Biomolecules

20 pages, 1082 KiB

Open AccessEditor’s ChoiceReview

Innate Immunity: A Balance between Disease and Adaption to Stress

by Irene Faenza and William L. Blalock

Biomolecules 2022, 12(5), 737; https://doi.org/10.3390/biom12050737 - 23 May 2022

Cited by 13 | Viewed by 4924

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation [...] Read more.

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Neuro-Muscular Degeneration, Metabolic Syndromes, Cancer and Infection)

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17 pages, 2074 KiB

Open AccessEditor’s ChoiceArticle

Reduced Platelet MAO-B Activity Is Associated with Psychotic, Positive, and Depressive Symptoms in PTSD

by Senka Repovecki, Gordana Nedic Erjavec, Suzana Uzun, Lucija Tudor, Matea Nikolac Perkovic, Marcela Konjevod, Oliver Kozumplik, Dubravka Svob Strac, Zrnka Kovacic Petrovic, Ninoslav Mimica and Nela Pivac

Biomolecules 2022, 12(5), 736; https://doi.org/10.3390/biom12050736 - 23 May 2022

Cited by 2 | Viewed by 3375

Abstract

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet [...] Read more.

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms. Full article

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

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16 pages, 1738 KiB

Open AccessArticle

Hyperhomocysteinemia Increases Cortical Excitability and Aggravates Mechanical Hyperalgesia and Anxiety in a Nitroglycerine-Induced Migraine Model in Rats

by Elena Gerasimova, Olga Yakovleva, Daniel Enikeev, Ksenia Bogatova, Anton Hermann, Rashid Giniatullin and Guzel Sitdikova

Biomolecules 2022, 12(5), 735; https://doi.org/10.3390/biom12050735 - 23 May 2022

Cited by 16 | Viewed by 3356

Abstract

Homocysteine is a sulfur-containing endogenous amino acid leading to neurotoxic effects at high concentrations. Population studies suggest an association between plasma homocysteine levels and the risk of migraine headaches. The aim of this study was to analyze the sensitivity of rats with prenatal [...] Read more.

Homocysteine is a sulfur-containing endogenous amino acid leading to neurotoxic effects at high concentrations. Population studies suggest an association between plasma homocysteine levels and the risk of migraine headaches. The aim of this study was to analyze the sensitivity of rats with prenatal hyperhomocysteinemia (hHCY) in respect of the development of behavioral correlates of headache and spreading cortical depolarization (CSD) in a migraine model induced by the administration of the nitric oxide (NO) donor nitroglycerin. Animals with hHCY were characterized by migraine-related symptoms such as mechanical hyperalgesia, high-level anxiety, photophobia, as well as an enhanced level of neuronal activity in the somatosensory cortex along with a lower threshold of CSD generation. Likewise, acute or chronic intermittent administration of nitroglycerin also induced the development of mechanical allodynia, photophobia and anxiety in control groups. However, these symptoms were more pronounced in rats with hHCY. Unlike hHCY, nitroglycerin administration did not affect the threshold of CSD generation, but like hHCY, increased the background neuronal activity in layers 2/3 and 4 of the cerebral cortex. The latter was more pronounced in animals with hHCY. Thus, the migraine profile associated with hHCY can be further exaggerated in conditions with enhanced levels of migraine triggering the gaseous transmitter NO. Our data are consistent with the view that high levels of plasma homocysteine can act as a risk factor for the development of migraine. Full article

(This article belongs to the Special Issue Homocysteine: Biochemistry, Molecular Biology, and Role in Disease 2021)

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16 pages, 3889 KiB

Open AccessEditor’s ChoiceArticle

Impairment of the Retinal Endothelial Cell Barrier Induced by Long-Term Treatment with VEGF-A₁₆₅ No Longer Depends on the Growth Factor’s Presence

by Heidrun L. Deissler, Matus Rehak and Armin Wolf

Biomolecules 2022, 12(5), 734; https://doi.org/10.3390/biom12050734 - 23 May 2022

Cited by 2 | Viewed by 2543

Abstract

As responses of immortalized endothelial cells of the bovine retina (iBREC) to VEGF-A₁₆₅ depend on exposure time to the growth factor, we investigated changes evident after long-term treatment for nine days. The cell index of iBREC cultivated on gold electrodes—determined as a [...] Read more.

As responses of immortalized endothelial cells of the bovine retina (iBREC) to VEGF-A₁₆₅ depend on exposure time to the growth factor, we investigated changes evident after long-term treatment for nine days. The cell index of iBREC cultivated on gold electrodes—determined as a measure of permeability—was persistently reduced by exposure to the growth factor. Late after addition of VEGF-A₁₆₅ protein levels of claudin-1 and CD49e were significantly lower, those of CD29 significantly higher, and the plasmalemma vesicle associated protein was no longer detected. Nuclear levels of β-catenin were only elevated on day two. Extracellular levels of VEGF-A—measured by ELISA—were very low. Similar to the binding of the growth factor by brolucizumab, inhibition of VEGFR2 by tyrosine kinase inhibitors tivozanib or nintedanib led to complete, although transient, recovery of the low cell index when added early, though was inefficient when added three or six days later. Additional inhibition of other receptor tyrosine kinases by nintedanib was similarly unsuccessful, but additional blocking of c-kit by tivozanib led to sustained recovery of the low cell index, an effect observed only when the inhibitor was added early. From these data, we conclude that several days after the addition of VEGF-A₁₆₅ to iBREC, barrier dysfunction is mainly sustained by increased paracellular flow and impaired adhesion. Even more important, these changes are most likely no longer VEGF-A-controlled. Full article

(This article belongs to the Special Issue Cell and Organ Cultures for Studying Retinal Diseases)

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14 pages, 1517 KiB

Open AccessArticle

Relationship between Liver Stiffness and Steatosis in Obesity Conditions: In Vivo and In Vitro Studies

by Francesca Baldini, Mohamad Khalil, Alice Bartolozzi, Massimo Vassalli, Agostino Di Ciaula, Piero Portincasa and Laura Vergani

Biomolecules 2022, 12(5), 733; https://doi.org/10.3390/biom12050733 - 23 May 2022

Cited by 9 | Viewed by 3450

Abstract

Obesity is a major risk factor for metabolic dysfunction such as non-alcoholic fatty liver disease (NAFLD). The NAFLD spectrum ranges from simple steatosis, to steatohepatitis, fibrosis, and cirrhosis. The aim of this study is to characterize the grade of steatosis being associated with [...] Read more.

