 classes based on their domain structure and organisation. These genes are widely expressed in different tissues, and mutations leading to loss of function are associated with a wide variety of pathologies while over-expression often results in cancer. Caenorhabditis elegans (C. elegans) is a small, free-living, non-parasitic nematode. ~38% of the genome of C. elegans has predicted orthologues in the human genome, making it a valuable tool to study the function of human counterparts and human diseases. To date, 8 unconventional myosin genes have been identified in the nematode, from 6 different classes with high homology to human paralogues. The hum-1 and hum-5 (heavy chain of an unconventional myosin) genes encode myosin of class I, hum-2 of class V, hum-3 and hum-8 of class VI, hum-6 of class VII and hum-7 of class IX. The hum-4 gene encodes a high molecular mass myosin (307 kDa) that is one of the most highly divergent myosins and is a member of class XII. Mutations in many of the human orthologues are lethal, indicating their essential properties. However, a functional characterisation for many of these genes in C. elegans has not yet been performed. This article reviews the current knowledge of unconventional myosin genes in C. elegans and explores the potential use of the nematode to study the function and regulation of myosin motors to provide valuable insights into their role in diseases. Full article

(This article belongs to the Special Issue Actin and Its Associates: Biophysical Aspects in Functional Roles)

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13 pages, 3688 KiB

Open AccessArticle

Exploiting the Generative Adversarial Network Approach to Create a Synthetic Topography Corneal Image

by Samer Kais Jameel, Sezgin Aydin, Nebras H. Ghaeb, Jafar Majidpour, Tarik A. Rashid, Sinan Q. Salih and Poh Soon JosephNg

Biomolecules 2022, 12(12), 1888; https://doi.org/10.3390/biom12121888 - 16 Dec 2022

Cited by 12 | Viewed by 2670

Abstract

Corneal diseases are the most common eye disorders. Deep learning techniques are used to perform automated diagnoses of cornea. Deep learning networks require large-scale annotated datasets, which is conceded as a weakness of deep learning. In this work, a method for synthesizing medical [...] Read more.

Corneal diseases are the most common eye disorders. Deep learning techniques are used to perform automated diagnoses of cornea. Deep learning networks require large-scale annotated datasets, which is conceded as a weakness of deep learning. In this work, a method for synthesizing medical images using conditional generative adversarial networks (CGANs), is presented. It also illustrates how produced medical images may be utilized to enrich medical data, improve clinical decisions, and boost the performance of the conventional neural network (CNN) for medical image diagnosis. The study includes using corneal topography captured using a Pentacam device from patients with corneal diseases. The dataset contained 3448 different corneal images. Furthermore, it shows how an unbalanced dataset affects the performance of classifiers, where the data are balanced using the resampling approach. Finally, the results obtained from CNN networks trained on the balanced dataset are compared to those obtained from CNN networks trained on the imbalanced dataset. For performance, the system estimated the diagnosis accuracy, precision, and F1-score metrics. Lastly, some generated images were shown to an expert for evaluation and to see how well experts could identify the type of image and its condition. The expert recognized the image as useful for medical diagnosis and for determining the severity class according to the shape and values, by generating images based on real cases that could be used as new different stages of illness between healthy and unhealthy patients. Full article

(This article belongs to the Special Issue Big Data Analysis in Human Disease)

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15 pages, 1947 KiB

Open AccessArticle

Portability of a Small-Molecule Binding Site between Disordered Proteins

by Rajesh Jaiprashad, Sachith Roch De Silva, Lisette M. Fred Lucena, Ella Meyer and Steven J. Metallo

Biomolecules 2022, 12(12), 1887; https://doi.org/10.3390/biom12121887 - 16 Dec 2022

Cited by 2 | Viewed by 2326

Abstract

Intrinsically disordered proteins (IDPs) are important in both normal and disease states. Small molecules can be targeted to disordered regions, but we currently have only a limited understanding of the nature of small-molecule binding sites in IDPs. Here, we show that a minimal [...] Read more.

