Biomolecules

Review

23 pages, 2023 KiB

Open AccessEditor’s ChoiceReview

Industrial Production of Proteins with Pichia pastoris—Komagataella phaffii

by Giovanni Davide Barone, Anita Emmerstorfer-Augustin, Antonino Biundo, Isabella Pisano, Paola Coccetti, Valeria Mapelli and Andrea Camattari

Biomolecules 2023, 13(3), 441; https://doi.org/10.3390/biom13030441 - 26 Feb 2023

Cited by 26 | Viewed by 7693

Abstract

Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific topic, [...] Read more.

Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific topic, and the importance for this approach is rising in the current era of environmental transition in human societies. This review aims to summarize fundamental and specific information in this scientific field. Additionally, an updated description of the relevant products produced with K. phaffii at industrial levels by a variety of companies—describing how the industry has leveraged its key features, from products for the ingredients of meat-free burgers (e.g., IMPOSSIBLE™ FOODS, USA) to diabetes therapeutics (e.g., Biocon, India)—is provided. Furthermore, active patents and the typical workflow for industrial protein production with this strain are reported. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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17 pages, 745 KiB

Open AccessEditor’s ChoiceReview

Molecular Targets in Campylobacter Infections

by Markus M. Heimesaat, Steffen Backert, Thomas Alter and Stefan Bereswill

Biomolecules 2023, 13(3), 409; https://doi.org/10.3390/biom13030409 - 22 Feb 2023

Cited by 5 | Viewed by 3660

Abstract

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients [...] Read more.

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients develop abdominal pain and diarrhea. Post-infectious disorders following acute enteritis may occur and affect the nervous system, the joints or the intestines. Immunocompromising comorbidities in infected patients favor bacteremia, leading to vascular inflammation and septicemia. Prevention of human infection is achieved by hygiene measures focusing on the reduction of pathogenic food contamination. Molecular targets for the treatment and prevention of campylobacteriosis include bacterial pathogenicity and virulence factors involved in motility, adhesion, invasion, oxygen detoxification, acid resistance and biofilm formation. This repertoire of intervention measures has recently been completed by drugs dampening the pro-inflammatory immune responses induced by the Campylobacter endotoxin lipo-oligosaccharide. Novel pharmaceutical strategies will combine anti-pathogenic and anti-inflammatory effects to reduce the risk of both anti-microbial resistance and post-infectious sequelae of acute enteritis. Novel strategies and actual trends in the combat of Campylobacter infections are presented in this review, alongside molecular targets applied for prevention and treatment strategies. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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20 pages, 1533 KiB

Open AccessEditor’s ChoiceReview

Cellular Pathogenesis of Hepatic Encephalopathy: An Update

by Kaihui Lu

Biomolecules 2023, 13(2), 396; https://doi.org/10.3390/biom13020396 - 19 Feb 2023

Cited by 10 | Viewed by 8651

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been [...] Read more.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions. Full article

(This article belongs to the Special Issue The Contribution of Astrocytes to Neuropathology)

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14 pages, 1452 KiB

Open AccessEditor’s ChoiceReview

Granzyme B in Autoimmune Skin Disease

by Anna Gleave and David J. Granville

Biomolecules 2023, 13(2), 388; https://doi.org/10.3390/biom13020388 - 18 Feb 2023

Cited by 8 | Viewed by 3272

Abstract

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. [...] Read more.

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. Hence, there is an unmet need for novel therapies that block molecular drivers of disease in a local and/or targeted manner. Granzyme B (GzmB) is a serine protease with known cytotoxic activity and emerging extracellular functions, including the cleavage of cell–cell junctions, basement membranes, cell receptors, and other structural proteins. While minimal to absent in healthy skin, GzmB is markedly elevated in alopecia areata, interface dermatitis, pemphigoid disease, psoriasis, systemic sclerosis, and vitiligo. This review will discuss the role of GzmB in immunity, blistering, apoptosis, and barrier dysfunction in the context of autoimmune skin disease. GzmB plays a causal role in the development of pemphigoid disease and carries diagnostic and prognostic significance in cutaneous lupus erythematosus, vitiligo, and alopecia areata. Taken together, these data support GzmB as a promising therapeutic target for autoimmune skin diseases impacted by impaired barrier function, inflammation, and/or blistering. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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15 pages, 2604 KiB

Open AccessEditor’s ChoiceReview

Opposing Roles of FACT for Euchromatin and Heterochromatin in Yeast

by Shinya Takahata and Yota Murakami

Biomolecules 2023, 13(2), 377; https://doi.org/10.3390/biom13020377 - 16 Feb 2023

Cited by 2 | Viewed by 2703

Abstract

DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is [...] Read more.

DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is characterized into low-density “euchromatin” and high-density “heterochromatin”, with various factors being involved in its regulation. Here, we focus on chromatin regulation and gene expression by the yeast FACT complex, which functions in both euchromatin and heterochromatin. FACT is known as a histone H2A/H2B chaperone and was initially reported as an elongation factor associated with RNA polymerase II. In budding yeast, FACT activates promoter chromatin by interacting with the transcriptional activators SBF/MBF via the regulation of G1/S cell cycle genes. In fission yeast, FACT plays an important role in the formation of higher-order chromatin structures and transcriptional repression by binding to Swi6, an HP1 family protein, at heterochromatin. This FACT property, which refers to the alternate chromatin-regulation depending on the binding partner, is an interesting phenomenon. Further analysis of nucleosome regulation within heterochromatin is expected in future studies. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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22 pages, 1726 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models

by Michele Brischigliaro, Erika Fernandez-Vizarra and Carlo Viscomi

Biomolecules 2023, 13(2), 378; https://doi.org/10.3390/biom13020378 - 16 Feb 2023

Cited by 5 | Viewed by 5505

Abstract

The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely [...] Read more.

The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders II)

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14 pages, 541 KiB

Open AccessEditor’s ChoiceReview

Complement as a Biomarker for Systemic Lupus Erythematosus

by Masahiro Ayano and Takahiko Horiuchi

Biomolecules 2023, 13(2), 367; https://doi.org/10.3390/biom13020367 - 15 Feb 2023

Cited by 12 | Viewed by 6616

Abstract

Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the [...] Read more.

Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the evaluation of complement status can be useful in the diagnosis of SLE, assessment of disease activity, and prediction of treatment response and prognosis. In addition, novel complement biomarkers, such as split products and cell-bound complement activation products, are considered to be more sensitive than traditional complement markers, such as serum C3 and C4 levels and total complement activity (CH50), which become more widely used. In this review, we report the complement testing in the management of SLE over the last decade and summarize their utility. Full article

(This article belongs to the Special Issue Biomarkers in Systemic Lupus Erythematosus)

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19 pages, 2944 KiB

Open AccessEditor’s ChoiceReview

Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System

by Hidekazu Sotoyama, Hisaaki Namba, Manavu Tohmi and Hiroyuki Nawa

Biomolecules 2023, 13(2), 372; https://doi.org/10.3390/biom13020372 - 15 Feb 2023

Cited by 3 | Viewed by 3073

Abstract

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the [...] Read more.