Obesity is a major risk factor for metabolic dysfunction such as non-alcoholic fatty liver disease (NAFLD). The NAFLD spectrum ranges from simple steatosis, to steatohepatitis, fibrosis, and cirrhosis. The aim of this study is to characterize the grade of steatosis being associated with overnutrition and obesity, both at the level of single hepatocyte and whole liver, and to correlate it with the hepatocyte/liver stiffness and dysfunction. For the in vivo study, 60 subjects were enrolled and grouped based on the stage of liver steatosis/fibrosis according to biochemical analyses, liver ultrasonography (USG) and acoustic radiation force impulse shear wave elastography (ARFI-SWE). For single hepatocyte analyses we employed in vitro models of moderate and severe steatosis on which to assess the single cell biomechanics by Single Cell Force Spectroscopy (SCFS) and Quantitative Phase Microscopy (QPM). Results show that in vivo liver stiffness depends mainly on the extent of fat accumulation and not on fibrosis. These results parallel the in vitro observations showing that hepatocyte stiffness and dysfunction increase with increasing fat accumulation and lipid droplet enlargement. Our findings indicate that the extent of steatosis markedly affects the biomechanical properties of both liver and single hepatocytes thus proving insights about the role of modulation of liver/hepatocyte elasticity as a physical mechanism transducing the obesity-dependent excess of plasmatic lipids towards liver steatosis and dysfunction. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Eating Disorders and Obesity)

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10 pages, 931 KiB

Open AccessArticle

Effects of Risperidone and Prenatal Poly I:C Exposure on GABA_A Receptors and AKT-GSK3β Pathway in the Ventral Tegmental Area of Female Juvenile Rats

by Shiyan Chen, Jiamei Lian, Yueqing Su and Chao Deng

Biomolecules 2022, 12(5), 732; https://doi.org/10.3390/biom12050732 - 23 May 2022

Cited by 2 | Viewed by 2668

Abstract

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABA_A receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal [...] Read more.

The ventral tegmental area (VTA) in the ventral midbrain is the origin of the dopaminergic neurotransmission pathways. Although GABA_A receptors and AKT-GSK3β signaling are involved in the pathophysiology of mental disorders and are modulated by antipsychotics, an unmet task is to reveal the pathological changes in these biomarkers and antipsychotic modulations in the VTA. Using a juvenile polyriboinosinic-polyribocytidylic acid (Poly I:C) psychiatric rat model, this study investigated the effects of adolescent risperidone treatment on GABA_A receptors and AKT/GSK3β in the VTA. Pregnant female Sprague–Dawley rats were administered Poly I:C (5mg/kg; i.p) or saline at gestational day 15. Juvenile female offspring received risperidone (0.9 mg/kg, twice per day) or a vehicle from postnatal day 35 for 25 days. Poly I:C offspring had significantly decreased mRNA expression of GABA_A receptor β3 subunits and glutamic acid decarboxylase (GAD2) in the VTA, while risperidone partially reversed the decreased GAD2 expression. Prenatal Poly I:C exposure led to increased expression of AKT2 and GSK3β. Risperidone decreased GABA_A receptor β2/3, but increased AKT2 mRNA expression in the VTA of healthy rats. This study suggests that Poly I:C-elicited maternal immune activation and risperidone differentially modulate GABAergic neurotransmission and AKT-GSK3β signaling in the VTA of adolescent rats. Full article

(This article belongs to the Special Issue GABA Receptors in Pharmacology and Neurobiology)

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19 pages, 4278 KiB

Open AccessArticle

Transcriptomal Insights of Heart Failure from Normality to Recovery

by Mohammed Quttainah, Vineesh Vimala Raveendran, Soad Saleh, Ranjit Parhar, Mansour Aljoufan, Narain Moorjani, Zohair Y. Al-Halees, Maie AlShahid, Kate S. Collison, Stephen Westaby and Futwan Al-Mohanna

Biomolecules 2022, 12(5), 731; https://doi.org/10.3390/biom12050731 - 23 May 2022

Cited by 5 | Viewed by 2545

Abstract

Current management of heart failure (HF) is centred on modulating the progression of symptoms and severity of left ventricular dysfunction. However, specific understandings of genetic and molecular targets are needed for more precise treatments. To attain a clearer picture of this, we studied [...] Read more.

Current management of heart failure (HF) is centred on modulating the progression of symptoms and severity of left ventricular dysfunction. However, specific understandings of genetic and molecular targets are needed for more precise treatments. To attain a clearer picture of this, we studied transcriptome changes in a chronic progressive HF model. Fifteen sheep (Ovis aries) underwent supracoronary aortic banding using an inflatable cuff. Controlled and progressive induction of pressure overload in the LV was monitored by echocardiography. Endomyocardial biopsies were collected throughout the development of LV failure (LVF) and during the stage of recovery. RNA-seq data were analysed using the PANTHER database, Metascape, and DisGeNET to annotate the gene expression for functional ontologies. Echocardiography revealed distinct clinical differences between the progressive stages of hypertrophy, dilatation, and failure. A unique set of transcript expressions in each stage was identified, despite an overlap of gene expression. The removal of pressure overload allowed the LV to recover functionally. Compared to the control stage, there were a total of 256 genes significantly changed in their expression in failure, 210 genes in hypertrophy, and 73 genes in dilatation. Gene expression in the recovery stage was comparable with the control stage with a well-noted improvement in LV function. RNA-seq revealed the expression of genes in each stage that are not reported in cardiovascular pathology. We identified genes that may be potentially involved in the aetiology of progressive stages of HF, and that may provide future targets for its management. Full article

(This article belongs to the Special Issue Genetics and Genomics of Heart Failure)

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20 pages, 3033 KiB

Open AccessArticle

A Comparative Study of Milk Fat Extracted from the Milk of Different Goat Breeds in China: Fatty Acids, Triacylglycerols and Thermal and Spectroscopic Characterization

by Sameh A. Korma, Li Li, Wei Wei, Pengzhan Liu, Xinghe Zhang, Ibrahim A. Bakry, Peipei An, Khaled A. E. Abdrabo, Muhammad Faisal Manzoor, Muhammad Umair, Ilaria Cacciotti, José M. Lorenzo and Carlos Adam Conte-Junior

Biomolecules 2022, 12(5), 730; https://doi.org/10.3390/biom12050730 - 22 May 2022

Cited by 5 | Viewed by 3392

Abstract

Goat milk (GM) is an excellent alternative to cow milk and has recently been used in commercial infant formula preparation due to its superior fat composition. Here, the fatty acid (FA) composition, triacylglycerol (TAG) molecular species, thermal behavior and infrared spectra of extracted [...] Read more.

Goat milk (GM) is an excellent alternative to cow milk and has recently been used in commercial infant formula preparation due to its superior fat composition. Here, the fatty acid (FA) composition, triacylglycerol (TAG) molecular species, thermal behavior and infrared spectra of extracted milk fat from the milk of the two main breeds of dairy goat bred in China (Guanzhong GM (GZG) and Xinong Saanen GM (XSG)) are investigated. Gas chromatography, Fourier-transform infrared spectroscopy, differential scanning calorimetry and ultra-performance convergence chromatography with quadrupole time-of-flight mass spectrometry are applied. The obtained results evidence significant fat compositional differences based on the breed that produced the considered GM. The major FAs in both GM fats were capric (C10:0), myristic (C14:0), palmitic (C16:0), stearic (C18:0) and oleic (C18:1 n-9c). GZG presented a higher content of medium-chain saturated FAs, while XSG had higher unsaturated FAs with higher ratios of L/Ln and n-6/n-3. A total of 339 and 359 TAGs were detected and quantified in GZG and XSG, and the major TAGs were those of m/z 740.6712 (14.10 ± 0.27%) and m/z 684.6094 (10.94 ± 0.02%), respectively. Milk TAGs of GZG and XSG showed 24–54 and 26–54 total acyl carbon numbers with a 0–4 and 0–5 double bond number at 68 and 72 various retention times, respectively. Thermal analysis showed that all GM fat samples melted below normal body temperature. Infrared spectra revealed higher absorption values of GZG milk fat. This study provides valuable information to the dairy industry sector about GM fat produced in China, assessing the appropriateness of Chinese GM fat to be applied in Chinese infant formula. Full article