Intrinsically disordered proteins (IDPs) are important in both normal and disease states. Small molecules can be targeted to disordered regions, but we currently have only a limited understanding of the nature of small-molecule binding sites in IDPs. Here, we show that a minimal small-molecule binding sequence of eight contiguous residues derived from the Myc protein can be ported into a different disordered protein and recapitulate small-molecule binding activity in the new context. We also find that the residue immediately flanking the binding site can have opposing effects on small-molecule binding in the different disordered protein contexts. The results demonstrate that small-molecule binding sites can act modularly and are portable between disordered protein contexts but that residues outside of the minimal binding site can modulate binding affinity. Full article

(This article belongs to the Special Issue Physics of Protein Folding, Misfolding, and Intrinsic Disorder: A Themed Issue in Honour of Professor Vladimir Uversky on the Occasion of His 60th Birthday)

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14 pages, 3511 KiB

Open AccessArticle

Insights into Non-Proteolytic Inhibitory Mechanisms of Polymorphic Early-Stage Amyloid β Oligomers by Insulin Degrading Enzyme

by Karina Abramov-Harpaz and Yifat Miller

Biomolecules 2022, 12(12), 1886; https://doi.org/10.3390/biom12121886 - 16 Dec 2022

Cited by 4 | Viewed by 1814

Abstract

Insulin degrading enzyme (IDE) has been detected in the cerebrospinal fluid media and plays a role in encapsulating and degrading the amyloid β (Aβ) monomer, thus regulating the levels of Aβ monomers. The current work illustrates a first study by which IDE encapsulates [...] Read more.

Insulin degrading enzyme (IDE) has been detected in the cerebrospinal fluid media and plays a role in encapsulating and degrading the amyloid β (Aβ) monomer, thus regulating the levels of Aβ monomers. The current work illustrates a first study by which IDE encapsulates polymorphic early-stage Aβ oligomers. The main goal of this study was to investigate the molecular mechanisms of IDE activity on the encapsulated early-stage Aβ dimers: fibril-like and random coil/α-helix dimers. Our work led to several findings. First, when the fibril-like Aβ dimer interacts with IDE-C domain, IDE does not impede the contact between the monomers, but plays a role as a ‘dead-end’ chaperone protein. Second, when the fibril-like Aβ dimer interacts with the IDE-N domain, IDE successfully impedes the contacts between monomers. Third, the inhibitory activity of IDE on random coil/α-helix dimers depends on the stability of the dimer. IDE could impede the contacts between monomers in relatively unstable random coil/α-helix dimers, but gets hard to impede in stable dimers. However, IDE encapsulates stable dimers and could serve as a ‘dead-end’ chaperone. Our results examine the molecular interactions between IDE and the dimers, and between the monomers within the dimers. Hence, this study provides insights into the inhibition mechanisms of the primary nucleation of Aβ aggregation and the basic knowledge for rational design to inhibit Aβ aggregation. Full article

(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)

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10 pages, 2304 KiB

Open AccessArticle

Mitochondrial Triglyceride Dysregulation in Optic Nerves Following Indirect Traumatic Optic Neuropathy

by Muhammad Z. Chauhan, Joseph G. Chacko, Alireza Ghaffarieh, Chloe M. Moulin, Daniel Pelaez, Sami H. Uwaydat and Sanjoy K. Bhattacharya

Biomolecules 2022, 12(12), 1885; https://doi.org/10.3390/biom12121885 - 15 Dec 2022

Cited by 2 | Viewed by 2296

Abstract

The purpose of this work is to identify mitochondrial optic nerve (ON) lipid alterations associated with sonication-induced traumatic optic neuropathy (TON). Briefly, a mouse model of indirect TON was generated using sound energy concentrated focally at the entrance of the optic canal using [...] Read more.

