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Protein tyrosine phosphatase 1B (PTP1B) is a non-receptor tyrosine phosphatase best known for its role in regulating insulin and leptin signalling. Recently, knowledge on the role of PTP1B as a major regulator of multiple signalling pathways involved in cell growth, proliferation, viability and metabolism has expanded, and PTP1B is recognised as a therapeutic target in several human disorders, including diabetes, obesity, cardiovascular diseases and hematopoietic malignancies. The function of PTP1B in the immune system was largely overlooked until it was discovered that PTP1B negatively regulates the Janus kinase—a signal transducer and activator of the transcription (JAK/STAT) signalling pathway, which plays a significant role in modulating immune responses. PTP1B is now known to determine the magnitude of many signalling pathways that drive immune cell activation and function. As such, PTP1B inhibitors are being developed and tested in the context of inflammation and autoimmune diseases. Here, we provide an up-to-date summary of the molecular role of PTP1B in regulating immune cell function and how targeting its expression and/or activity has the potential to change the outcomes of immune-mediated and inflammatory disorders. [ABSTRACT FROM AUTHOR]

Lysosomes are highly dynamic organelles that maintain cellular homeostasis and regulate fundamental cellular processes by integrating multiple metabolic pathways. Lysosomal ion channels such as TRPML1-3, TPC1/2, ClC6/7, CLN7, and TMEM175 mediate the flux of Ca2+, Cl−, Na+, H+, and K+ across lysosomal membranes in response to osmotic stimulus, nutrient-dependent signals, and cellular stresses. These ion channels serve as the crucial transducers of cell signals and are essential for the regulation of lysosomal biogenesis, motility, membrane contact site formation, and lysosomal homeostasis. In terms of pathophysiology, genetic variations in these channel genes have been associated with the development of lysosomal storage diseases, neurodegenerative diseases, inflammation, and cancer. This review aims to discuss the current understanding of the role of these ion channels in the central nervous system and to assess their potential as drug targets. [ABSTRACT FROM AUTHOR]

Noncoding RNAs (ncRNAs) are a class of nucleotide sequences that cannot be translated into peptides. ncRNAs can function post-transcriptionally by splicing complementary sequences of mRNAs or other ncRNAs or by directly engaging in protein interactions. Over the past few decades, the pervasiveness of ncRNAs in cell physiology and their pivotal roles in various diseases have been identified. One target regulated by ncRNAs is connexin (Cx), a protein that forms gap junctions and hemichannels and facilitates intercellular molecule exchange. The aberrant expression and misdistribution of connexins have been implicated in central nervous system diseases, cardiovascular diseases, bone diseases, and cancer. Current databases and technologies have enabled researchers to identify the direct or indirect relationships between ncRNAs and connexins, thereby elucidating their correlation with diseases. In this review, we selected the literature published in the past five years concerning disorders regulated by ncRNAs via corresponding connexins. Among it, microRNAs that regulate the expression of Cx43 play a crucial role in disease development and are predominantly reviewed. The distinctive perspective of the ncRNA–Cx axis interprets pathology in an epigenetic manner and is expected to motivate research for the development of biomarkers and therapeutics. [ABSTRACT FROM AUTHOR]

The human skeleton is a metabolically active system that is constantly regenerating via the tightly regulated and highly coordinated processes of bone resorption and formation. Emerging evidence reveals fascinating new insights into the role of sphingolipids, including sphingomyelin, sphingosine, ceramide, and sphingosine-1-phosphate, in bone homeostasis. Sphingolipids are a major class of highly bioactive lipids able to activate distinct protein targets including, lipases, phosphatases, and kinases, thereby conferring distinct cellular functions beyond energy metabolism. Lipids are known to contribute to the progression of chronic inflammation, and notably, an increase in bone marrow adiposity parallel to elevated bone loss is observed in most pathological bone conditions, including aging, rheumatoid arthritis, osteoarthritis, and osteomyelitis. Of the numerous classes of lipids that form, sphingolipids are considered among the most deleterious. This review highlights the important primary role of sphingolipids in bone homeostasis and how dysregulation of these bioactive metabolites appears central to many chronic bone-related diseases. Further, their contribution to the invasion, virulence, and colonization of both viral and bacterial host cell infections is also discussed. Many unmet clinical needs remain, and data to date suggest the future use of sphingolipid-targeted therapy to regulate bone dysfunction due to a variety of diseases or infection are highly promising. However, deciphering the biochemical and molecular mechanisms of this diverse and extremely complex sphingolipidome, both in terms of bone health and disease, is considered the next frontier in the field. [ABSTRACT FROM AUTHOR]