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

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14 pages, 1586 KiB

Open AccessReview

Targeting Nrf2 with Probiotics and Postbiotics in the Treatment of Periodontitis

by Basar Karaca, Mustafa Yilmaz and Ulvi Kahraman Gursoy

Biomolecules 2022, 12(5), 729; https://doi.org/10.3390/biom12050729 - 22 May 2022

Cited by 14 | Viewed by 5107

Abstract

Periodontitis is a destructive disease of the tooth-surrounding tissues. Infection is the etiological cause of the disease, but its extent and severity depend on the immune–inflammatory response of the host. Immune cells use reactive oxygen species to suppress infections, and there is homeostasis [...] Read more.

Periodontitis is a destructive disease of the tooth-surrounding tissues. Infection is the etiological cause of the disease, but its extent and severity depend on the immune–inflammatory response of the host. Immune cells use reactive oxygen species to suppress infections, and there is homeostasis between oxidative and antioxidant mechanisms during periodontal health. During periodontitis, however, increased oxidative stress triggers tissue damage, either directly by activating apoptosis and DNA damage or indirectly by activating proteolytic cascades. Periodontal treatment aims to maintain an infection and inflammation-free zone and, in some cases, regenerate lost tissues. Although mechanical disruption of the oral biofilm is an indispensable part of periodontal treatment, adjunctive measures, such as antibiotics or anti-inflammatory medications, are also frequently used, especially in patients with suppressed immune responses. Recent studies have shown that probiotics activate antioxidant mechanisms and can suppress extensive oxidative stress via their ability to activate nuclear factor erythroid 2-related factor 2 (Nrf2). The aim of this narrative review is to describe the essential role of Nrf2 in the maintenance of periodontal health and to propose possible mechanisms to restore the impaired Nrf2 response in periodontitis, with the aid of probiotic and postbiotics. Full article

(This article belongs to the Special Issue Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II)

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16 pages, 2656 KiB

Open AccessArticle

Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury

by Sisi Wang, Xue Li, Qingwen Ma, Qi Wang, Junping Wu, Hongzhi Yu, Kuan Li, Yu Li, Jianhai Wang, Qiuyang Zhang, Youwei Wang, Qi Wu and Huaiyong Chen

Biomolecules 2022, 12(5), 728; https://doi.org/10.3390/biom12050728 - 22 May 2022

Cited by 15 | Viewed by 4486

Abstract

(1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine [...] Read more.

(1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine metabolism in the maintenance of the alveolar epithelium remains unclear. In this study, we investigated the role of glutamine metabolism in AT2 cells of patients with IPF and in mice with bleomycin-induced fibrosis. (2) Methods: Single-cell RNA sequencing (scRNA-seq), transcriptome, and metabolomics analyses were conducted to investigate the changes in the glutamine metabolic pathway during pulmonary fibrosis. Metabolic inhibitors were used to stimulate AT2 cells to block glutamine metabolism. Regeneration of AT2 cells was detected using bleomycin-induced mouse lung fibrosis and organoid models. (3) Results: Single-cell analysis showed that the expression levels of catalytic enzymes responsible for glutamine catabolism were downregulated (p < 0.001) in AT2 cells of patients with IPF, suggesting the accumulation of unusable glutamine. Combined analysis of the transcriptome (p < 0.05) and metabolome (p < 0.001) revealed similar changes in glutamine metabolism in bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inhibition of the key enzymes involved in glucose metabolism, glutaminase-1 (GLS1) and glutamic-pyruvate transaminase-2 (GPT2) leads to reduced proliferation (p < 0.01) and differentiation (p < 0.01) of AT2 cells. (4) Conclusions: Glutamine metabolism is required for alveolar epithelial regeneration during lung injury. Full article

(This article belongs to the Special Issue State-of-the-Art Biophysics, Biochemistry and Molecular Biology in China)

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20 pages, 4302 KiB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effects of GM1 Ganglioside on Endotoxin-Induced Uveitis in Rats

by Tzu-Heng Weng, Chang-Chih Ke and Yuahn-Sieh Huang

Biomolecules 2022, 12(5), 727; https://doi.org/10.3390/biom12050727 - 21 May 2022

Cited by 3 | Viewed by 3325

Abstract

Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide [...] Read more.

Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide (LPS). GM1 was injected intraperitoneally for three consecutive days prior to the LPS injection. Twenty-four hours after the LPS injection, the integrity of the blood-aqueous barrier was evaluated by determining the protein concentration and number of infiltrating cells in the aqueous humor (AqH). Immunohistochemical and Western blot analyses of the iris-ciliary body (ICB) were performed to evaluate the effect of GM1 on the LPS-induced expression of cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1). The effect of GM1 on proinflammatory mediators and signaling cascades was examined in LPS-stimulated RAW 264.7 cells using Western blotting and immunofluorescence staining to further clarify the underlying anti-inflammatory mechanism. Results: GM1 significantly reduced the protein concentration and number of infiltrating cells in the AqH of rats with EIU. GM1 also decreased the LPS-induced expression of the ICAM-1 and COX-2 proteins in the ICB. In RAW 264.7 cells, GM1 inhibited the proinflammatory mediators induced by LPS, including inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and this inhibitory effect was potentially mediated by suppressing reactive oxygen species (ROS)-mediated activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Conclusions: Based on this study, GM1 may be a potential anti-inflammatory agent for ocular inflammatory diseases. Full article

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

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11 pages, 2537 KiB

Open AccessArticle

Heterologous Expression of Full-Length and Truncated Human ZIP4 Zinc Transporter in Saccharomyces cerevisiae

by Yuting Liu, Elizabeth M. Bafaro and Robert E. Dempski

Biomolecules 2022, 12(5), 726; https://doi.org/10.3390/biom12050726 - 21 May 2022

Cited by 1 | Viewed by 2363

Abstract

The human (h) transporter hZIP4 is the primary Zn²⁺ importer in the intestine. hZIP4 is also expressed in a variety of organs such as the pancreas and brain. Dysfunction of hZIP4 can result in the Zn²⁺ deficiency disease acrodermatitis enteropathica (AE). [...] Read more.