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune–inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors. Full article

(This article belongs to the Special Issue Neurotrophic Factors and Growth Factors - Historical Perspective and New Directions for Medical Use)

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17 pages, 3315 KiB

Open AccessEditor’s ChoiceReview

The Actin Network Interfacing Diverse Integrin-Mediated Adhesions

by Benjamin Geiger, Rajaa Boujemaa-Paterski, Sabina E. Winograd-Katz, Jubina Balan Venghateri, Wen-Lu Chung and Ohad Medalia

Biomolecules 2023, 13(2), 294; https://doi.org/10.3390/biom13020294 - 4 Feb 2023

Cited by 5 | Viewed by 3148

Abstract

The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of [...] Read more.

The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of invading cancer cells display distinct morphologies and apparent functions. Yet, all three share a similar composition and mode of coupling between a protrusive structure (the lamellipodium, the core actin bundle of the podosome, and the invadopodia protrusion, respectively), and a nearby adhesion site. Cytoskeletal or external forces, applied to the adhesion sites, trigger a cascade of unfolding and activation of key adhesome components (e.g., talin, vinculin, integrin), which in turn, trigger the assembly of adhesion sites and generation of adhesion-mediated signals that affect cell behavior and fate. The structural and molecular mechanisms underlying the dynamic crosstalk between the actin cytoskeleton and the adhesome network are discussed. Full article

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

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18 pages, 1505 KiB

Open AccessEditor’s ChoiceReview

Comparative Research: Regulatory Mechanisms of Ribosomal Gene Transcription in Saccharomyces cerevisiae and Schizosaccharomyces pombe

by Hayato Hirai and Kunihiro Ohta

Biomolecules 2023, 13(2), 288; https://doi.org/10.3390/biom13020288 - 3 Feb 2023

Cited by 5 | Viewed by 2906

Abstract

Restricting ribosome biosynthesis and assembly in response to nutrient starvation is a universal phenomenon that enables cells to survive with limited intracellular resources. When cells experience starvation, nutrient signaling pathways, such as the target of rapamycin (TOR) and protein kinase A (PKA), become [...] Read more.

Restricting ribosome biosynthesis and assembly in response to nutrient starvation is a universal phenomenon that enables cells to survive with limited intracellular resources. When cells experience starvation, nutrient signaling pathways, such as the target of rapamycin (TOR) and protein kinase A (PKA), become quiescent, leading to several transcription factors and histone modification enzymes cooperatively and rapidly repressing ribosomal genes. Fission yeast has factors for heterochromatin formation similar to mammalian cells, such as H3K9 methyltransferase and HP1 protein, which are absent in budding yeast. However, limited studies on heterochromatinization in ribosomal genes have been conducted on fission yeast. Herein, we shed light on and compare the regulatory mechanisms of ribosomal gene transcription in two species with the latest insights. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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16 pages, 1862 KiB

Open AccessEditor’s ChoiceReview

Recent Developments in Biopolymer-Based Hydrogels for Tissue Engineering Applications

by Rikako Hama, Anudari Ulziibayar, James W. Reinhardt, Tatsuya Watanabe, John Kelly and Toshiharu Shinoka

Biomolecules 2023, 13(2), 280; https://doi.org/10.3390/biom13020280 - 2 Feb 2023

Cited by 38 | Viewed by 3799

Abstract

Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the [...] Read more.

Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the molecular structure, especially in the case of polymers. Furthermore, many high-functional hydrogels with drug delivery systems (DDSs), in which drugs or bioactive substances are contained in controlled hydrogels, have been reported. This review focuses on the molecular design and function of biopolymer-based hydrogels and introduces recent developments in functional hydrogels for clinical applications. Full article

(This article belongs to the Special Issue Novel Materials for Biomedical Applications)

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44 pages, 5252 KiB

Open AccessEditor’s ChoiceReview

Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies

by Andrew Manley, Bahar I. Meshkat, Monica M. Jablonski and T.J. Hollingsworth

Biomolecules 2023, 13(2), 271; https://doi.org/10.3390/biom13020271 - 1 Feb 2023

Cited by 7 | Viewed by 4233

Abstract

Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The [...] Read more.

Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation. Full article

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

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16 pages, 1293 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease

by Kyle S. McCommis and Brian N. Finck

Biomolecules 2023, 13(2), 261; https://doi.org/10.3390/biom13020261 - 31 Jan 2023

Cited by 6 | Viewed by 3999

Abstract

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become [...] Read more.

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition. Full article

(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)

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13 pages, 1037 KiB

Open AccessEditor’s ChoiceReview

Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a

by Joyita Bharati, Praveen N. Chander and Pravin C. Singhal

Biomolecules 2023, 13(2), 266; https://doi.org/10.3390/biom13020266 - 31 Jan 2023

Cited by 2 | Viewed by 2582

Abstract

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, [...] Read more.

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms’ tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a. Full article

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

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Graphical abstract

23 pages, 992 KiB

Open AccessEditor’s ChoiceReview

Nuclear PTEN’s Functions in Suppressing Tumorigenesis: Implications for Rare Cancers

by Casey G. Langdon

Biomolecules 2023, 13(2), 259; https://doi.org/10.3390/biom13020259 - 30 Jan 2023

Cited by 6 | Viewed by 3494

Abstract

Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect [...] Read more.

Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)

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14 pages, 870 KiB

Open AccessEditor’s ChoiceReview

Organismal Roles of Hsp90

by Patricija van Oosten-Hawle

Biomolecules 2023, 13(2), 251; https://doi.org/10.3390/biom13020251 - 29 Jan 2023

Cited by 6 | Viewed by 2401

Abstract

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation [...] Read more.

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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27 pages, 2700 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Mitochondrial Modulators: The Defender

by Emmanuel Makinde, Linlin Ma, George D. Mellick and Yunjiang Feng

Biomolecules 2023, 13(2), 226; https://doi.org/10.3390/biom13020226 - 24 Jan 2023

Cited by 9 | Viewed by 3368

Abstract

Mitochondria are widely considered the “power hub” of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to [...] Read more.