The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions. [ABSTRACT FROM AUTHOR]

Mitochondria are double-membrane organelles within eukaryotic cells that act as cellular power houses owing to their ability to efficiently generate the ATP required to sustain normal cell function. Also, they represent a "hub" for the regulation of a plethora of processes, including cellular homeostasis, metabolism, the defense against oxidative stress, and cell death. Mitochondrial dysfunctions are associated with a wide range of human diseases with complex pathologies, including metabolic diseases, neurodegenerative disorders, and cancer. Therefore, regulating dysfunctional mitochondria represents a pivotal therapeutic opportunity in biomedicine. Marine ecosystems are biologically very diversified and harbor a broad range of organisms, providing both novel bioactive substances and molecules with meaningful biomedical and pharmacological applications. Recently, many mitochondria-targeting marine-derived molecules have been described to regulate mitochondrial biology, thus exerting therapeutic effects by inhibiting mitochondrial abnormalities, both in vitro and in vivo, through different mechanisms of action. Here, we review different strategies that are derived from marine organisms which modulate specific mitochondrial processes or mitochondrial molecular pathways and ultimately aim to find key molecules to treat a wide range of human diseases characterized by impaired mitochondrial function. [ABSTRACT FROM AUTHOR]

Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that function as "holdases" and prevent protein aggregation due to changes in temperature, pH, or oxidation state. sHsps have a conserved α-crystallin domain (ACD), which forms the dimer building block, flanked by variable N- and C-terminal regions. sHsps populate various oligomeric states as a function of their sequestrase activity, and these dynamic structural features allow the proteins to interact with a plethora of cellular substrates. However, the molecular mechanisms of their dynamic conformational assembly and the interactions with various substrates remains unclear. Therefore, it is important to gain insight into the underlying physicochemical properties that influence sHsp structure in an effort to understand their mechanism(s) of action. We evaluated several disease-relevant mutations, D109A, F113Y, R116C, R120G, and R120C, in the ACD of HspB5 for changes to in vitro chaperone activity relative to that of wildtype. Structural characteristics were also evaluated by ANS fluorescence and CD spectroscopy. Our results indicated that mutation Y113F is an efficient holdase, while D109A and R120G, which are found in patients with myofibrillar myopathy and cataracts, respectively, exhibit a large reduction in holdase activity in a chaperone-like light-scattering assay, which indicated alterations in substrate–sHsp interactions. The extent of the reductions in chaperone activities are different among the mutants and specific to the substrate protein, suggesting that while sHsps are able to interact with many substrates, specific interactions provide selectivity for some substrates compared to others. This work is consistent with a model for chaperone activity where key electrostatic interactions in the sHsp dimer provide structural stability and influence both higher-order sHsp interactions and facilitate interactions with substrate proteins that define chaperone holdase activity. [ABSTRACT FROM AUTHOR]

Long interspersed element-1 (LINE-1; L1s) are mobile genetic elements that comprise nearly 20% of the human genome. L1s have been shown to have important functions in various biological processes, and their dysfunction is thought to be linked with diseases and cancers. However, the roles of the repetitive elements are largely not understood. While the CRISPR activation (CRISPRa) system based on catalytically deadCas9 (dCas9) is widely used for genome-wide interrogation of gene function and genetic interaction, few studies have been conducted on L1s. Here, we report using the CRISPRa method to efficiently activate L1s in human L02 cells, a derivative of the HeLa cancer cell line. After CRISPRa, the young L1 subfamilies such as L1HS/L1PA1 and L1PA2 are found to be expressed at higher levels than the older L1s. The L1s with high levels of transcription are closer to full-length and are more densely occupied by the YY1 transcription factor. The activated L1s can either be mis-spliced to form chimeric transcripts or act as alternative promoters or enhancers to facilitate the expression of neighboring genes. The method described here can be used for studying the functional roles of young L1s in cultured cells of interest. [ABSTRACT FROM AUTHOR]

Ginseng is usually consumed as a daily food supplement to improve health and has been shown to benefit skeletal muscle, improve glucose metabolism, and ameliorate muscle-wasting conditions, cardiovascular diseases, stroke, and the effects of aging and cancers. Ginseng has also been reported to help maintain bone strength and liver (digestion, metabolism, detoxification, and protein synthesis) and kidney functions. In addition, ginseng is often used to treat age-associated neurodegenerative disorders, and ginseng and ginseng-derived natural products are popular natural remedies for diseases such as diabetes, obesity, oxidative stress, and inflammation, as well as fungal, bacterial, and viral infections. Ginseng is a well-known herbal medication, known to alleviate the actions of several cytokines. The article concludes with future directions and significant application of ginseng compounds for researchers in understanding the promising role of ginseng in the treatment of several diseases. Overall, this study was undertaken to highlight the broad-spectrum therapeutic applications of ginseng compounds for health management. [ABSTRACT FROM AUTHOR]