The human (h) transporter hZIP4 is the primary Zn²⁺ importer in the intestine. hZIP4 is also expressed in a variety of organs such as the pancreas and brain. Dysfunction of hZIP4 can result in the Zn²⁺ deficiency disease acrodermatitis enteropathica (AE). AE can disrupt digestive and immune system homeostasis. A limited number of hZIP4 expression strategies have hindered increasing knowledge about this essential transmembrane protein. Here, we report the heterologous expression of hZIP4 in Saccharomyces cerevisiae. Both a wild-type and a mutant S. cerevisiae strain, in which the endogenous Zn²⁺ transporters were deleted, were used to test the expression and localization of an hZIP4–GFP fusion protein. A full-length hZIP4–GFP and a truncated membrane-domain-only (mhZIP4–GFP) protein were observed to be present in the plasma membrane in yeast. Full article

(This article belongs to the Collection Advances in Metal Binding Proteins)

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12 pages, 1941 KiB

Open AccessArticle

Effect of Trimethine Cyanine Dye- and Folate-Conjugation on the In Vitro Biological Activity of Proapoptotic Peptides

by Davide Cardella, Wenjing Deng, Louis Y. P. Luk and Yu-Hsuan Tsai

Biomolecules 2022, 12(5), 725; https://doi.org/10.3390/biom12050725 - 20 May 2022

Viewed by 2989

Abstract

Despite continuous advances, anticancer therapy still faces several technical hurdles, such as selectivity on cellular and subcellular targets of therapeutics. Toward addressing these limitations, we have combined the use of proapoptotic peptides, trimethine cyanine dye, and folate to target the mitochondria of tumor [...] Read more.

Despite continuous advances, anticancer therapy still faces several technical hurdles, such as selectivity on cellular and subcellular targets of therapeutics. Toward addressing these limitations, we have combined the use of proapoptotic peptides, trimethine cyanine dye, and folate to target the mitochondria of tumor cells. A series of proapoptotic peptides and their conjugates with a cyanine dye and/or folate were synthesized in the solid phase, and their toxicity in different human cell lines was assessed. Cyanine-bearing conjugates were found to be up to 100-fold more cytotoxic than the parent peptides and to localize in mitochondria. However, the addition of a folate motif did not enhance the potency or selectivity of the resulting conjugates toward tumor cells that overexpress folate receptor α. Furthermore, while dual-labeled constructs were also found to localize within the target organelle, they were not generally selective towards folate receptor α-positive cell lines in vitro. Full article

(This article belongs to the Section Chemical Biology)

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18 pages, 35190 KiB

Open AccessFeature PaperArticle

Preferential Expression of Ca²⁺-Stimulable Adenylyl Cyclase III in the Supraventricular Area, including Arrhythmogenic Pulmonary Vein of the Rat Heart

by Yosuke Okamoto, Naing Ye Aung, Masahiro Tanaka, Yuji Takeda, Daichi Takagi, Wataru Igarashi, Kuniaki Ishii, Mitsunori Yamakawa and Kyoichi Ono

Biomolecules 2022, 12(5), 724; https://doi.org/10.3390/biom12050724 - 20 May 2022

Cited by 6 | Viewed by 2579

Abstract

Ectopic excitability in pulmonary veins (PVs) is the major cause of atrial fibrillation. We previously reported that the inositol trisphosphate receptor in rat PV cardiomyocytes cooperates with the Na⁺-Ca²⁺ exchanger to provoke ectopic automaticity in response to norepinephrine. Here, we [...] Read more.

Ectopic excitability in pulmonary veins (PVs) is the major cause of atrial fibrillation. We previously reported that the inositol trisphosphate receptor in rat PV cardiomyocytes cooperates with the Na⁺-Ca²⁺ exchanger to provoke ectopic automaticity in response to norepinephrine. Here, we focused on adenylyl cyclase (AC) as another effector of norepinephrine stimulation. RT-PCR, immunohistochemistry, and Western blotting revealed that the abundant expression of Ca²⁺-stimulable AC3 was restricted to the supraventricular area, including the PVs. All the other AC isotypes hardly displayed any region-specific expressions. Immunostaining of isolated cardiomyocytes showed an enriched expression of AC3 along the t-tubules in PV myocytes. The cAMP-dependent response of L-type Ca²⁺ currents in the PV and LA cells is strengthened by the 0.1 mM intracellular Ca²⁺ condition, unlike in the ventricular cells. The norepinephrine-induced automaticity of PV cardiomyocytes was reversibly suppressed by 100 µM SQ22536, an adenine-like AC inhibitor. These findings suggest that the specific expression of AC3 along t-tubules may contribute to arrhythmogenic automaticity in rat PV cardiomyocytes. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

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20 pages, 2502 KiB

Open AccessFeature PaperEditor’s ChoiceReview

PPARα Signaling: A Candidate Target in Psychiatric Disorder Management

by Simona Scheggi, Graziano Pinna, Giulia Braccagni, Maria Graziella De Montis and Carla Gambarana

Biomolecules 2022, 12(5), 723; https://doi.org/10.3390/biom12050723 - 20 May 2022

Cited by 11 | Viewed by 4813

Abstract

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in [...] Read more.

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD. Full article

(This article belongs to the Special Issue Role of PPARs in Neurological and Psychiatric Disorders)

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12 pages, 3316 KiB

Open AccessArticle

Effects of Systemic or Local Administration of Mesenchymal Stem Cells from Patients with Osteoporosis or Osteoarthritis on Femoral Fracture Healing in a Mouse Model

by Esther Laguna, María Isabel Pérez-Núñez, Álvaro del Real, Guillermo Menéndez, José A. Sáinz-Aja, Laura López-Delgado, Carolina Sañudo, Alicia Martín, Remigio Mazorra, Diego Ferreño, Belén García-Montesinos and José A. Riancho

Biomolecules 2022, 12(5), 722; https://doi.org/10.3390/biom12050722 - 19 May 2022

Cited by 6 | Viewed by 2491

Abstract

The purpose of this study was to analyze the regenerative capacity of mesenchymal stem cells (MSCs) in the treatment of fractures. MSCs extracted from patients with osteoporotic hip fractures or hip osteoarthritis undergoing hip replacement surgeries were cultured and injected into mice with [...] Read more.

The purpose of this study was to analyze the regenerative capacity of mesenchymal stem cells (MSCs) in the treatment of fractures. MSCs extracted from patients with osteoporotic hip fractures or hip osteoarthritis undergoing hip replacement surgeries were cultured and injected into mice with femoral fracture. Two experimental models were established, one for the systemic administration of MSCs (n = 29) and another one for local administration (n = 30). Fracture consolidation was assessed by micro-CT and histology. The degree of radiological consolidation and corticalization was better with MSCs from osteoporosis than from osteoarthritis, being significant after systemic administration (p = 0.0302 consolidation; p = 0.0243 corticalization). The histological degree of consolidation was also better with MSCs from osteoporosis than from osteoarthritis. Differences in histological scores after systemic infusion were as follows: Allen, p = 0.0278; Huo, p = 0.3471; and Bone Bridge, p = 0.0935. After local administration at the fracture site, differences in histological scores were as follows: Allen, p = 0.0764; Huo, p = 0.0256; and Bone Bridge, p = 0.0012. As osteoporosis and control groups were similar, those differences depended on an inhibitory influence by MSCs from patients with osteoarthritis. In conclusion, we found an unexpected impairment of consolidation induced by MSCs from patients with osteoarthritis. However, MSCs from patients with osteoporosis compared favorably with cells from patients with osteoarthritis. In other words, based on this study and previous studies, MSCs from patients with osteoporosis do not appear to have worse bone-regenerating capabilities than MSCs from non-osteoporotic individuals of similar age. Full article

(This article belongs to the Special Issue Advances in Mesenchymal Stem Cells)

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21 pages, 1652 KiB

Open AccessReview

Construction of Multiscale Genome-Scale Metabolic Models: Frameworks and Challenges

by Xinyu Bi, Yanfeng Liu, Jianghua Li, Guocheng Du, Xueqin Lv and Long Liu

Biomolecules 2022, 12(5), 721; https://doi.org/10.3390/biom12050721 - 19 May 2022

Cited by 14 | Viewed by 5089

Abstract

Genome-scale metabolic models (GEMs) are effective tools for metabolic engineering and have been widely used to guide cell metabolic regulation. However, the single gene–protein-reaction data type in GEMs limits the understanding of biological complexity. As a result, multiscale models that add constraints or [...] Read more.

