Quality control (QC) processes include a network of cellular pathways that prevent the accumulation of toxic aggregates by repairing, recycling, and/or eliminating defective components, including mitochondria. Among these pathways are the proteostasis network, which regulates the proteome, and mitochondrial quality control (MQC) mechanisms, which maintain mitochondrial number and integrity. QC relies on a hierarchically and spatially integrated regulatory axis rather than individual parallel units. Such systems coordinate mitochondrial biogenesis, dynamics, and autophagic recycling with proteostasis to ensure the maintenance of high-quality mitochondria and bioenergetically efficient cells. Neurons, post-mitotic cells with high energy demands, depend heavily on these mechanisms and on the spatial coordination of MQC. Here, we discuss how failure of this integrated QC axis, rather than dysfunction of its individual components alone, can drive neuronal decline and contribute to the neurodegeneration.
Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, plays a context-dependent dual role in tumor immunity and immunotherapy. On one hand, it can act as an immunogenic cell death mechanism, releasing damage-associated molecular patterns that activate dendritic cells and promote T cell priming. On the other hand, ferroptosis may suppress antitumor immunity by triggering death or dysfunction in key immune cells, including T lymphocytes, dendritic cells, and macrophages. This review synthesizes current insights into the molecular determinants of ferroptosis sensitivity within the tumor microenvironment. It examines how immune cells can induce ferroptosis in cancer cells, and how tumors evolve resistance through upregulation of proteins like GPX4 and FSP1 or metabolic rewiring. The interplay between ferroptosis and immunity offers promising therapeutic avenues, such as combining ferroptosis inducers with immune checkpoint inhibitors or employing nanotechnology for targeted delivery. However, the net immunogenic outcome depends on temporal, cellular, and microenvironmental factors. Future strategies must aim to selectively induce immunogenic ferroptosis in tumors while preserving immune cell function, leveraging biomarkers and microenvironment modulation to optimize combination therapies in cancer immunotherapy.
Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies. Pathogenic variants in SF3B4, which encodes a core spliceosomal component, represent the primary known genetic cause of NS. This review synthesizes recent findings from cellular, zebrafish, Xenopus, and mouse models to elucidate how SF3B4 deficiency perturbs neural crest cell (NCC) biology and multi-tissue development. Loss of SF3B4 induces widespread splicing abnormalities, with preferential exon skipping affecting AT-rich and GC-poor exons, thereby altering the expression of genes critical for NCC survival, proliferation, migration, and lineage specification. These cellular defects are further exacerbated by oxidative stress and activation of the p53 pathway, resulting in a broad spectrum of developmental abnormalities involving craniofacial, cardiac, skeletal, and sensory (auditory and ocular) systems. Together, these findings highlight the essential role of SF3B4 in coordinating early morphogenesis. Cross-species comparisons reveal conserved NCC vulnerabilities alongside model-specific phenotypes, highlighting the challenge of linking individual splicing alterations to distinct structural outcomes in NS. Future research directions include defining tissue-specific SF3B4-dependent splicing targets, developing human induced pluripotent stem cell-derived models, and exploring therapeutic strategies aimed at restoring splicing homeostasis or compensating for disrupted developmental signaling pathways. This article is categorized under: Congenital Diseases > Molecular and Cellular Physiology Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Stem Cells and Development.