In this review, the structure, isoform, and physiological role of the carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) are summarized. There are three isoforms of CAPON in humans, including long CAPON protein (CAPON-L), short CAPON protein (CAPON-S), and CAPON-S' protein. CAPON-L includes three functional regions: a C-terminal PDZ-binding motif, carboxypeptidase (CPE)-binding region, and N-terminal phosphotyrosine (PTB) structural domain. Both CAPON-S and CAPON-S' only contain the C-terminal PDZ-binding motif. The C-terminal PDZ-binding motif of CAPON can bind with neuronal nitric oxide synthase (nNOS) and participates in regulating NO production and neuronal development. An overview is given on the relationship between CAPON and heart diseases, diabetes, psychiatric disorders, and tumors. This review will clarify future research directions on the signal pathways related to CAPON, which will be helpful for studying the regulatory mechanism of CAPON. CAPON may be used as a drug target, which will provide new ideas and solutions for treating human diseases. [ABSTRACT FROM AUTHOR]

Ovarian aging and disease-related decline in fertility are challenging medical and economic issues with an increasing prevalence. Polyamines are a class of polycationic alkylamines widely distributed in mammals. They are small molecules essential for cell growth and development. Polyamines alleviate ovarian aging through various biological processes, including reproductive hormone synthesis, cell metabolism, programmed cell death, etc. However, an abnormal increase in polyamine levels can lead to ovarian damage and promote the development of ovarian disease. Therefore, polyamines have long been considered potential therapeutic targets for aging and disease, but their regulatory roles in the ovary deserve further investigation. This review discusses the mechanisms by which polyamines ameliorate human ovarian aging and disease through different biological processes, such as autophagy and oxidative stress, to develop safe and effective polyamine targeted therapy strategies for ovarian aging and the diseases. [ABSTRACT FROM AUTHOR]

Fruits, vegetables, and spices are natural sources of bioactive phytochemicals, such as polyphenols, carotenoids, flavonoids, curcuminoids, terpenoids, and capsaicinoids, possessing multiple health benefits and relatively low toxicity. These compounds found in the diet play a central role in organism development and fitness. Given the complexity of the whole-body response to dietary changes, invertebrate model organisms can be valuable tools to examine the interplay between genes, signaling pathways, and metabolism. Drosophila melanogaster, an invertebrate model with its extensively studied genome, has more than 70% gene homology to humans and has been used as a model system in biological studies for a long time. The notable advantages of Drosophila as a model system, such as their low maintenance cost, high reproductive rate, short generation time and lifespan, and the high similarity of metabolic pathways between Drosophila and mammals, have encouraged the use of Drosophila in the context of screening and evaluating the impact of phytochemicals present in the diet. Here, we review the benefits of Drosophila as a model system for use in the study of phytochemical ingestion and describe the previously reported effects of phytochemical consumption in Drosophila. [ABSTRACT FROM AUTHOR]

Melanocortins play crucial roles in regulating the stress response, inflammation, and skin pigmentation. In this review, we focus on the melanocortin 1 receptor (MC1R), a G protein-coupled receptor primarily known for regulating skin pigmentation and exhibiting anti-inflammatory effects. First, we provide an overview of the structure, signaling pathways, and related diseases of MC1R. Next, we discuss the potential therapeutic use of synthetic peptides and small molecule modulators of MC1R, highlighting the development of various drugs that enhance stability through amino acid sequence modifications and small molecule drugs to overcome limitations associated with peptide characteristics. Notably, MC1R-targeted drugs have applications beyond skin pigmentation-related diseases, which predominantly affect MC1R in melanocytes. These drugs can also be useful in treating inflammatory diseases with MC1R expression present in various cells. Our review underscores the potential of MC1R-targeted drugs to treat a wide range of diseases and encourages further research in this area. [ABSTRACT FROM AUTHOR]