Mitochondria are widely considered the “power hub” of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to calcium homeostasis, reactive oxygen species (ROS) balance, and cell apoptosis. The mitochondria also perform crucial multifaceted roles in biosynthetic pathways, serving as an important source of building blocks for the biosynthesis of fatty acid, cholesterol, amino acid, glucose, and heme. Since mitochondria play multiple vital roles in the cell, it is not surprising that disruption of mitochondrial function has been linked to a myriad of diseases, including neurodegenerative diseases, cancer, and metabolic disorders. In this review, we discuss the key physiological and pathological functions of mitochondria and present bioactive compounds with protective effects on the mitochondria and their mechanisms of action. We highlight promising compounds and existing difficulties limiting the therapeutic use of these compounds and potential solutions. We also provide insights and perspectives into future research windows on mitochondrial modulators. Full article

(This article belongs to the Special Issue Advances in the Role of Mitochondria in Regulated Cell Death Dysfunctions Associated with Human Pathologies)

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22 pages, 958 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Type 2 Diabetes and Alzheimer’s Disease: The Emerging Role of Cellular Lipotoxicity

by Nicola Marrano, Giuseppina Biondi, Anna Borrelli, Martina Rella, Tommaso Zambetta, Ludovico Di Gioia, Mariangela Caporusso, Giancarlo Logroscino, Sebastio Perrini, Francesco Giorgino and Annalisa Natalicchio

Biomolecules 2023, 13(1), 183; https://doi.org/10.3390/biom13010183 - 16 Jan 2023

Cited by 15 | Viewed by 4830

Abstract

Type 2 diabetes (T2D) and Alzheimer’s diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4–2-fold increase in the risk of [...] Read more.

Type 2 diabetes (T2D) and Alzheimer’s diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4–2-fold increase in the risk of developing AD among T2D patients, the involvement of possible common triggers in the pathogenesis of these two diseases remains largely unknown. Of note, recent mechanistic insights suggest that lipotoxicity could represent the missing ring in the pathogenetic mechanisms linking T2D to AD. Indeed, obesity, which represents the main cause of lipotoxicity, has been recognized as a major risk factor for both pathological conditions. Lipotoxicity can lead to inflammation, insulin resistance, oxidative stress, ceramide and amyloid accumulation, endoplasmic reticulum stress, ferroptosis, and autophagy, which are shared biological events in the pathogenesis of T2D and AD. In the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in T2D and AD, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives. Full article

(This article belongs to the Special Issue Role of Fatty Acid-Induced Multi-Organ Damage on Diabetes Onset and Progression: Implications for Therapeutic Strategies)

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15 pages, 1822 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson’s Disease?

by Tatou Iseki, Yuzuru Imai and Nobutaka Hattori

Biomolecules 2023, 13(1), 178; https://doi.org/10.3390/biom13010178 - 15 Jan 2023

Cited by 8 | Viewed by 3252

Abstract

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with [...] Read more.

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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26 pages, 1670 KiB

Open AccessEditor’s ChoiceReview

The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging

by Nekane Romero-García, Javier Huete-Acevedo, Cristina Mas-Bargues, Jorge Sanz-Ros, Mar Dromant and Consuelo Borrás

Biomolecules 2023, 13(1), 165; https://doi.org/10.3390/biom13010165 - 13 Jan 2023

Cited by 7 | Viewed by 3127

Abstract

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply [...] Read more.

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply inter-related and act together to drive the aging process. Altered intercellular communication is particularly relevant since it explains how damage at the cellular level translates into age-related loss of function at the organismal level. As the main effectors of intercellular communication, extracellular vesicles (EVs) might play a key role in the aggravation or mitigation of the hallmarks of aging. This review aims to summarize this role and to provide context for the multiple emerging EV-based gerotherapeutic strategies that are currently under study. Full article

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25 pages, 1260 KiB

Open AccessEditor’s ChoiceReview

The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer

by Bryce Wallis, Katherine Redd Bowman, Phong Lu and Carol S. Lim

Biomolecules 2023, 13(1), 159; https://doi.org/10.3390/biom13010159 - 12 Jan 2023

Cited by 18 | Viewed by 5893

Abstract

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, [...] Read more.

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, despite accounting for only 2.5% of all female malignancies. The overall 5-year survival rate for ovarian cancer is around 47%; however, this drops to an abysmal 29% for the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC). HGSOC has upwards of 96% of cases expressing mutations in p53. Therefore, wild-type (WT) p53 and p53-based therapies have been explored as treatment options via a plethora of drug delivery vehicles including nanoparticles, viruses, polymers, and liposomes. However, previous p53 therapeutics have faced many challenges, which have resulted in their limited translational success to date. This review highlights a selection of these historical p53-targeted therapeutics for ovarian cancer, why they failed, and what the future could hold for a new generation of this class of therapies. Full article

(This article belongs to the Collection p53 Function and Dysfunction in Human Health and Diseases)

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12 pages, 687 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Insulin Resistance in Mitochondrial Diabetes

by Chika Takano, Erika Ogawa and Satoshi Hayakawa

Biomolecules 2023, 13(1), 126; https://doi.org/10.3390/biom13010126 - 7 Jan 2023

Cited by 11 | Viewed by 4807

Abstract

Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature [...] Read more.

Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature of MD. As mitochondrial dysfunction is one of the important factors causing IR, we need to focus on IR as another pathophysiology of MD. In this special issue, we first briefly summarized the insulin signaling and molecular mechanisms of IR. Second, we overviewed currently confirmed pathogenic mitochondrial DNA (mtDNA) mutations from the MITOMAP database. The variants causing diabetes were mostly point mutations in the transfer RNA (tRNA) of the mitochondrial genome. Third, we focused on these variants leading to the recently described “tRNA modopathies” and reviewed the clinical features of patients with diabetes. Finally, we discussed the pathophysiology of MD caused by mtDNA mutations and explored the possible mechanism underlying the development of IR. This review should be beneficial to all clinicians involved in diagnostics and therapeutics related to diabetes and mitochondrial diseases. Full article

(This article belongs to the Special Issue Insulin Resistance: Metabolic Mechanisms and Consequences Both In Vivo and Vitro)

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27 pages, 3169 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Archaea as a Model System for Molecular Biology and Biotechnology

by Federica De Lise, Roberta Iacono, Marco Moracci, Andrea Strazzulli and Beatrice Cobucci-Ponzano

Biomolecules 2023, 13(1), 114; https://doi.org/10.3390/biom13010114 - 6 Jan 2023

Cited by 7 | Viewed by 4006

Abstract

Archaea represents the third domain of life, displaying a closer relationship with eukaryotes than bacteria. These microorganisms are valuable model systems for molecular biology and biotechnology. In fact, nowadays, methanogens, halophiles, thermophilic euryarchaeota, and crenarchaeota are the four groups of archaea for which [...] Read more.