Genome-scale metabolic models (GEMs) are effective tools for metabolic engineering and have been widely used to guide cell metabolic regulation. However, the single gene–protein-reaction data type in GEMs limits the understanding of biological complexity. As a result, multiscale models that add constraints or integrate omics data based on GEMs have been developed to more accurately predict phenotype from genotype. This review summarized the recent advances in the development of multiscale GEMs, including multiconstraint, multiomic, and whole-cell models, and outlined machine learning applications in GEM construction. This review focused on the frameworks, toolkits, and algorithms for constructing multiscale GEMs. The challenges and perspectives of multiscale GEM development are also discussed. Full article

(This article belongs to the Special Issue Computational Biology for Metabolic Modelling and Pathway Design)

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22 pages, 3607 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Evidence of Failed Resolution Mechanisms in Arrhythmogenic Inflammation, Fibrosis and Right Heart Disease

by Rim Younes, Charles-Alexandre LeBlanc and Roddy Hiram

Biomolecules 2022, 12(5), 720; https://doi.org/10.3390/biom12050720 - 19 May 2022

Cited by 8 | Viewed by 5637

Abstract

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can [...] Read more.

Inflammation is a complex program of active processes characterized by the well-orchestrated succession of an initiation and a resolution phase aiming to promote homeostasis. When the resolution of inflammation fails, the tissue undergoes an unresolved inflammatory status which, if it remains uncontrolled, can lead to chronic inflammatory disorders due to aggravation of structural damages, development of a fibrous area, and loss of function. Various human conditions show a typical unresolved inflammatory profile. Inflammatory diseases include cancer, neurodegenerative disease, asthma, right heart disease, atherosclerosis, myocardial infarction, or atrial fibrillation. New evidence has started to emerge on the role, including pro-resolution involvement of chemical mediators in the acute phase of inflammation. Although flourishing knowledge is available about the role of specialized pro-resolving mediators in neurodegenerative diseases, atherosclerosis, obesity, or hepatic fibrosis, little is known about their efficacy to combat inflammation-associated arrhythmogenic cardiac disorders. It has been shown that resolvins, including RvD1, RvE1, or Mar1, are bioactive mediators of resolution. Resolvins can stop neutrophil activation and infiltration, stimulate monocytes polarization into anti-inflammatory-M2-macrophages, and activate macrophage phagocytosis of inflammation-debris and neutrophils to promote efferocytosis and clearance. This review aims to discuss the paradigm of failed-resolution mechanisms (FRM) potentially promoting arrhythmogenicity in right heart disease-induced inflammatory status. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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11 pages, 586 KiB

Open AccessArticle

Effect of Locally Delivered Minocycline on the Profile of Subgingival Bacterial Genera in Patients with Periodontitis: A Prospective Pilot Study

by Toshiya Morozumi, Yohei Nakayama, Satoshi Shirakawa, Kentaro Imamura, Kaname Nohno, Takatoshi Nagano, Haruna Miyazawa, Takahiro Hokari, Ryo Takuma, Shuntaro Sugihara, Kazuhiro Gomi, Atsushi Saito, Yorimasa Ogata and Motohiro Komaki

Biomolecules 2022, 12(5), 719; https://doi.org/10.3390/biom12050719 - 18 May 2022

Cited by 2 | Viewed by 3107

Abstract

This prospective pilot study aimed to evaluate the effect of minocycline-HCl ointment (MO), locally delivered as an adjunct to scaling and root planing (SRP), on subgingival microflora. A total of 59 periodontitis patients received SRP as an initial periodontal therapy. In the selected [...] Read more.

This prospective pilot study aimed to evaluate the effect of minocycline-HCl ointment (MO), locally delivered as an adjunct to scaling and root planing (SRP), on subgingival microflora. A total of 59 periodontitis patients received SRP as an initial periodontal therapy. In the selected periodontal pockets with probing depths (PD) of 6–9 mm, the sites that exhibited a positive reaction following a bacterial test using an immunochromatographic device were subsequently treated with MO (SRP + MO group, n = 25). No additional treatment was performed at sites showing a negative reaction (SRP group, n = 34). In addition to subgingival plaque sampling, measurement of clinical parameters including PD, clinical attachment level (CAL), bleeding on probing (BOP), plaque index and gingival index (GI) were performed at baseline and 4 weeks after the initial periodontal therapy. The subgingival microflora were assessed by terminal restriction fragment-length polymorphism analysis. Relative to baseline values, the mean scores for PD-, CAL-, BOP-, and GI-sampled sites were significantly decreased post treatment in both groups (p < 0.01). The intra-comparisons showed a significant decrease in the counts of the genera Eubacterium, Parvimonas, Filifactor, Veillonella, Fusobacterium, Porphyromonas, Prevotella, and unknown species in the SRP + MO group (p < 0.05). Inter-comparisons indicated a significant decrease in the genera Veillonella in the SRP + MO group (p = 0.01). Combination therapy of SRP and local MO induced a change in the subgingival microbial community: particularly, the number of Veillonella spp. was markedly reduced. Full article

(This article belongs to the Special Issue Advances in Basic and Clinical Periodontal Research)

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10 pages, 634 KiB

Open AccessArticle

Conformational Entropy as a Potential Liability of Computationally Designed Antibodies

by Thomas Löhr, Pietro Sormanni and Michele Vendruscolo

Biomolecules 2022, 12(5), 718; https://doi.org/10.3390/biom12050718 - 18 May 2022

Cited by 10 | Viewed by 3106

Abstract

In silico antibody discovery is emerging as a viable alternative to traditional in vivo and in vitro approaches. Many challenges, however, remain open to enabling the properties of designed antibodies to match those produced by the immune system. A major question concerns the [...] Read more.