The purpose of this work is to identify mitochondrial optic nerve (ON) lipid alterations associated with sonication-induced traumatic optic neuropathy (TON). Briefly, a mouse model of indirect TON was generated using sound energy concentrated focally at the entrance of the optic canal using a laboratory sonifier (Branson Digital Sonifier 450, Danbury, CT, USA) with a microtip probe. We performed an analysis of a previously generated dataset from high-performance liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS). We analyzed lipids from isolated mitochondria from the ON at 1 day, 7 days, and 14 days post-sonication compared to non-sonicated controls. Lipid abundance alterations in post-sonicated ON mitochondria were evaluated with 1-way ANOVA (FDR-adjusted significant p-value < 0.01), debiased sparse partial correlation (DSPC) network modeling, and partial least squares-discriminant analysis (PLS-DA). We find temporal alterations in triglyceride metabolism are observed in ON mitochondria of mice following sonication-induced optic neuropathy with notable depletions of TG(18:1/18:2/18:2), TG(18:1/18:1/18:1), and TG(16:0/16:0/18:1). Depletion of mitochondrial triglycerides may mediate ON damage in indirect traumatic optic neuropathy through loss energy substrates for neuronal metabolism. Full article

(This article belongs to the Special Issue New Discoveries in Retinal Cell Degeneration and Retinal Diseases)

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10 pages, 278 KiB

Open AccessArticle

Vascular Endothelial Growth Factor and Its Soluble Receptor in Systemic Lupus Erythematosus Patients

by Fuensanta Gómez-Bernal, Yolanda Fernández-Cladera, Juan Carlos Quevedo-Abeledo, María García-González, Agustín F. González-Rivero, Antonia de Vera-González, Candelaria Martín-González, Miguel Á. González-Gay and Iván Ferraz-Amaro

Biomolecules 2022, 12(12), 1884; https://doi.org/10.3390/biom12121884 - 15 Dec 2022

Cited by 3 | Viewed by 1683

Abstract

Vascular endothelial growth factor (VEGF) is a major regulator of physiological and pathological angiogenesis. Its soluble receptor (sVEGFR) is a potent VEGF antagonist. Systemic lupus erythematosus (SLE) is an autoimmune disease with a diverse array of clinical manifestations that affect virtually any organ. [...] Read more.

Vascular endothelial growth factor (VEGF) is a major regulator of physiological and pathological angiogenesis. Its soluble receptor (sVEGFR) is a potent VEGF antagonist. Systemic lupus erythematosus (SLE) is an autoimmune disease with a diverse array of clinical manifestations that affect virtually any organ. We aimed to analyze the relationship of VEGF and sVEGFR with SLE disease-related features including disease activity, damage, and severity. Serum levels of VEGF165 isoform and sVEGFR (receptor 1) were assessed in 284 well-characterized patients with SLE. Linear regression analysis was performed to analyze the relationship of disease characteristics with both VEGF and sVEGFR. Patients with a disease damage index (SLICC score) equal to or greater than 1 had significantly elevated serum levels of VEGF and sVEGFR. Regarding disease-specific features, musculoskeletal manifestations were the disease feature most commonly associated with the upregulation of both VEGF and sVEGFR. SLE disease damage is associated with higher levels of VEGF and sVEGFR. Full article

36 pages, 14991 KiB

Open AccessArticle

An Integrated Analysis of Mechanistic Insights into Biomolecular Interactions and Molecular Dynamics of Bio-Inspired Cu(II) and Zn(II) Complexes towards DNA/BSA/SARS-CoV-2 3CL^pro by Molecular Docking-Based Virtual Screening and FRET Detection

by Karunganathan Sakthikumar, Bienfait Kabuyaya Isamura and Rui Werner Maçedo Krause

Biomolecules 2022, 12(12), 1883; https://doi.org/10.3390/biom12121883 - 15 Dec 2022

Cited by 2 | Viewed by 2459

Abstract

Novel constructed bioactive mixed-ligand complexes (1b) [Cu^II(L)₂(phen)] and (2b) [Zn^II(L)₂(phen)] {where, L = 2-(4-morpholinobenzylideneamino)phenol), phen = 1,10-phenanthroline} have been structurally analysed by various analytical and spectroscopic techniques, including, magnetic moments, thermogravimetric [...] Read more.