Archaea represents the third domain of life, displaying a closer relationship with eukaryotes than bacteria. These microorganisms are valuable model systems for molecular biology and biotechnology. In fact, nowadays, methanogens, halophiles, thermophilic euryarchaeota, and crenarchaeota are the four groups of archaea for which genetic systems have been well established, making them suitable as model systems and allowing for the increasing study of archaeal genes’ functions. Furthermore, thermophiles are used to explore several aspects of archaeal biology, such as stress responses, DNA replication and repair, transcription, translation and its regulation mechanisms, CRISPR systems, and carbon and energy metabolism. Extremophilic archaea also represent a valuable source of new biomolecules for biological and biotechnological applications, and there is growing interest in the development of engineered strains. In this review, we report on some of the most important aspects of the use of archaea as a model system for genetic evolution, the development of genetic tools, and their application for the elucidation of the basal molecular mechanisms in this domain of life. Furthermore, an overview on the discovery of new enzymes of biotechnological interest from archaea thriving in extreme environments is reported. Full article

(This article belongs to the Special Issue Theme Issue Honoring Scientist Louis Pasteur on His 200th Birthday)

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16 pages, 596 KiB

Open AccessEditor’s ChoiceReview

HDL Functions—Current Status and Future Perspectives

by Yasuhiro Endo, Masanori Fujita and Katsunori Ikewaki

Biomolecules 2023, 13(1), 105; https://doi.org/10.3390/biom13010105 - 4 Jan 2023

Cited by 17 | Viewed by 3656

Abstract

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with [...] Read more.

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with extremely high HDL-C levels. Furthermore, HDL-C raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce CVD events. Based on this background, HDL functions rather than HDL-C could be a novel biomarker; research on the clinical utility of HDL functionality is ongoing. In this review, we summarize the current status of HDL functions and their future perspectives from the findings of basic research and clinical trials. Full article

(This article belongs to the Special Issue Lipids in Atherosclerosis)

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11 pages, 839 KiB

Open AccessEditor’s ChoiceReview

Efavirenz: History, Development and Future

by Bárbara Costa and Nuno Vale

Biomolecules 2023, 13(1), 88; https://doi.org/10.3390/biom13010088 - 31 Dec 2022

Cited by 13 | Viewed by 3514

Abstract

Efavirenz (Sustiva^®) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to prevent the spread of HIV. In 1998, the FDA authorized efavirenz for the treatment of HIV-1 infection. Patients formerly [...] Read more.

Efavirenz (Sustiva^®) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to prevent the spread of HIV. In 1998, the FDA authorized efavirenz for the treatment of HIV-1 infection. Patients formerly required three 200 mg efavirenz capsules daily, which was rapidly updated to a 600 mg tablet that only required one tablet per day. However, when given 600 mg once daily, plasma efavirenz concentrations were linked not only to poor HIV suppression but also to toxicity. Clinical data suggested that the standard dose of efavirenz could be reduced without compromising its effectiveness, resulting in a reduction in side effects and making the drug more affordable. Therefore, ENCORE1 was performed to compare the efficiency and safeness of a reduced dose of efavirenz (400 mg) with the standard dose (600 mg) plus two NRTI in antiretroviral-naïve HIV-infected individuals. Nowadays, due to the emergence of integrase strand transfer inhibitors (INSTIs), some consider that it is time to stop using efavirenz as a first-line treatment on a global scale, in the parts of the world where that is possible. Efavirenz has been a primary first-line antiviral drug for more than 15 years. However, at this moment, the best use for efavirenz could be for pre-exposure prophylaxis (PrEP) and repurposing in medicine. Full article

(This article belongs to the Special Issue New Advances in Drug Repurposing for Oncology)

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45 pages, 2307 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblast Heterogeneity, Activation and Function: Implications for Prostate Cancer

by Jasmine S. Owen, Aled Clayton and Helen B. Pearson

Biomolecules 2023, 13(1), 67; https://doi.org/10.3390/biom13010067 - 29 Dec 2022

Cited by 15 | Viewed by 5171

Abstract

The continuous remodeling of the tumor microenvironment (TME) during prostate tumorigenesis is emerging as a critical event that facilitates cancer growth, progression and drug-resistance. Recent advances have identified extensive communication networks that enable tumor–stroma cross-talk, and emphasized the functional importance of diverse, heterogeneous [...] Read more.

The continuous remodeling of the tumor microenvironment (TME) during prostate tumorigenesis is emerging as a critical event that facilitates cancer growth, progression and drug-resistance. Recent advances have identified extensive communication networks that enable tumor–stroma cross-talk, and emphasized the functional importance of diverse, heterogeneous stromal fibroblast populations during malignant growth. Cancer-associated fibroblasts (CAFs) are a vital component of the TME, which mediate key oncogenic events including angiogenesis, immunosuppression, metastatic progression and therapeutic resistance, thus presenting an attractive therapeutic target. Nevertheless, how fibroblast heterogeneity, recruitment, cell-of-origin and differential functions contribute to prostate cancer remains to be fully delineated. Developing our molecular understanding of these processes is fundamental to developing new therapies and biomarkers that can ultimately improve clinical outcomes. In this review, we explore the current challenges surrounding fibroblast identification, discuss new mechanistic insights into fibroblast functions during normal prostate tissue homeostasis and tumorigenesis, and illustrate the diverse nature of fibroblast recruitment and CAF generation. We also highlight the promise of CAF-targeted therapies for the treatment of prostate cancer. Full article

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31 pages, 3181 KiB

Open AccessEditor’s ChoiceReview

Advances and Innovations of 3D Bioprinting Skin

by Moon Sung Kang, Jinju Jang, Hyo Jung Jo, Won-Hyeon Kim, Bongju Kim, Heoung-Jae Chun, Dohyung Lim and Dong-Wook Han

Biomolecules 2023, 13(1), 55; https://doi.org/10.3390/biom13010055 - 27 Dec 2022

Cited by 14 | Viewed by 5189

Abstract

Three-dimensional (3D) bioprinted skin equivalents are highlighted as the new gold standard for alternative models to animal testing, as well as full-thickness wound healing. In this review, we focus on the advances and innovations of 3D bioprinting skin for skin regeneration, within the [...] Read more.

Three-dimensional (3D) bioprinted skin equivalents are highlighted as the new gold standard for alternative models to animal testing, as well as full-thickness wound healing. In this review, we focus on the advances and innovations of 3D bioprinting skin for skin regeneration, within the last five years. After a brief introduction to skin anatomy, 3D bioprinting methods and the remarkable features of recent studies are classified as advances in materials, structures, and functions. We will discuss several ways to improve the clinical potential of 3D bioprinted skin, with state-of-the-art printing technology and novel biomaterials. After the breakthrough in the bottleneck of the current studies, highly developed skin can be fabricated, comprising stratified epidermis, dermis, and hypodermis with blood vessels, nerves, muscles, and skin appendages. We hope that this review will be priming water for future research and clinical applications, that will guide us to break new ground for the next generation of skin regeneration. Full article

(This article belongs to the Special Issue 3D Printing Biological and Medical Application)

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19 pages, 1931 KiB

Open AccessEditor’s ChoiceReview

Biological Effects of Human Exposure to Environmental Cadmium

by Massimiliano Peana, Alessio Pelucelli, Christos T. Chasapis, Spyros P. Perlepes, Vlasoula Bekiari, Serenella Medici and Maria Antonietta Zoroddu

Biomolecules 2023, 13(1), 36; https://doi.org/10.3390/biom13010036 - 24 Dec 2022

Cited by 63 | Viewed by 9135

Abstract

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the [...] Read more.