The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has revealed the virus's ability to induce multi-organ damage, including significant liver injury. The molecular mechanisms of liver dysfunction in COVID-19 patients are explored, focusing on direct viral infection, immune-mediated damage, and the gut–liver axis. SARS-CoV-2 enters liver cells through the Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) receptors, but alternative pathways, such as CD209/Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) and AXL receptors, can also contribute to viral entry. Additionally, immune responses, particularly the cytokine storm, exacerbate liver inflammation, leading to hepatocyte damage. Pre-existing liver conditions, such as metabolic-associated fatty liver disease (MAFLD), alcohol-related liver disease (ALD), and liver fibrosis, heighten the risk of severe outcomes in COVID-19 patients. Post-COVID-19 liver complications, including fibrosis progression and persistent liver damage, have been reported, with emerging evidence suggesting chronic inflammation, viral persistence, and autoimmune reactions as potential contributors. Furthermore, Drug-Induced Liver Injury (DILI) from COVID-19 treatments remains a concern, highlighting the need for careful management. Consequently, understanding the interplay between SARS-CoV-2 and the liver is critical for improving patient outcomes and developing targeted therapies to mitigate liver-related complications in both acute and Long COVID-19 phases. This article is categorized under:
The immune-oncology-microbiome (IOM) trio highlights the significant role of microbiomes in cancer progression by modulating immune evasion, genomic instability, and inflammation-key hallmarks of cancer. While microbiomes can exert both protective and detrimental effects on tumor development and treatment response, the mechanistic underpinnings-particularly those involving intratumoral microbiomes-remain poorly understood. To elucidate these dynamics, we frame the interplay between cancer, immune cells, and microbiomes through the lens of the Anna Karenina Principle (AKP)-using Leo Tolstoy's aphorism: "All happy families are alike; each unhappy family is unhappy in its own way." In biomedical terms, this translates to: all healthy systems including intratumoral microbiomes are alike, but each dysfunctional system fails in its own way. We hypothesize that either AKP or its inverse (anti-AKP) may govern microbial interactions that influence cancer progression. Analyzing four published cancer tissue microbiome datasets (Nejman 2020, Science), we identified two distinct patterns: AKP-driven increased microbial heterogeneity in lung and ovarian cancers, and anti-AKP-driven decreased heterogeneity in breast and colon cancers. We further propose cancer microbiome therapy (CMT) as an emerging frontier in microbiome-based therapeutics. The CMT may include the following strategies: (i) Restoring a healthy microbiome (including barrier tissue, tumor, blood microbiomes) to enhance immune function through ecosystem engineering; (ii) Developing specific microbial agents (species or their metabolites) to modulate crossroads of cancer immunotherapy; (iii) Engineering microbial agents to suppress cancer-causing microbes (oncomicrobes and complicit) and halt cancer progression; (iv) Reviving historical approaches like Coley's toxin and oncolytic viruses for direct cancer cell targeting. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Cancer > Computational Models.
The Coronavirus Disease 2019 (COVID-19) pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has revealed the virus's ability to induce multi-organ damage, including significant liver injury. The molecular mechanisms of liver dysfunction in COVID-19 patients are explored, focusing on direct viral infection, immune-mediated damage, and the gut-liver axis. SARS-CoV-2 enters liver cells through the Angiotensin-Converting Enzyme 2 (ACE2) and Transmembrane Serine Protease 2 (TMPRSS2) receptors, but alternative pathways, such as CD209/Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) and AXL receptors, can also contribute to viral entry. Additionally, immune responses, particularly the cytokine storm, exacerbate liver inflammation, leading to hepatocyte damage. Pre-existing liver conditions, such as metabolic-associated fatty liver disease (MAFLD), alcohol-related liver disease (ALD), and liver fibrosis, heighten the risk of severe outcomes in COVID-19 patients. Post-COVID-19 liver complications, including fibrosis progression and persistent liver damage, have been reported, with emerging evidence suggesting chronic inflammation, viral persistence, and autoimmune reactions as potential contributors. Furthermore, Drug-Induced Liver Injury (DILI) from COVID-19 treatments remains a concern, highlighting the need for careful management. Consequently, understanding the interplay between SARS-CoV-2 and the liver is critical for improving patient outcomes and developing targeted therapies to mitigate liver-related complications in both acute and Long COVID-19 phases. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology.
The nucleolus, traditionally known for its role in ribosome biogenesis, is now recognized for its broader functions, including cellular stress adaptation and its involvement in various pathological processes, such as ribosomal alterations, viral infections, autoimmune disorders, and age-related diseases. Disruptions in nucleolar function can impair protein synthesis, cellular homeostasis, and immune responses, leading to multisystem disorders and increased susceptibility to neoplasms. This review classifies nucleolus-associated diseases into seven categories: deficiencies in protein synthesis, ribosomal and non-ribosomal alterations, cancer and nucleolar alterations, diseases related to aging and cellular stress, autoimmune diseases, and viral diseases. Understanding the complexity of the nucleolus and its dysfunctions represents a fundamental step toward advancing knowledge of the molecular basis of these pathologies, laying the groundwork for future research addressing its implications in cell biology and the development of human diseases. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.