Novel constructed bioactive mixed-ligand complexes (1b) [Cu^II(L)₂(phen)] and (2b) [Zn^II(L)₂(phen)] {where, L = 2-(4-morpholinobenzylideneamino)phenol), phen = 1,10-phenanthroline} have been structurally analysed by various analytical and spectroscopic techniques, including, magnetic moments, thermogravimetric analysis, and X-ray crystallography. Various analytical and spectral measurements assigned showed that all complexes appear to have an octahedral geometry. Agar gel electrophoresis’s output demonstrated that the Cu(II) complex (1b) had efficient deoxyribonucleic cleavage and complex (2b) demonstrated the partial cleavage accomplished with an oxidation agent, which generates spreadable OH^● through the Fenton type mechanism. The DNA binding constants observed from viscosity, UV–Vis spectral, fluorometric, and electrochemical titrations were in the following sequence: (1b) > (2b) > (HL), which suggests that the complexes (1b–2b) might intercalate DNA, a possibility that is supported by the biothermodynamic measurements. In addition, the observed binding constant results of BSA by electronic absorption and fluorometric titrations indicate that complex (1b) revealed the best binding efficacy as compared to complex (2b) and free ligand. Interestingly, all compounds are found to interact with BSA through a static approach, as further attested by FRET detection. The DFT and molecular docking calculations were also performed to realize the electronic structure, reactivity, and binding capability of all test samples with CT-DNA, BSA, and the SARS-CoV-2 3CL^Pro, which revealed the binding energies were in a range of −8.1 to −8.9, −7.5 to −10.5 and −6.7–−8.8 kcal/mol, respectively. The higher reactivity of the complexes than the free ligand is supported by the FMO theory. Among all the observed data for antioxidant properties against DPPH^᛫, ^᛫OH, O₂^−• and NO^᛫ free radicals, complex (1a) had the best biological efficacy. The antimicrobial and cytotoxic characteristics of all test compounds have been studied by screening against certain selected microorganisms as well as against A549, HepG2, MCF-7, and NHDF cell lines, respectively. The observed findings revealed that the activity enhances coordination as compared to free ligand via Overtone’s and Tweedy’s chelation mechanisms. This is especially encouraging given that in every case, the experimental findings and theoretical detections were in perfect accord. Full article

(This article belongs to the Topic Bioactive Compounds with Application Potentials in Nutraceuticals and Nutricosmetics: Focus on Mechanism of Action and Application Science)

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20 pages, 1160 KiB

Open AccessReview

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma

by Peijun Zhu, Ting Li, Qingqing Li, Yawen Gu, Yuan Shu, Kaibo Hu, Leifeng Chen, Xiaogang Peng, Jie Peng and Liang Hao

Biomolecules 2022, 12(12), 1882; https://doi.org/10.3390/biom12121882 - 15 Dec 2022

Cited by 7 | Viewed by 3068

Abstract

Osteosarcoma is the most common malignant bone tumor, often occurring in children and adolescents. The etiology of most patients is unclear, and the current conventional treatment methods are chemotherapy, radiotherapy, and surgical resection. However, the sensitivity of osteosarcoma to radiotherapy and chemotherapy is [...] Read more.

Osteosarcoma is the most common malignant bone tumor, often occurring in children and adolescents. The etiology of most patients is unclear, and the current conventional treatment methods are chemotherapy, radiotherapy, and surgical resection. However, the sensitivity of osteosarcoma to radiotherapy and chemotherapy is low, and the prognosis is poor. The development of new and useful treatment strategies for improving patient survival is an urgent need. It has been found that endoplasmic reticulum (ER) stress (ERS) affects tumor angiogenesis, invasion, etc. By summarizing the literature related to osteosarcoma and ERS, we found that the unfolded protein response (UPR) pathway activated by ERS has a regulatory role in osteosarcoma proliferation, apoptosis, and chemoresistance. In osteosarcoma, the UPR pathway plays an important role by crosstalk with autophagy, oxidative stress, and other pathways. Overall, this article focuses on the relationship between ERS and osteosarcoma and reviews the potential of drugs or gene targets associated with ERS for the treatment of osteosarcoma. Full article