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin; chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd²⁺ can also replace essential metal ions, including redox-active ones. A total of 12 cancer types associated with specific genes coding for the Cd-metalloproteome were identified in this work. In addition, we summarize the proper treatments of Cd poisoning, based on the use of selected Cd detoxifying agents and chelators, and the potential for preventive approaches to counteract its chronic exposure. Full article

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

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19 pages, 1215 KiB

Open AccessEditor’s ChoiceReview

Message in a Scaffold: Natural Biomaterials for Three-Dimensional (3D) Bioprinting of Human Brain Organoids

by Pierre Layrolle, Pierre Payoux and Stéphane Chavanas

Biomolecules 2023, 13(1), 25; https://doi.org/10.3390/biom13010025 - 22 Dec 2022

Cited by 5 | Viewed by 3170

Abstract

Brain organoids are invaluable tools for pathophysiological studies or drug screening, but there are still challenges to overcome in making them more reproducible and relevant. Recent advances in three-dimensional (3D) bioprinting of human neural organoids is an emerging approach that may overcome the [...] Read more.

Brain organoids are invaluable tools for pathophysiological studies or drug screening, but there are still challenges to overcome in making them more reproducible and relevant. Recent advances in three-dimensional (3D) bioprinting of human neural organoids is an emerging approach that may overcome the limitations of self-organized organoids. It requires the development of optimal hydrogels, and a wealth of research has improved our knowledge about biomaterials both in terms of their intrinsic properties and their relevance on 3D culture of brain cells and tissue. Although biomaterials are rarely biologically neutral, few articles have reviewed their roles on neural cells. We here review the current knowledge on unmodified biomaterials amenable to support 3D bioprinting of neural organoids with a particular interest in their impact on cell homeostasis. Alginate is a particularly suitable bioink base for cell encapsulation. Gelatine is a valuable helper agent for 3D bioprinting due to its viscosity. Collagen, fibrin, hyaluronic acid and laminin provide biological support to adhesion, motility, differentiation or synaptogenesis and optimize the 3D culture of neural cells. Optimization of specialized hydrogels to direct differentiation of stem cells together with an increased resolution in phenotype analysis will further extend the spectrum of possible bioprinted brain disease models. Full article

(This article belongs to the Special Issue 3D Printing Biological and Medical Application)

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20 pages, 5119 KiB

Open AccessEditor’s ChoiceReview

Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia

by Teresa Zalewska, Paulina Pawelec, Karolina Ziabska and Malgorzata Ziemka-Nalecz

Biomolecules 2023, 13(1), 26; https://doi.org/10.3390/biom13010026 - 22 Dec 2022

Cited by 8 | Viewed by 2989

Abstract

Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are [...] Read more.

Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are achieved through the complex interplay of several factors contributing to this phenomenon, such as sex hormones, as well as genetic and epigenetic differences. Despite recent advances, the precise link between these factors and brain disorders is incompletely understood. This review aims to briefly outline the most relevant aspects that differ between men and women in ischemia and neurodegenerative disorders (AD, PD, HD, ALS, and SM). Recognition of disparities between both sexes could aid the development of individual approaches to ameliorate or slow the progression of intractable disorders. Full article

(This article belongs to the Special Issue Signaling Biomolecules in the Central Nervous System (CNS)—At the Nexus of Neuropsychiatric and Neurodegenerative Disorders)

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17 pages, 1119 KiB

Open AccessEditor’s ChoiceReview

NRF2 in the Epidermal Pigmentary System

by Tatsuya Ogawa and Yosuke Ishitsuka

Biomolecules 2023, 13(1), 20; https://doi.org/10.3390/biom13010020 - 22 Dec 2022

Cited by 3 | Viewed by 2582

Abstract

Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte [...] Read more.

Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte biology with a particular focus on the “master regulator” of oxidative stress responses (i.e., the Kelch-like erythroid cell-derived protein with cap‘n’collar homology-associated protein 1-nuclear factor erythroid-2-related factor 2 system) and the autoimmune pigment disorder vitiligo. Our investigation revealed that the former is essential in pigmentogenesis, whereas the latter results from unbalanced redox homeostasis and/or defective intercellular communication in the interfollicular epidermis (IFE). Finally, we propose a model in which keratinocytes provide a “niche” for differentiated melanocytes and may “imprint” IFE pigmentation. 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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13 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Use of Insect Promoters in Genetic Engineering to Control Mosquito-Borne Diseases

by Vanessa Bottino-Rojas and Anthony A. James

Biomolecules 2023, 13(1), 16; https://doi.org/10.3390/biom13010016 - 21 Dec 2022

Cited by 6 | Viewed by 4274

Abstract

Mosquito transgenesis and gene-drive technologies provide the basis for developing promising new tools for vector-borne disease prevention by either suppressing wild mosquito populations or reducing their capacity from transmitting pathogens. Many studies of the regulatory DNA and promoters of genes with robust sex-, [...] Read more.

Mosquito transgenesis and gene-drive technologies provide the basis for developing promising new tools for vector-borne disease prevention by either suppressing wild mosquito populations or reducing their capacity from transmitting pathogens. Many studies of the regulatory DNA and promoters of genes with robust sex-, tissue- and stage-specific expression profiles have supported the development of new tools and strategies that could bring mosquito-borne diseases under control. Although the list of regulatory elements available is significant, only a limited set of those can reliably drive spatial–temporal expression. Here, we review the advances in our ability to express beneficial and other genes in mosquitoes, and highlight the information needed for the development of new mosquito-control and anti-disease strategies. Full article

(This article belongs to the Special Issue Contributions of Promoters to the Physiology, Biochemistry and Molecular Biology Processes of Insects)

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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 19 | Viewed by 3027

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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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 8 | Viewed by 3692

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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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 35 | Viewed by 4132

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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18 pages, 1489 KiB

Open AccessEditor’s ChoiceReview

The Effect of Electrical Stimulation on Nerve Regeneration Following Peripheral Nerve Injury

by Luke Juckett, Tiam Mana Saffari, Benjamin Ormseth, Jenna-Lynn Senger and Amy M. Moore

Biomolecules 2022, 12(12), 1856; https://doi.org/10.3390/biom12121856 - 12 Dec 2022

Cited by 24 | Viewed by 9157

Abstract

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from [...] Read more.