In silico antibody discovery is emerging as a viable alternative to traditional in vivo and in vitro approaches. Many challenges, however, remain open to enabling the properties of designed antibodies to match those produced by the immune system. A major question concerns the structural features of computer-designed complementarity determining regions (CDRs), including the role of conformational entropy in determining the stability and binding affinity of the designed antibodies. To address this problem, we used enhanced-sampling molecular dynamics simulations to compare the free energy landscapes of single-domain antibodies (sdAbs) designed using structure-based (DesAb-HSA-D3) and sequence-based approaches (DesAbO), with that of a nanobody derived from llama immunization (Nb10). Our results indicate that the CDR3 of DesAbO is more conformationally heterogeneous than those of both DesAb-HSA-D3 and Nb10, and the CDR3 of DesAb-HSA-D3 is slightly more dynamic than that of Nb10, which is the original scaffold used for the design of DesAb-HSA-D3. These differences underline the challenges in the rational design of antibodies by revealing the presence of conformational substates likely to have different binding properties and to generate a high entropic cost upon binding. Full article

(This article belongs to the Special Issue Protein Folding Stability and Dynamics: Commemorative Issue in Honor of Professor Sir Christopher Dobson (1949–2019))

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6 pages, 329 KiB

Open AccessReview

Oxygen Therapy during Exercise in Patients with Interstitial Lung Diseases

by Magda Viani, Vittoria Ventura, Francesco Bianchi, Miriana d’Alessandro, Laura Bergantini, Piersante Sestini and Elena Bargagli

Biomolecules 2022, 12(5), 717; https://doi.org/10.3390/biom12050717 - 18 May 2022

Cited by 1 | Viewed by 2475

Abstract

Introduction: ILDs are a varied group of diffuse parenchymal lung diseases associated with high morbidity and mortality. Current treatments can only slow their progression but not cure the disease. Other treatments such as oxygen therapy can also be used as support. We know [...] Read more.

Introduction: ILDs are a varied group of diffuse parenchymal lung diseases associated with high morbidity and mortality. Current treatments can only slow their progression but not cure the disease. Other treatments such as oxygen therapy can also be used as support. We know very little about the effects of oxygen therapy on patients with ILDs. The aim of this study was to collect data from the literature in order to determine whether oxygen therapy can actually decrease the mortality rate or whether it is only suitable for supportive therapy for patients with ILDs. Methods: We reviewed the literature since 2010 on oxygen therapy during exercise in patients with ILDs. Studies that used cardio-pulmonary tests were excluded. We only reviewed those that used the 6 min walking test (6MWT) or the free walking test. We located 11 relevant articles. Results: All the articles except a Japanese study showed an augmentation in oxyhaemoglobin saturation during exercise when oxygen was supplied. A 2018 study called AmbOx provided important data on the effects of oxygen therapy during daily activities, showing significant improvements in quality of life. Conclusions: This review showed that the literature on the benefits of oxygen therapy in patients with ILDs does not provide sufficient evidence to draft specific guidelines. It was not possible to conclude whether oxygen therapy has an effect on mortality or can only play a supportive role. Full article

(This article belongs to the Section Chemical Biology)

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17 pages, 2458 KiB

Open AccessArticle

Immunometabolic Markers in a Small Patient Cohort Undergoing Immunotherapy

by Joshua Hofbauer, Andreas Hauck, Carina Matos, Nathalie Babl, Sonja-Maria Decking, Michael Rechenmacher, Christian Schulz, Sabine Regotta, Marion Mickler, Sebastian Haferkamp, Peter J. Siska, Wolfgang Herr, Kathrin Renner, Marina Kreutz and Annette Schnell

Biomolecules 2022, 12(5), 716; https://doi.org/10.3390/biom12050716 - 18 May 2022

Cited by 4 | Viewed by 2846

Abstract

Although the discovery of immune checkpoints was hailed as a major breakthrough in cancer therapy, generating a sufficient response to immunotherapy is still limited. Thus, the objective of this exploratory, hypothesis-generating study was to identify potentially novel peripheral biomarkers and discuss the possible [...] Read more.

Although the discovery of immune checkpoints was hailed as a major breakthrough in cancer therapy, generating a sufficient response to immunotherapy is still limited. Thus, the objective of this exploratory, hypothesis-generating study was to identify potentially novel peripheral biomarkers and discuss the possible predictive relevance of combining scarcely investigated metabolic and hormonal markers with immune subsets. Sixteen markers that differed significantly between responders and non-responders were identified. In a further step, the correlation with progression-free survival (PFS) and false discovery correction (Benjamini and Hochberg) revealed potential predictive roles for the immune subset absolute lymphocyte count (rs = 0.51; p = 0.0224 *), absolute basophil count (rs = 0.43; p = 0.04 *), PD-1+ monocytes (rs = −0.49; p = 0.04 *), hemoglobin (rs = 0.44; p = 0.04 *), metabolic markers LDL (rs = 0.53; p = 0.0224 *), free androgen index (rs = 0.57; p = 0.0224 *) and CRP (rs = −0.46; p = 0.0352 *). The absolute lymphocyte count, LDL and free androgen index were the most significant individual markers, and combining the immune subsets with the metabolic markers into a biomarker ratio enhanced correlation with PFS (rs = −0.74; p ≤ 0.0001 ****). In summary, in addition to well-established markers, we identified PD-1+ monocytes and the free androgen index as potentially novel peripheral markers in the context of immunotherapy. Furthermore, the combination of immune subsets with metabolic and hormonal markers may have the potential to enhance the power of future predictive scores and should, therefore, be investigated further in larger trials. Full article

(This article belongs to the Special Issue Immunotherapy and Cancer)

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19 pages, 9530 KiB

Open AccessReview

Metabolic Engineering and Regulation of Diol Biosynthesis from Renewable Biomass in Escherichia coli

by Tong Wu, Yumei Liu, Jinsheng Liu, Zhenya Chen and Yi-Xin Huo

Biomolecules 2022, 12(5), 715; https://doi.org/10.3390/biom12050715 - 18 May 2022

Cited by 5 | Viewed by 3828

Abstract

As bulk chemicals, diols have wide applications in many fields, such as clothing, biofuels, food, surfactant and cosmetics. The traditional chemical synthesis of diols consumes numerous non-renewable energy resources and leads to environmental pollution. Green biosynthesis has emerged as an alternative method to [...] Read more.

As bulk chemicals, diols have wide applications in many fields, such as clothing, biofuels, food, surfactant and cosmetics. The traditional chemical synthesis of diols consumes numerous non-renewable energy resources and leads to environmental pollution. Green biosynthesis has emerged as an alternative method to produce diols. Escherichia coli as an ideal microbial factory has been engineered to biosynthesize diols from carbon sources. Here, we comprehensively summarized the biosynthetic pathways of diols from renewable biomass in E. coli and discussed the metabolic-engineering strategies that could enhance the production of diols, including the optimization of biosynthetic pathways, improvement of cofactor supplementation, and reprogramming of the metabolic network. We then investigated the dynamic regulation by multiple control modules to balance the growth and production, so as to direct carbon sources for diol production. Finally, we proposed the challenges in the diol-biosynthesis process and suggested some potential methods to improve the diol-producing ability of the host. Full article

(This article belongs to the Special Issue Computational Biology for Metabolic Modelling and Pathway Design)

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38 pages, 1515 KiB

Open AccessEditor’s ChoiceReview

Cerebral Iron Deposition in Neurodegeneration

by Petr Dusek, Tim Hofer, Jan Alexander, Per M. Roos and Jan O. Aaseth

Biomolecules 2022, 12(5), 714; https://doi.org/10.3390/biom12050714 - 17 May 2022

Cited by 68 | Viewed by 25028

Abstract

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance [...] Read more.