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19 pages, 4372 KiB

Open AccessArticle

Rapid and Highly Efficient Genetic Transformation and Application of Interleukin-17B Expressed in Duckweed as Mucosal Vaccine Adjuvant

by Xiao Tan, Shuang Chen, Yang Fang, Penghui Liu, Zhubin Hu, Yanling Jin, Zhuolin Yi, Kaize He, Xing Li, Leyi Zhao, Hongning Wang and Hai Zhao

Biomolecules 2022, 12(12), 1881; https://doi.org/10.3390/biom12121881 - 15 Dec 2022

Cited by 5 | Viewed by 3243

Abstract

Molecular farming utilizes plants as a platform for producing recombinant biopharmaceuticals. Duckweed, the smallest and fastest growing aquatic plant, is a promising candidate for molecular farming. However, the efficiency of current transformation methods is generally not high in duckweed. Here, we developed a [...] Read more.

Molecular farming utilizes plants as a platform for producing recombinant biopharmaceuticals. Duckweed, the smallest and fastest growing aquatic plant, is a promising candidate for molecular farming. However, the efficiency of current transformation methods is generally not high in duckweed. Here, we developed a fast and efficient transformation procedure in Lemna minor ZH0403, requiring 7–8 weeks from screening calluses to transgenic plants with a stable transformation efficiency of 88% at the DNA level and 86% at the protein level. We then used this transformation system to produce chicken interleukin-17B (chIL-17B). The plant-produced chIL-17B activated the NF-κB pathway, JAK-STAT pathway, and their downstream cytokines in DF-1 cells. Furthermore, we administrated chIL-17B transgenic duckweed orally as an immunoadjuvant with mucosal vaccine against infectious bronchitis virus (IBV) in chickens. Both IBV-specific antibody titer and the concentration of secretory immunoglobulin A (sIgA) were significantly higher in the group fed with chIL-17B transgenic plant. This indicates that the duckweed-produced chIL-17B enhanced the humoral and mucosal immune responses. Moreover, chickens fed with chIL-17B transgenic plant demonstrated the lowest viral loads in different tissues among all groups. Our work suggests that cytokines are a promising adjuvant for mucosal vaccination through the oral route. Our work also demonstrates the potential of duckweed in molecular farming. Full article

(This article belongs to the Collection Feature Papers in Synthetic Biology and Bioengineering)

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17 pages, 1281 KiB

Open AccessReview

Receptor-Mediated Redox Imbalance: An Emerging Clinical Avenue against Aggressive Cancers

by Xiaofeng Dai, Erik W. Thompson and Kostya (Ken) Ostrikov

Biomolecules 2022, 12(12), 1880; https://doi.org/10.3390/biom12121880 - 15 Dec 2022

Cited by 4 | Viewed by 2127

Abstract

Cancer cells are more vulnerable to abnormal redox fluctuations due to their imbalanced antioxidant system, where cell surface receptors sense stress and trigger intracellular signal relay. As canonical targets of many targeted therapies, cell receptors sensitize the cells to specific drugs. On the [...] Read more.

Cancer cells are more vulnerable to abnormal redox fluctuations due to their imbalanced antioxidant system, where cell surface receptors sense stress and trigger intracellular signal relay. As canonical targets of many targeted therapies, cell receptors sensitize the cells to specific drugs. On the other hand, cell target mutations are commonly associated with drug resistance. Thus, exploring effective therapeutics targeting diverse cell receptors may open new clinical avenues against aggressive cancers. This paper uses focused case studies to reveal the intrinsic relationship between the cell receptors of different categories and the primary cancer hallmarks that are associated with the responses to external or internal redox perturbations. Cold atmospheric plasma (CAP) is examined as a promising redox modulation medium and highly selective anti-cancer therapeutic modality featuring dynamically varying receptor targets and minimized drug resistance against aggressive cancers. Full article

(This article belongs to the Special Issue Advances in Plasma Bioscience and Medicine)

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17 pages, 2689 KiB

Open AccessArticle

UV Radiation Induces Specific Changes in the Carotenoid Profile of Arabidopsis thaliana

by Uthman O. Badmus, Gaia Crestani, Natalie Cunningham, Michel Havaux, Otmar Urban and Marcel A. K. Jansen

Biomolecules 2022, 12(12), 1879; https://doi.org/10.3390/biom12121879 - 14 Dec 2022

Cited by 12 | Viewed by 2482

Abstract

UV-B and UV-A radiation are natural components of solar radiation that can cause plant stress, as well as induce a range of acclimatory responses mediated by photoreceptors. UV-mediated accumulation of flavonoids and glucosinolates is well documented, but much less is known about UV [...] Read more.