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed. Full article

(This article belongs to the Special Issue Peripheral Nerve Plasticity: Development and Regeneration)

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12 pages, 305 KiB

Open AccessEditor’s ChoiceReview

Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction

by Francesca Bianco, Giulia Lattanzio, Luca Lorenzini, Maurizio Mazzoni, Paolo Clavenzani, Laura Calzà, Luciana Giardino, Catia Sternini, Anna Costanzini, Elena Bonora and Roberto De Giorgio

Biomolecules 2022, 12(12), 1849; https://doi.org/10.3390/biom12121849 - 10 Dec 2022

Cited by 9 | Viewed by 2403

Abstract

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is [...] Read more.

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

18 pages, 1921 KiB

Open AccessEditor’s ChoiceReview

The Emerging Role of Deubiquitinases in Cell Death

by Zhuan Zhou, Xinxin Song, Rui Kang and Daolin Tang

Biomolecules 2022, 12(12), 1825; https://doi.org/10.3390/biom12121825 - 6 Dec 2022

Cited by 2 | Viewed by 2995

Abstract

Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, [...] Read more.

Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, including mono- or polyubiquitination. Functionally, ubiquitination can affect protein abundance, localization, and activity. Like other post-translational modifications, ubiquitination is a dynamic and reversible process mediated by deubiquitinases, a large class of proteases that cleave ubiquitin from proteins and other substrates. The balance between ubiquitination and deubiquitination machinery determines cell fate under stressful conditions. Here, we review the latest advances in our understanding of the role of deubiquitinases in regulating the main types of RCD, including apoptosis, necroptosis, pyroptosis, and ferroptosis. This knowledge may contribute to identifying new protein degradation-related prognostic markers and therapeutic targets for human disease. Full article

(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)

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11 pages, 1618 KiB

Open AccessEditor’s ChoiceReview

Advances in Gene Therapy Techniques to Treat LRRK2 Gene Mutation

by Sun-Ku Chung and Seo-Young Lee

Biomolecules 2022, 12(12), 1814; https://doi.org/10.3390/biom12121814 - 5 Dec 2022

Cited by 2 | Viewed by 2664

Abstract

Leucine-rich repeat kinase 2 (LRRK2) gene mutation is an autosomal dominant mutation associated with Parkinson’s disease (PD). Among LRRK2 gene mutations, the LRRK2 G2019S mutation is frequently involved in PD onset. Currently, diverse gene correction tools such as zinc finger nucleases [...] Read more.

Leucine-rich repeat kinase 2 (LRRK2) gene mutation is an autosomal dominant mutation associated with Parkinson’s disease (PD). Among LRRK2 gene mutations, the LRRK2 G2019S mutation is frequently involved in PD onset. Currently, diverse gene correction tools such as zinc finger nucleases (ZFNs), helper-dependent adenoviral vector (HDAdV), the bacterial artificial chromosome-based homologous recombination (BAC-based HR) system, and CRISPR/Cas9-homology-directed repair (HDR) or adenine base editor (ABE) are used in genome editing. Gene correction of the LRRK2 G2019S mutation has been applied whenever new gene therapy tools emerge, being mainly applied to induced pluripotent stem cells (LRRK2 G2019S-mutant iPSCs). Here, we comprehensively introduce the principles and methods of each programmable nuclease such as ZFN, CRISPR/Cas9-HDR or ABE applied to LRRK2 G2019S, as well as those of HDAdV or BAC-based HR systems used as nonprogrammable nuclease systems. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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14 pages, 1064 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Benzodiazepine Modulation of GABA_A Receptors: A Mechanistic Perspective

by Marcel P. Goldschen-Ohm

Biomolecules 2022, 12(12), 1784; https://doi.org/10.3390/biom12121784 - 30 Nov 2022

Cited by 17 | Viewed by 10382

Abstract

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABA_A receptors (GABA_ARs) to tune inhibitory synaptic signaling throughout the central nervous system. Despite knowing their molecular target for over 40 years, we still do not fully understand [...] Read more.

Benzodiazepines (BZDs) are a class of widely prescribed psychotropic drugs that target GABA_A receptors (GABA_ARs) to tune inhibitory synaptic signaling throughout the central nervous system. Despite knowing their molecular target for over 40 years, we still do not fully understand the mechanism of modulation at the level of the channel protein. Nonetheless, functional studies, together with recent cryo-EM structures of GABA_A(α1)₂(βX)₂(γ2)₁ receptors in complex with BZDs, provide a wealth of information to aid in addressing this gap in knowledge. Here, mechanistic interpretations of functional and structural evidence for the action of BZDs at GABA_A(α1)₂(βX)₂(γ2)₁ receptors are reviewed. The goal is not to describe each of the many studies that are relevant to this discussion nor to dissect in detail all the effects of individual mutations or perturbations but rather to highlight general mechanistic principles in the context of recent structural information. Full article

(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)

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15 pages, 1569 KiB

Open AccessEditor’s ChoiceReview

The Pathophysiological Significance of “Mitochondrial Ejection” from Cells

by Qintao Fan, Yasuhiro Maejima, Lai Wei, Shun Nakagama, Yuka Shiheido-Watanabe and Tetsuo Sasano

Biomolecules 2022, 12(12), 1770; https://doi.org/10.3390/biom12121770 - 28 Nov 2022

Cited by 2 | Viewed by 4812

Abstract

Mitochondria have beneficial effects on cells by producing ATP and contributing to various biosynthetic procedures. On the other hand, dysfunctional mitochondria have detrimental effects on cells by inducing cellular damage, inflammation, and causing apoptosis in response to various stimuli. Therefore, a series of [...] Read more.

Mitochondria have beneficial effects on cells by producing ATP and contributing to various biosynthetic procedures. On the other hand, dysfunctional mitochondria have detrimental effects on cells by inducing cellular damage, inflammation, and causing apoptosis in response to various stimuli. Therefore, a series of mitochondrial quality control pathways are required for the physiological state of cells to be maintained. Recent research has provided solid evidence to support that mitochondria are ejected from cells for transcellular degradation or transferred to other cells as metabolic support or regulatory messengers. In this review, we summarize the current understanding of the regulation of mitochondrial transmigration across the plasma membranes and discuss the functional significance of this unexpected phenomenon, with an additional focus on the impact on the pathogenesis of cardiovascular diseases. We also provide some perspective concerning the unrevealed mechanisms underlying mitochondrial ejection as well as existing problems and challenges concerning the therapeutic application of mitochondrial ejection. Full article

(This article belongs to the Special Issue Advances in the Role of Mitochondria in Regulated Cell Death Dysfunctions Associated with Human Pathologies)

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16 pages, 2563 KiB

Open AccessEditor’s ChoiceReview

Boosting the Full Potential of PyMOL with Structural Biology Plugins

by Serena Rosignoli and Alessandro Paiardini

Biomolecules 2022, 12(12), 1764; https://doi.org/10.3390/biom12121764 - 27 Nov 2022

Cited by 36 | Viewed by 6343

Abstract

Over the past few decades, the number of available structural bioinformatics pipelines, libraries, plugins, web resources and software has increased exponentially and become accessible to the broad realm of life scientists. This expansion has shaped the field as a tangled network of methods, [...] Read more.