Disruption of cerebral iron regulation appears to have a role in aging and in the pathogenesis of various neurodegenerative disorders. Possible unfavorable impacts of iron accumulation include reactive oxygen species generation, induction of ferroptosis, and acceleration of inflammatory changes. Whole-brain iron-sensitive magnetic resonance imaging (MRI) techniques allow the examination of macroscopic patterns of brain iron deposits in vivo, while modern analytical methods ex vivo enable the determination of metal-specific content inside individual cell-types, sometimes also within specific cellular compartments. The present review summarizes the whole brain, cellular, and subcellular patterns of iron accumulation in neurodegenerative diseases of genetic and sporadic origin. We also provide an update on mechanisms, biomarkers, and effects of brain iron accumulation in these disorders, focusing on recent publications. In Parkinson’s disease, Friedreich’s disease, and several disorders within the neurodegeneration with brain iron accumulation group, there is a focal siderosis, typically in regions with the most pronounced neuropathological changes. The second group of disorders including multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis shows iron accumulation in the globus pallidus, caudate, and putamen, and in specific cortical regions. Yet, other disorders such as aceruloplasminemia, neuroferritinopathy, or Wilson disease manifest with diffuse iron accumulation in the deep gray matter in a pattern comparable to or even more extensive than that observed during normal aging. On the microscopic level, brain iron deposits are present mostly in dystrophic microglia variably accompanied by iron-laden macrophages and in astrocytes, implicating a role of inflammatory changes and blood–brain barrier disturbance in iron accumulation. Options and potential benefits of iron reducing strategies in neurodegeneration are discussed. Future research investigating whether genetic predispositions play a role in brain Fe accumulation is necessary. If confirmed, the prevention of further brain Fe uptake in individuals at risk may be key for preventing neurodegenerative disorders. Full article

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

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15 pages, 1374 KiB

Open AccessEditor’s ChoiceArticle

DYT-PRKRA Mutation P222L Enhances PACT’s Stimulatory Activity on Type I Interferon Induction

by Lauren S. Vaughn, Kenneth Frederick, Samuel B. Burnett, Nutan Sharma, D. Cristopher Bragg, Sarah Camargos, Francisco Cardoso and Rekha C. Patel

Biomolecules 2022, 12(5), 713; https://doi.org/10.3390/biom12050713 - 17 May 2022

Cited by 2 | Viewed by 3658

Abstract

DYT-PRKRA (dystonia 16 or DYT-PRKRA) is caused by mutations in the PRKRA gene that encodes PACT, the protein activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR). PACT participates in several cellular pathways, of which its role as a [...] Read more.

DYT-PRKRA (dystonia 16 or DYT-PRKRA) is caused by mutations in the PRKRA gene that encodes PACT, the protein activator of interferon (IFN)-induced double-stranded (ds) RNA-activated protein kinase (PKR). PACT participates in several cellular pathways, of which its role as a PKR activator protein during integrated stress response (ISR) is the best characterized. Previously, we have established that the DYT-PRKRA mutations cause enhanced activation of PKR during ISR to sensitize DYT-PRKRA cells to apoptosis. In this study, we evaluate if the most prevalent substitution mutation reported in DYT-PRKRA patients alters PACT’s functional role in induction of type I IFNs via the retinoic acid-inducible gene I (RIG-I) signaling. Our results indicate that the P222L mutation augments PACT’s ability to induce IFN β in response to dsRNA and the basal expression of IFN β and IFN-stimulated genes (ISGs) is higher in DYT-PRKRA patient cells compared to cells from the unaffected controls. Additionally, IFN β and ISGs are also induced at higher levels in DYT-PRKRA cells in response to dsRNA. These results offer a new avenue for investigations directed towards understanding the underlying molecular pathomechanisms in DYT-PRKRA. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Neuro-Muscular Degeneration, Metabolic Syndromes, Cancer and Infection)

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12 pages, 848 KiB

Open AccessArticle

Insulin-Like Growth Factor-Binding Protein 7 (IGFBP-7)—New Diagnostic and Prognostic Marker in Symptomatic Peripheral Arterial Disease?—Pilot Study

by Anna Szyszkowska, Sylwia Barańska, Robert Sawicki, Ewa Tarasiuk, Marlena Dubatówka, Marcin Kondraciuk, Emilia Sawicka-Śmiarowska, Małgorzata Knapp, Jerzy Głowiński, Karol Kamiński and Anna Lisowska

Biomolecules 2022, 12(5), 712; https://doi.org/10.3390/biom12050712 - 17 May 2022

Cited by 3 | Viewed by 2422

Abstract

The aim of our study was to evaluate the importance of insulin-like growth-factor-binding protein 7 (IGFBP-7) as a potential marker of symptomatic peripheral artery disease (PAD) occurrence. The study group consisted of 145 patients with diagnosed PAD, who qualified for the invasive treatment. [...] Read more.

The aim of our study was to evaluate the importance of insulin-like growth-factor-binding protein 7 (IGFBP-7) as a potential marker of symptomatic peripheral artery disease (PAD) occurrence. The study group consisted of 145 patients with diagnosed PAD, who qualified for the invasive treatment. The control group consisted of 67 individuals representing the local population and an ischemic heart disease (IHD) group of 88 patients after myocardial infarction or percutaneous coronary intervention. Patients with PAD had significantly higher IGFBP-7 concentrations than control group (1.80 ± 1.62 vs. 1.41 ± 0.45 ng/mL, p = 0.04). No significant differences between PAD patients and IHD patients were found (1.80 ± 1.62 vs. 1.76 ± 1.04 ng/mL, p = 0.783). Patients with multilevel PAD presented significantly higher IGFBP-7 concentrations than patients with aortoiliac PAD—median 1.18 (IQR 0.48–2.23) vs. 1.42 ng/mL (0.71–2.63), p = 0.035. In the group of patients who died or had a major adverse cardiovascular event (MACE) during six months of follow-up, a statistically significant higher IGFBP-7 concentration was found (median 2.66 (IQR 1.80–4.93) vs. 1.36 ng/mL (IQR 0.65–2.34), p = 0.004). It seems that IGFBP-7 is elevated in patients with atherosclerotic lesions—regardless of their locations. Further research should be conducted to verify IGFBP-7 usefulness as a predictor of MACE or death. Full article

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9 pages, 1483 KiB

Open AccessEditor’s ChoiceArticle

Fluorescent Anti-CEA Nanobody for Rapid Tumor-Targeting and Imaging in Mouse Models of Pancreatic Cancer

by Thinzar M. Lwin, Michael A. Turner, Hiroto Nishino, Siamak Amirfakhri, Sophie Hernot, Robert M. Hoffman and Michael Bouvet

Biomolecules 2022, 12(5), 711; https://doi.org/10.3390/biom12050711 - 16 May 2022

Cited by 8 | Viewed by 3478

Abstract

Tumor-specific targeting with fluorescent probes can enhance contrast for identification of cancer during surgical resection and visualize otherwise invisible tumor margins. Nanobodies are the smallest naturally-occurring antigen-binding molecules with rapid pharmacokinetics. The present work demonstrates the efficacy of a fluorescent anti-CEA nanobody conjugated [...] Read more.