UV-B and UV-A radiation are natural components of solar radiation that can cause plant stress, as well as induce a range of acclimatory responses mediated by photoreceptors. UV-mediated accumulation of flavonoids and glucosinolates is well documented, but much less is known about UV effects on carotenoid content. Carotenoids are involved in a range of plant physiological processes, including photoprotection of the photosynthetic machinery. UV-induced changes in carotenoid profile were quantified in plants (Arabidopsis thaliana) exposed for up to ten days to supplemental UV radiation under growth chamber conditions. UV induces specific changes in carotenoid profile, including increases in antheraxanthin, neoxanthin, violaxanthin and lutein contents in leaves. The extent of induction was dependent on exposure duration. No individual UV-B (UVR8) or UV-A (Cryptochrome or Phototropin) photoreceptor was found to mediate this induction. Remarkably, UV-induced accumulation of violaxanthin could not be linked to protection of the photosynthetic machinery from UV damage, questioning the functional relevance of this UV response. Here, it is argued that plants exploit UV radiation as a proxy for other stressors. Thus, it is speculated that the function of UV-induced alterations in carotenoid profile is not UV protection, but rather protection against other environmental stressors such as high intensity visible light that will normally accompany UV radiation. Full article

(This article belongs to the Special Issue Functional Plant Metabolism 2.0)

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9 pages, 1952 KiB

Open AccessConcept Paper

Lipidomic Profile Analysis of Lung Tissues Revealed Lipointoxication in Pulmonary Veno-Occlusive Disease

by Spiro Khoury, Antoine Beauvais, Jenny Colas, Anaïs Saint-Martin Willer, Frédéric Perros, Marc Humbert, Clarisse Vandebrouck, David Montani, Thierry Ferreira and Fabrice Antigny

Biomolecules 2022, 12(12), 1878; https://doi.org/10.3390/biom12121878 - 14 Dec 2022

Cited by 3 | Viewed by 2279

Abstract

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure [...] Read more.

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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17 pages, 8277 KiB

Open AccessArticle

TGF-β Pathways Stratify Colorectal Cancer into Two Subtypes with Distinct Cartilage Oligomeric Matrix Protein (COMP) Expression-Related Characteristics

by Jia-Tong Ding, Hao-Nan Zhou, Ying-Feng Huang, Jie Peng, Hao-Yu Huang, Hao Yi, Zhen Zong and Zhi-Kun Ning

Biomolecules 2022, 12(12), 1877; https://doi.org/10.3390/biom12121877 - 14 Dec 2022

Cited by 3 | Viewed by 2174

Abstract

Background: Colorectal cancers (CRCs) continue to be the leading cause of cancer-related deaths worldwide. The exact landscape of the molecular features of TGF-β pathway-inducing CRCs remains uncharacterized. Methods: Unsupervised hierarchical clustering was performed to stratify samples into two clusters based on the differences [...] Read more.

Background: Colorectal cancers (CRCs) continue to be the leading cause of cancer-related deaths worldwide. The exact landscape of the molecular features of TGF-β pathway-inducing CRCs remains uncharacterized. Methods: Unsupervised hierarchical clustering was performed to stratify samples into two clusters based on the differences in TGF-β pathways. Weighted gene co-expression network analysis was applied to identify the key gene modules mediating the different characteristics between two subtypes. An algorithm integrating the least absolute shrinkage and selection operator (LASSO), XGBoost, and random forest regression was performed to narrow down the candidate genes. Further bioinformatic analyses were performed focusing on COMP-related immune infiltration and functions. Results: The integrated machine learning algorithm identified COMP as the hub gene, which exhibited a significant predictive value for two subtypes with an area under the curve (AUC) value equaling 0.91. Further bioinformatic analysis revealed that COMP was significantly upregulated in various cancers, especially in advanced CRCs, and regulated the immune infiltration, especially M2 macrophages and cancer-associated fibroblasts in CRCs. Conclusions: Comprehensive immune analysis and experimental validation demonstrate that COMP is a reliable signature for subtype prediction. Our results could provide a new point for TGFβ-targeted anticancer drugs and contribute to guiding clinical decision making for CRC patients. Full article