Molecular research has gradually revealed the biological significance of genetically encoded information and how this information is transmitted and utilized in a cell. The scientific advances of the last few decades have brought about paradigm shifts in the strategies traditionally used to decipher biological information. From unidirectional approaches, we now have multidirectional model-system-based integrated OMICs that aim to describe the pathophysiology of diseases through a combination of genetic, transcriptomic, proteomic, and metabolomic data. Compared to other vertebrate models, zebrafish have a wealth of advantages that make them a powerful tool with a wide range of applications in biomedical research. The high degree of genetic conservation with humans, coupled with the availability of various gene manipulation techniques, has made zebrafish an immensely popular multi-utility genetic toolbox. This review describes the advances in the field of zebrafish-based biomedical research with a focus on its applications in disease modeling, functional omics, toxicology, and pharmacology. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Infectious Diseases > Molecular and Cellular Physiology Congenital Diseases > Molecular and Cellular Physiology.
Noncanonical proteins, encoded by previously overlooked genomic regions (part of the "dark genome"), are emerging as crucial players in human health and disease, expanding our understanding of the "dark proteome." This review explores their landscape, including proteins derived from long non-coding RNAs, circular RNAs, and alternative open reading frames. Recent advances in ribosome profiling, mass spectrometry, and proteogenomics have unveiled their involvement in critical cellular processes. We examine their roles in cancer, neurological disorders, cardiovascular diseases, and infectious diseases, highlighting their potential as novel biomarkers and therapeutic targets. The review addresses challenges in identifying and characterizing these proteins, particularly recently evolved ones, and discusses implications for drug discovery, including cancer immunotherapy and neoantigen sources. By synthesizing recent findings, we underscore the significance of noncanonical proteins in expanding our understanding of the human genome and proteome, and their promise in developing innovative diagnostic tools and targeted therapies. This overview aims to stimulate further research into this unexplored biological space, potentially revolutionizing approaches to disease treatment and personalized medicine.
The progression of tumors is influenced by mechanical forces and biological elements, such as hypoxia and angiogenesis. Mechanical factors, including stress, pressure, interstitial fluid pressure, and cellular traction forces, compromise normal tissue architecture, augmenting stiffness and thus promoting tumor growth and invasion. The selective elimination of specific tumor components can reduce growth-induced mechanical stress, thereby improving therapeutic efficacy. Furthermore, stress-relief drugs have the potential in enhancing chemotherapy outcomes. In this setting, computational modeling functions as an essential tool for quantitatively elucidating the mechanical principles underlying tumor formation. These models can precisely replicate the impact of mechanical pressures on solid tumors, offering insight into the regulation of tumor behavior by these forces. Tumor growth produces mechanical forces, including compression, displacement, and deformation, leading to irregular stress patterns, expedited tumor advancement, and reduced treatment efficacy. This review analyzes the impact of mechanical forces on carcinogenesis and solid tumor proliferation, emphasizing the significance of stress alleviation in regulating tumor growth. Furthermore, we investigate the influence of mechanical forces on tumor dissemination and emphasize the promise of integrating computational modeling with force-targeted cancer therapies to improve treatment efficacy by tackling the fundamental mechanics of tumor proliferation.
Understanding of microbial pathogenesis has greatly revolutionized after conventional culture-based techniques are replaced by molecular methods. This technological shift is generating huge host-pathogen interactions (HPIs) data. Moreover, computational predictions of biological interactions are also adding to HPI understanding. Recently, several dedicated databases are developed for exclusively cataloging HPIs. Present article covers about some available HPI databases, types, and evolution of this area, along with recent trends in the application of these databases for biological research. As per the recent understanding in microbial pathogenesis, HPIs are considered highly dynamic in nature with multiple outcomes, which goes beyond simple microbes-disease association. Therefore, careful cataloging of complete information about HPIs can open several avenues to understand microbial pathogenesis considering their multifaceted effects on host system. HPI databases are indispensable tools for understanding microbial pathogenesis, and this article provides comprehensive information about their uses in the field of microbial pathogenesis research.
Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. Despite its initial description in the late 19th century by French neurologist Guillaume Duchenne de Boulogne, and identification of causal DMD genetic mutations in the 1980s, therapeutics remain challenging. The current standard of care is corticosteroid treatment, which delays the progression of muscle dysfunction but is associated with significant adverse effects. Emerging therapeutic approaches, including AAV-mediated gene transfer, CRISPR gene editing, and small molecule interventions, are under development but face considerable obstacles. Although DMD is viewed as a progressive muscle disease, muscle damage and abnormal molecular signatures are already evident during fetal myogenesis. This early onset of pathology suggests that the limited success of current therapies may partly be due to their administration after aberrant embryonic myogenesis has occurred in the absence of dystrophin. Consequently, identifying optimal therapeutic strategies and intervention windows for DMD may depend on a better understanding of the earliest DMD disease mechanisms. As newer techniques are applied, the field is gaining increasingly detailed insights into the early muscle developmental abnormalities in DMD. A comprehensive understanding of the initial events in DMD pathogenesis and progression will facilitate the generation and testing of effective therapeutic interventions.
Nearly one-fourth of the global population is infected by Mycobacterium tuberculosis (Mtb), and approximately 90%-95% remain asymptomatic as latent tuberculosis infection (LTBI), an estimated 5%-10% of those with latent infections will eventually progress to active tuberculosis (ATB). Although it is widely accepted that LTBI transitioning to ATB results from a disruption of host immune balance and a weakening of protective immune responses, the exact underlying immunological mechanisms that promote this conversion are not well characterized. Thus, it is difficult to accurately predict tuberculosis (TB) progression in advance, leaving the LTBI population as a significant threat to TB prevention and control. This article systematically explores three aspects related to the immunoregulatory mechanisms and translational research about LTBI: (1) the distinct immunocytological characteristics of LTBI and ATB, (2) LTBI diagnostic markers discovery related to host anti-TB immunity and metabolic pathways, and (3) vaccine development focus on LTBI. This article is categorized under: Infectious Diseases > Molecular and Cellular Physiology Infectious Diseases > Genetics/Genomics/Epigenetics Immune System Diseases > Genetics/Genomics/Epigenetics.
Neural circuits in the brain, primarily in the hypothalamus, are paramount to the homeostatic control of feeding and energy utilization. They integrate hunger, satiety, and body adiposity cues from the periphery and mediate the appropriate behavioral and physiological responses to satisfy the energy demands of the animal. Notably, perturbations in central homeostatic circuits have been linked to the etiology of excessive feeding and obesity. Considering the ever-changing energy requirements of the animal and required adaptations, it is not surprising that brain-feeding circuits remain plastic in adulthood and are subject to changes in synaptic strength as a consequence of nutritional status. Indeed, synapse density, probability of presynaptic transmitter release, and postsynaptic responses in hypothalamic energy balance centers are tailored to behavioral and physiological responses required to sustain survival. Mounting evidence supports key roles of astrocytes facilitating some of this plasticity. Here we discuss these synaptic plasticity mechanisms and the emerging roles of astrocytes influencing energy and glucose balance control in health and disease. This article is categorized under: Cancer > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.
Liver disease represents a significant global burden, placing individuals at a heightened risk of developing cirrhosis and liver cancer. Viral infections act as a primary cause of liver diseases on a worldwide scale. Infections involving hepatitis viruses, notably hepatitis B, C, and E viruses, stand out as the most prevalent contributors to acute and chronic intrahepatic adverse outcome, although the hepatitis C virus (HCV) can be effectively cured with antiviral drugs, but no preventative vaccination developed. Hepatitis B virus (HBV) and HCV can lead to both acute and chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC), which are principal causes of worldwide morbidity and mortality. Other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), are capable of causing liver damage. Therefore, it is essential to recognize that virus infections and liver diseases are intricate and interconnected processes. A profound understanding of the underlying relationship between virus infections and liver diseases proves pivotal in the effective prevention, diagnosis, and treatment of these conditions. In this review, we delve into the mechanisms by which virus infections induce liver diseases, as well as explore the pathogenesis, diagnosis, and treatment of liver diseases. This article is categorized under: Infectious Diseases > Biomedical Engineering.