Over the past few decades, the number of available structural bioinformatics pipelines, libraries, plugins, web resources and software has increased exponentially and become accessible to the broad realm of life scientists. This expansion has shaped the field as a tangled network of methods, algorithms and user interfaces. In recent years PyMOL, widely used software for biomolecules visualization and analysis, has started to play a key role in providing an open platform for the successful implementation of expert knowledge into an easy-to-use molecular graphics tool. This review outlines the plugins and features that make PyMOL an eligible environment for supporting structural bioinformatics analyses. Full article

(This article belongs to the Special Issue Protein Structure Prediction in Drug Discovery)

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15 pages, 1544 KiB

Open AccessEditor’s ChoiceReview

Essential Components of Synthetic Infectious Prion Formation De Novo

by Kezia Jack, Graham S. Jackson and Jan Bieschke

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

Cited by 2 | Viewed by 2634

Abstract

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

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

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

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13 pages, 1240 KiB

Open AccessFeature PaperEditor’s ChoiceReview

cGMP Signaling in the Neurovascular Unit—Implications for Retinal Ganglion Cell Survival in Glaucoma

by Ameer A. Haider, Tonia S. Rex and Lauren K. Wareham

Biomolecules 2022, 12(11), 1671; https://doi.org/10.3390/biom12111671 - 11 Nov 2022

Cited by 4 | Viewed by 3523

Abstract

Glaucoma is a progressive age-related disease of the visual system and the leading cause of irreversible blindness worldwide. Currently, intraocular pressure (IOP) is the only modifiable risk factor for the disease, but even as IOP is lowered, the pathology of the disease often [...] Read more.

Glaucoma is a progressive age-related disease of the visual system and the leading cause of irreversible blindness worldwide. Currently, intraocular pressure (IOP) is the only modifiable risk factor for the disease, but even as IOP is lowered, the pathology of the disease often progresses. Hence, effective clinical targets for the treatment of glaucoma remain elusive. Glaucoma shares comorbidities with a multitude of vascular diseases, and evidence in humans and animal models demonstrates an association between vascular dysfunction of the retina and glaucoma pathology. Integral to the survival of retinal ganglion cells (RGCs) is functional neurovascular coupling (NVC), providing RGCs with metabolic support in response to neuronal activity. NVC is mediated by cells of the neurovascular unit (NVU), which include vascular cells, glial cells, and neurons. Nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling is a prime mediator of NVC between endothelial cells and neurons, but emerging evidence suggests that cGMP signaling is also important in the physiology of other cells of the NVU. NO-cGMP signaling has been implicated in glaucomatous neurodegeneration in humans and mice. In this review, we explore the role of cGMP signaling in the different cell types of the NVU and investigate the potential links between cGMP signaling, breakdown of neurovascular function, and glaucoma pathology. Full article

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

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31 pages, 953 KiB

Open AccessEditor’s ChoiceReview

Macrophages in Skin Wounds: Functions and Therapeutic Potential

by Seen Ling Sim, Snehlata Kumari, Simranpreet Kaur and Kiarash Khosrotehrani

Biomolecules 2022, 12(11), 1659; https://doi.org/10.3390/biom12111659 - 8 Nov 2022

Cited by 22 | Viewed by 5557

Abstract

Macrophages regulate cutaneous wound healing by immune surveillance, tissue repair and remodelling. The depletion of dermal macrophages during the early and middle stages of wound healing has a detrimental impact on wound closure, characterised by reduced vessel density, fibroblast and myofibroblast proliferation, delayed [...] Read more.

Macrophages regulate cutaneous wound healing by immune surveillance, tissue repair and remodelling. The depletion of dermal macrophages during the early and middle stages of wound healing has a detrimental impact on wound closure, characterised by reduced vessel density, fibroblast and myofibroblast proliferation, delayed re-epithelization and abated post-healing fibrosis and scar formation. However, in some animal species, oral mucosa and foetal life, cutaneous wounds can heal normally and remain scarless without any involvement of macrophages. These paradoxical observations have created much controversy on macrophages’ indispensable role in skin wound healing. Advanced knowledge gained by characterising macrophage subsets, their plasticity in switching phenotypes and molecular drivers provides new insights into their functional importance during cutaneous wound healing. In this review, we highlight the recent findings on skin macrophage subsets, their functional role in adult cutaneous wound healing and the potential benefits of targeting them for therapeutic use. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

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19 pages, 1186 KiB

Open AccessEditor’s ChoiceReview

Multi-Layered Regulations on the Chromatin Architectures: Establishing the Tight and Specific Responses of Fission Yeast fbp1 Gene Transcription

by Ryuta Asada and Kouji Hirota

Biomolecules 2022, 12(11), 1642; https://doi.org/10.3390/biom12111642 - 5 Nov 2022

Cited by 3 | Viewed by 2618

Abstract

Transcriptional regulation is pivotal for all living organisms and is required for adequate response to environmental fluctuations and intercellular signaling molecules. For precise regulation of transcription, cells have evolved regulatory systems on the genome architecture, including the chromosome higher-order structure (e.g., chromatin loops), [...] Read more.

Transcriptional regulation is pivotal for all living organisms and is required for adequate response to environmental fluctuations and intercellular signaling molecules. For precise regulation of transcription, cells have evolved regulatory systems on the genome architecture, including the chromosome higher-order structure (e.g., chromatin loops), location of transcription factor (TF)-binding sequences, non-coding RNA (ncRNA) transcription, chromatin configuration (e.g., nucleosome positioning and histone modifications), and the topological state of the DNA double helix. To understand how these genome-chromatin architectures and their regulators establish tight and specific responses at the transcription stage, the fission yeast fbp1 gene has been analyzed as a model system for decades. The fission yeast fbp1 gene is tightly repressed in the presence of glucose, and this gene is induced by over three orders of magnitude upon glucose starvation with a cascade of multi-layered regulations on various levels of genome and chromatin architecture. In this review article, we summarize the multi-layered transcriptional regulatory systems revealed by the analysis of the fission yeast fbp1 gene as a model system. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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17 pages, 19407 KiB

Open AccessEditor’s ChoiceReview

Postbiotics and Their Health Modulatory Biomolecules

by Emma Scott, Kim De Paepe and Tom Van de Wiele

Biomolecules 2022, 12(11), 1640; https://doi.org/10.3390/biom12111640 - 4 Nov 2022

Cited by 33 | Viewed by 7229

Abstract

Postbiotics are a new category of biotics that have the potential to confer health benefits but, unlike probiotics, do not require living cells to induce health effects and thus are not subject to the food safety requirements that apply to live microorganisms. Postbiotics [...] Read more.