(This article belongs to the Special Issue Cancer Systems Biology: Investigating Cancer Dynamics from a Complex Systems Perspective)

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19 pages, 3323 KiB

Open AccessReview

Functional Implications of Dynamic Structures of Intrinsically Disordered Proteins Revealed by High-Speed AFM Imaging

by Toshio Ando

Biomolecules 2022, 12(12), 1876; https://doi.org/10.3390/biom12121876 - 14 Dec 2022

Cited by 8 | Viewed by 2549

Abstract

The unique functions of intrinsically disordered proteins (IDPs) depend on their dynamic protean structure that often eludes analysis. High-speed atomic force microscopy (HS-AFM) can conduct this difficult analysis by directly visualizing individual IDP molecules in dynamic motion at sub-molecular resolution. After brief descriptions [...] Read more.

The unique functions of intrinsically disordered proteins (IDPs) depend on their dynamic protean structure that often eludes analysis. High-speed atomic force microscopy (HS-AFM) can conduct this difficult analysis by directly visualizing individual IDP molecules in dynamic motion at sub-molecular resolution. After brief descriptions of the microscopy technique, this review first shows that the intermittent tip–sample contact does not alter the dynamic structure of IDPs and then describes how the number of amino acids contained in a fully disordered region can be estimated from its HS-AFM images. Next, the functional relevance of a dumbbell-like structure that has often been observed on IDPs is discussed. Finally, the dynamic structural information of two measles virus IDPs acquired from their HS-AFM and NMR analyses is described together with its functional implications. Full article

(This article belongs to the Special Issue Structural Disorder within Viral Proteins: A Themed Issue Dedicated to Doctor Sonia Longhi)

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14 pages, 3546 KiB

Open AccessArticle

Effect of the Biopolymer Carrier on Staphylococcus aureus Bacteriophage Lytic Activity

by Liga Stipniece, Dace Rezevska, Juta Kroica and Karlis Racenis

Biomolecules 2022, 12(12), 1875; https://doi.org/10.3390/biom12121875 - 14 Dec 2022

Cited by 3 | Viewed by 1928

Abstract

The use of implant materials is always associated with the risk of infection. Moreover, the effectiveness of antibiotics is reduced due to antibiotic-resistant pathogens. Thus, selecting the appropriate alternative antimicrobials for local delivery systems is correlated with successful infection management. We evaluated immobilization [...] Read more.

The use of implant materials is always associated with the risk of infection. Moreover, the effectiveness of antibiotics is reduced due to antibiotic-resistant pathogens. Thus, selecting the appropriate alternative antimicrobials for local delivery systems is correlated with successful infection management. We evaluated immobilization of the S. aureus specific bacteriophages in clinically recognized biopolymers, i.e., chitosan and alginate, to control the release profile of the antimicrobials. The high-titre S. aureus specific bacteriophages were prepared from commercial bacteriophage cocktails. The polymer mixtures with the propagated bacteriophages were then prepared. The stability of the S. aureus bacteriophages in the biopolymer solutions was assessed. In the case of chitosan, no plaques indicating the presence of the lytic bacteriophages were observed. The titre reduction of the S. aureus bacteriophages in the Na-alginate was below 1 log unit. Furthermore, the bacteriophages retained their lytic activity in the alginate after crosslinking with Ca²⁺ ions. The release of the lytic S. aureus bacteriophages from the Ca-alginate matrices in the TRIS-HCl buffer solution (pH 7.4 ± 0.2) was determined. After 72 h—0.292 ± 0.021% of bacteriophages from the Ca-alginate matrices were released. Thus, sustained release of the lytic S. aureus bacteriophages can be ensured. Full article

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