Solute carrier family 40 member 1 (SLC40A1) plays an essential role in transporting iron from intracellular to extracellular environments. When SLC40A1 expression is abnormal, cellular iron metabolism becomes dysregulated, resulting in an overload of intracellular iron, which induces cell ferroptosis. Numerous studies have confirmed that ferroptosis is closely associated with the development of many diseases. Here, we review recent findings on SLC40A1 in ferroptosis and its association with various diseases, intending to explore new directions for research on disease pathogenesis and new therapeutic targets for prevention and treatment. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics Metabolic Diseases > Molecular and Cellular Physiology
Glaucoma is a heterogeneous group of progressive diseases that leads to irreversible blindness. Secondary glaucoma refers to glaucoma caused by a known underlying condition. Pseudoexfoliation and pigment dispersion syndromes are common causes of secondary glaucoma. Their respective deposits may obstruct the trabecular meshwork, leading to aqueous humor outflow resistance, ocular hypertension, and optic neuropathy. There are no disease-specific interventions available for either. Pseudoexfoliation syndrome is characterized by fibrillar deposits (pseudoexfoliative material) on anterior segment structures. Over a decade of multiomics analyses taken together with the current knowledge on pseudoexfoliative glaucoma warrant a re-think of mechanistic possibilities. We propose that the presence of nucleation centers (e.g., vitamin D binding protein), crosslinking enzymes (e.g., transglutaminase 2), aberrant extracellular matrix, flawed endocytosis, and abnormal aqueous-blood barrier contribute to the formation of proteolytically resistant pseudoexfoliative material. Pigment dispersion syndrome is characterized by abnormal iridolenticular contact that disrupts iris pigment epithelium and liberates melanin granules. Iris melanogenesis is aberrant in this condition. Cytotoxic melanogenesis intermediates leak out of melanosomes and cause iris melanocyte and pigment epithelium cell death. Targeting melanogenesis can likely decrease the risk of pigmentary glaucoma. Skin and melanoma research provides insights into potential therapeutics. We propose that specific prostanoid agonists and fenofibrates may reduce melanogenesis by inhibiting cholesterol internalization and de novo synthesis. Additionally, melatonin is a potent melanogenesis suppressor, antioxidant, and hypotensive agent, rendering it a valuable agent for pigmentary glaucoma. In pseudoexfoliative glaucoma, where environmental insults drive pseudoexfoliative material formation, melatonin's antioxidant and hypotensive properties may offer adjunct therapeutic benefits. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.
Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC-derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs-derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC-derived 2D models, iPSC-derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC-derived organoids present advantages in terms of versatility, patient-specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs. This article is categorized under: Cancer > Stem Cells and Development.
Melanoma is one of the leading fatal forms of cancer, yet from a treatment perspective, we have minimal control over its reoccurrence and resistance to current pharmacotherapies. The endocannabinoid system (ECS) has recently been accepted as a multifaceted homeostatic regulator, influencing various physiological processes across different biological compartments, including the skin. This review presents an overview of the pathophysiology of melanoma, current pharmacotherapy used for treatment, and the challenges associated with the different pharmacological approaches. Furthermore, it highlights the utility of cannabinoids as an additive remedy for melanoma by restoring the balance between downregulated immunomodulatory pathways and elevated inflammatory cytokines during chronic skin conditions as one of the suggested critical approaches in treating this immunogenic tumor. This article is categorized under: Cancer > Molecular and Cellular Physiology.
Biological sex is an important variable that influences the immune system's susceptibility to infectious and non-infectious diseases and their outcomes. Sex dimorphic features in innate and adaptive immune cells and their activities may help to explain sex differences in immune responses. T lymphocytes in the adaptive immune system are essential to providing protection against infectious and chronic inflammatory diseases. In this review, T cell responses are discussed with focus on the current knowledge of biological sex differences in CD8+ T cell mediated adaptive immune responses in infectious and chronic inflammatory diseases. Future directions aimed at investigating the molecular and cellular mechanisms underlying sex differences in diverse T cell responses will continue to underscore the significance of understanding sex differences in protective immunity at the cellular level, to induce appropriate T cell-based immune responses in infection, autoimmunity, and cancer. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Infectious Diseases > Molecular and Cellular Physiology.