Postbiotics are a new category of biotics that have the potential to confer health benefits but, unlike probiotics, do not require living cells to induce health effects and thus are not subject to the food safety requirements that apply to live microorganisms. Postbiotics are defined as a “preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Postbiotic components include short-chain fatty acids, exopolysaccharides, vitamins, teichoic acids, bacteriocins, enzymes and peptides in a non-purified inactivated cell preparation. While research into postbiotics is in its infancy, there is increasing evidence that postbiotics have the potential to modulate human health. Specifically, a number of postbiotics have been shown to improve gut health by strengthening the gut barrier, reducing inflammation and promoting antimicrobial activity against gut pathogens. Additionally, research is being conducted into the potential application of postbiotics to other areas of the body, including the skin, vagina and oral cavity. The purpose of this review is to set out the current research on postbiotics, demonstrate how postbiotics are currently used in commercial products and identify a number of knowledge gaps where further research is needed to identify the potential for future applications of postbiotics. Full article

(This article belongs to the Special Issue Probiotics and Their Metabolites)

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18 pages, 1592 KiB

Open AccessEditor’s ChoiceReview

LRRK2 and Lipid Pathways: Implications for Parkinson’s Disease

by Jasmin Galper, Woojin S. Kim and Nicolas Dzamko

Biomolecules 2022, 12(11), 1597; https://doi.org/10.3390/biom12111597 - 30 Oct 2022

Cited by 11 | Viewed by 4256

Abstract

Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in [...] Read more.

Genetic alterations in the LRRK2 gene, encoding leucine-rich repeat kinase 2, are a common risk factor for Parkinson’s disease. How LRRK2 alterations lead to cell pathology is an area of ongoing investigation, however, multiple lines of evidence suggest a role for LRRK2 in lipid pathways. It is increasingly recognized that in addition to being energy reservoirs and structural entities, some lipids, including neural lipids, participate in signaling cascades. Early investigations revealed that LRRK2 localized to membranous and vesicular structures, suggesting an interaction of LRRK2 and lipids or lipid-associated proteins. LRRK2 substrates from the Rab GTPase family play a critical role in vesicle trafficking, lipid metabolism and lipid storage, all processes which rely on lipid dynamics. In addition, LRRK2 is associated with the phosphorylation and activity of enzymes that catabolize plasma membrane and lysosomal lipids. Furthermore, LRRK2 knockout studies have revealed that blood, brain and urine exhibit lipid level changes, including alterations to sterols, sphingolipids and phospholipids, respectively. In human LRRK2 mutation carriers, changes to sterols, sphingolipids, phospholipids, fatty acyls and glycerolipids are reported in multiple tissues. This review summarizes the evidence regarding associations between LRRK2 and lipids, and the functional consequences of LRRK2-associated lipid changes are discussed. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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29 pages, 7575 KiB

Open AccessEditor’s ChoiceReview

Small-Angle Neutron Scattering for Studying Lipid Bilayer Membranes

by William T. Heller

Biomolecules 2022, 12(11), 1591; https://doi.org/10.3390/biom12111591 - 29 Oct 2022

Cited by 4 | Viewed by 3623

Abstract

Small-angle neutron scattering (SANS) is a powerful tool for studying biological membranes and model lipid bilayer membranes. The length scales probed by SANS, being from 1 nm to over 100 nm, are well-matched to the relevant length scales of the bilayer, particularly when [...] Read more.

Small-angle neutron scattering (SANS) is a powerful tool for studying biological membranes and model lipid bilayer membranes. The length scales probed by SANS, being from 1 nm to over 100 nm, are well-matched to the relevant length scales of the bilayer, particularly when it is in the form of a vesicle. However, it is the ability of SANS to differentiate between isotopes of hydrogen as well as the availability of deuterium labeled lipids that truly enable SANS to reveal details of membranes that are not accessible with the use of other techniques, such as small-angle X-ray scattering. In this work, an overview of the use of SANS for studying unilamellar lipid bilayer vesicles is presented. The technique is briefly presented, and the power of selective deuteration and contrast variation methods is discussed. Approaches to modeling SANS data from unilamellar lipid bilayer vesicles are presented. Finally, recent examples are discussed. While the emphasis is on studies of unilamellar vesicles, examples of the use of SANS to study intact cells are also presented. Full article

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

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20 pages, 596 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Molecular Insights into Epigenetics and Cannabinoid Receptors

by Balapal S. Basavarajappa and Shivakumar Subbanna

Biomolecules 2022, 12(11), 1560; https://doi.org/10.3390/biom12111560 - 26 Oct 2022

Cited by 8 | Viewed by 2818

Abstract

The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB₁ and CB₂ [...] Read more.

The actions of cannabis are mediated by G protein-coupled receptors that are part of an endogenous cannabinoid system (ECS). ECS consists of the naturally occurring ligands N-arachidonylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB₁ and CB₂ cannabinoid receptors. Epigenetics are heritable changes that affect gene expression without changing the DNA sequence, transducing external stimuli in stable alterations of the DNA or chromatin structure. Cannabinoid receptors are crucial candidates for exploring their functions through epigenetic approaches due to their significant roles in health and diseases. Epigenetic changes usually promote alterations in the expression of genes and proteins that can be evaluated by various transcriptomic and proteomic analyses. Despite the exponential growth of new evidence on the critical functions of cannabinoid receptors, much is still unknown regarding the contribution of various genetic and epigenetic factors that regulate cannabinoid receptor gene expression. Recent studies have identified several immediate and long-lasting epigenetic changes, such as DNA methylation, DNA-associated histone proteins, and RNA regulatory networks, in cannabinoid receptor function. Thus, they can offer solutions to many cellular, molecular, and behavioral impairments found after modulation of cannabinoid receptor activities. In this review, we discuss the significant research advances in different epigenetic factors contributing to the regulation of cannabinoid receptors and their functions under both physiological and pathological conditions. Increasing our understanding of the epigenetics of cannabinoid receptors will significantly advance our knowledge and could lead to the identification of novel therapeutic targets and innovative treatment strategies for diseases associated with altered cannabinoid receptor functions. Full article

(This article belongs to the Special Issue New Advances of Cannabinoid Receptors in Health and Disease)

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