Tumor-specific targeting with fluorescent probes can enhance contrast for identification of cancer during surgical resection and visualize otherwise invisible tumor margins. Nanobodies are the smallest naturally-occurring antigen-binding molecules with rapid pharmacokinetics. The present work demonstrates the efficacy of a fluorescent anti-CEA nanobody conjugated to an IR800 dye to target and label patient derived pancreatic cancer xenografts. After intravenous administration, the probe rapidly localized to the pancreatic cancer tumors within an hour and had a tumor-to-background ratio of 2.0 by 3 h. The fluorescence signal was durable over a prolonged period of time. With the rapid kinetics afforded by fluorescent nanobodies, both targeting and imaging can be performed on the same day as surgery. Full article

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11 pages, 1156 KiB

Open AccessArticle

Increase in Serum MMP-9 and TIMP-1 Concentrations during Alcohol Intoxication in Adolescents—A Preliminary Study

by Katarzyna Zdanowicz, Monika Kowalczuk-Kryston, Witold Olanski, Irena Werpachowska, Wlodzimierz Mielech and Dariusz Marek Lebensztejn

Biomolecules 2022, 12(5), 710; https://doi.org/10.3390/biom12050710 - 16 May 2022

Cited by 14 | Viewed by 2376

Abstract

Background: Alcohol consumption by adolescents is responsible for a number of adverse health and social outcomes. Despite the well-established effect of alcohol use on the development of alcoholic liver disease, the relationship between the pattern of alcohol consumption and liver fibrosis is still [...] Read more.

Background: Alcohol consumption by adolescents is responsible for a number of adverse health and social outcomes. Despite the well-established effect of alcohol use on the development of alcoholic liver disease, the relationship between the pattern of alcohol consumption and liver fibrosis is still unclear. This study is a follow-up to work on liver damage from alcohol intoxication. The aim of our study was to explore the early effects of alcohol intoxication on liver fibrosis in adolescents. Methods: The prospective study included 57 adolescents aged 14–17 years admitted to the emergency department (ED) from February 2017 to June 2018 due to acute alcohol intoxication. Serum levels of amino terminal propeptide of type III procollagen (PIIINP), type IV collagen, matrix metallopeptidase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) were determined by enzyme-linked immunosorbent assays. Results: There were significant differences in MMP-9 (p = 0.02) and TIMP-1 (p = 0.007) levels between the study and control groups. Liver parameters and selected markers of fibrosis were similar in groups in terms of blood alcohol concentrations (BAC). MMP-9 was positively correlated with alanine aminotransferase (ALT) (r = 0.38; p = 0.004) and total bilirubin (r = 0.39; p = 0.004). Positive significant correlations were also found between TIMP-1 and ALT (r = 0.47; p < 0.001), AST (r = 0.29; p = 0.03) and total bilirubin (r = 0.32; p = 0.02). In receiver operating characteristic (ROC) analysis, MMP-9 (AUC = 0.67, p = 0.02) and TIMP-1 (AUC = 0.69, p = 0.003) allowed for the differentiation of patients with and without alcohol intoxication. Conclusion: Our results show that even a single episode of alcohol intoxication in adolescents can lead to imbalance in markers of fibrosis. Full article

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21 pages, 3283 KiB

Open AccessArticle

A High Throughput Lipidomics Method Using Scheduled Multiple Reaction Monitoring

by Akash Kumar Bhaskar, Salwa Naushin, Arjun Ray, Praveen Singh, Anurag Raj, Shalini Pradhan, Khushboo Adlakha, Towfida Jahan Siddiqua, Dipankar Malakar, Debasis Dash and Shantanu Sengupta

Biomolecules 2022, 12(5), 709; https://doi.org/10.3390/biom12050709 - 16 May 2022

Cited by 9 | Viewed by 4500

Abstract

Lipid compositions of cells, tissues, and bio-fluids are complex, with varying concentrations and structural diversity making their identification challenging. Newer methods for comprehensive analysis of lipids are thus necessary. Herein, we propose a targeted-mass spectrometry based lipidomics screening method using a combination of [...] Read more.

Lipid compositions of cells, tissues, and bio-fluids are complex, with varying concentrations and structural diversity making their identification challenging. Newer methods for comprehensive analysis of lipids are thus necessary. Herein, we propose a targeted-mass spectrometry based lipidomics screening method using a combination of variable retention time window and relative dwell time weightage. Using this method, we identified more than 1000 lipid species within 24-min. The limit of detection varied from the femtomolar to the nanomolar range. About 883 lipid species were detected with a coefficient of variance <30%. We used this method to identify plasma lipids altered due to vitamin B₁₂ deficiency and found a total of 18 lipid species to be altered. Some of the lipid species with ω-6 fatty acid chains were found to be significantly increased while ω-3 decreased in vitamin B₁₂ deficient samples. This method enables rapid screening of a large number of lipid species in a single experiment and would substantially advance our understanding of the role of lipids in biological processes. Full article

(This article belongs to the Special Issue Integrative Multi-Omics Studies in Development and Diseases)

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13 pages, 2105 KiB

Open AccessArticle

Artemisia dracunculus L. Ethanolic Extract and an Isolated Component, DMC2, Ameliorate Inflammatory Signaling in Pancreatic β-Cells via Inhibition of p38 MAPK

by Peter Smoak, Susan J. Burke, Thomas M. Martin, Heidi M. Batdorf, Z. Elizabeth Floyd and J. Jason Collier

Biomolecules 2022, 12(5), 708; https://doi.org/10.3390/biom12050708 - 15 May 2022

Cited by 3 | Viewed by 2233

Abstract

Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. [...] Read more.

Non-resolving pancreatic islet inflammation is widely viewed as a contributor to decreases in β-cell mass and function that occur in both Type 1 and Type 2 diabetes. Therefore, strategies aimed at reducing or eliminating pathological inflammation would be useful to protect islet β-cells. Herein, we described the use of 2′,4′-dihydroxy-4-methoxydihydrochalcone (DMC2), a bioactive molecule isolated from an ethanolic extract of Artemisia dracunculus L., as a novel anti-inflammatory agent. The ethanolic extract, termed PMI 5011, reduced IL-1β-mediated NF-κB activity. DMC2 retained this ability, indicating this compound as the likely source of anti-inflammatory activity within the overall PMI 5011 extract. We further examined NF-κB activity using promoter-luciferase reporter constructs, Western blots, mRNA abundance, and protein secretion. Specifically, we found that PMI 5011 and DMC2 each reduced the ability of IL-1β to promote increases in the expression of the Ccl2 and Ccl20 genes. These genes encode proteins that promote immune cell recruitment and are secreted by β-cells in response to IL-1β. Phosphorylation of IκBα and the p65 subunit of NF-κB were not reduced by either PMI 5011 or DMC2; however, phosphorylation of p38 MAPK was blunted in the presence of DMC2. Finally, we observed that while PMI 5011 impaired glucose-stimulated insulin secretion, insulin output was preserved in the presence of DMC2. In conclusion, PMI 5011 and DMC2 reduced inflammation, but only DMC2 did so with the preservation of glucose-stimulated insulin secretion. Full article

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

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