Proliferating cell nuclear antigen (PCNA) is the key regulator of human DNA metabolism. One important interaction partner is p15, involved in DNA replication and repair. Targeting the PCNA–p15 interaction is a promising therapeutic strategy against cancer. Here, a Förster resonance energy transfer (FRET)-based assay for the analysis of the PCNA–p15 interaction was developed. Next to the application as screening tool for the identification and characterization of PCNA–p15 interaction inhibitors, the assay is also suitable for the investigation of mutation-induced changes in their affinity. This is particularly useful for analyzing disease associated PCNA or p15 variants at the molecular level. Recently, the PCNA variant C148S has been associated with Ataxia-telangiectasia-like disorder type 2 (ATLD2). ATLD2 is a neurodegenerative disease based on defects in DNA repair due to an impaired PCNA. Incubation time dependent FRET measurements indicated no effect on PCNAC148S–p15 affinity, but on PCNA stability. The impaired stability and increased aggregation behavior of PCNAC148S was confirmed by intrinsic tryptophan fluorescence, differential scanning fluorimetry (DSF) and asymmetrical flow field-flow fractionation (AF4) measurements. The analysis of the disease associated PCNA variant demonstrated the versatility of the interaction assay as developed. [ABSTRACT FROM AUTHOR]

Secondary metabolism plays an important role in the adaptation of plants to their environments, particularly by mediating bio-interactions and protecting plants from herbivores, insects, and pathogens. Terpenoids form the largest group of plant secondary metabolites, and their biosynthesis and regulation are extremely complicated. Terpenoids are key players in the interactions and defense reactions between plants, microorganisms, and animals. Terpene compounds are of great significance both to plants themselves and the ecological environment. On the one hand, while protecting plants themselves, they can also have an impact on the environment, thereby affecting the evolution of plant communities and even ecosystems. On the other hand, their economic value is gradually becoming clear in various aspects of human life; their potential is enormous, and they have broad application prospects. Therefore, research on terpenoids is crucial for plants, especially crops. This review paper is mainly focused on the following six aspects: plant terpenes (especially terpene volatiles and plant defense); their ecological functions; their biosynthesis and transport; related synthesis genes and their regulation; terpene homologues; and research and application prospects. We will provide readers with a systematic introduction to terpenoids covering the above aspects. [ABSTRACT FROM AUTHOR]

The collagen family contains 28 proteins, predominantly expressed in the extracellular matrix (ECM) and characterized by a triple-helix structure. Collagens undergo several maturation steps, including post-translational modifications (PTMs) and cross-linking. These proteins are associated with multiple diseases, the most pronounced of which are fibrosis and bone diseases. This review focuses on the most abundant ECM protein highly implicated in disease, type I collagen (collagen I), in particular on its predominant chain collagen type I alpha 1 (COLα1 (I)). An overview of the regulators of COLα1 (I) and COLα1 (I) interactors is presented. Manuscripts were retrieved searching PubMed, using specific keywords related to COLα1 (I). COL1A1 regulators at the epigenetic, transcriptional, post-transcriptional and post-translational levels include DNA Methyl Transferases (DNMTs), Tumour Growth Factor β (TGFβ), Terminal Nucleotidyltransferase 5A (TENT5A) and Bone Morphogenic Protein 1 (BMP1), respectively. COLα1 (I) interacts with a variety of cell receptors including integrinβ, Endo180 and Discoidin Domain Receptors (DDRs). Collectively, even though multiple factors have been identified in association to COLα1 (I) function, the implicated pathways frequently remain unclear, underscoring the need for a more spherical analysis considering all molecular levels simultaneously. [ABSTRACT FROM AUTHOR]

Systemic acquired resistance (SAR) is a potent innate immunity system in plants that is induced through the salicylic acid (SA)-mediated signaling pathway. Here, we characterized 3-chloro-1-methyl-1H-pyrazole-5-carboxylic acid (CMPA) as an effective SAR inducer in Arabidopsis. The soil drench application of CMPA enhanced a broad range of disease resistance against the bacterial pathogen Pseudomonas syringae and fungal pathogens Colletotrichum higginsianum and Botrytis cinerea in Arabidopsis, whereas CMPA did not show antibacterial activity. Foliar spraying with CMPA induced the expression of SA-responsible genes such as PR1, PR2 and PR5. The effects of CMPA on resistance against the bacterial pathogen and the expression of PR genes were observed in the SA biosynthesis mutant, however, while they were not observed in the SA-receptor-deficient npr1 mutant. Thus, these findings indicate that CMPA induces SAR by triggering the downstream signaling of SA biosynthesis in the SA-mediated signaling pathway. [ABSTRACT FROM AUTHOR]

Oxidative stress (OS) arises as a consequence of an imbalance between the formation of reactive oxygen species (ROS) and the capacity of antioxidant defense mechanisms to neutralize them. Excessive ROS production can lead to the damage of critical biomolecules, such as lipids, proteins, and DNA, ultimately contributing to the onset and progression of a multitude of diseases, including atherosclerosis, chronic obstructive pulmonary disease, Alzheimer's disease, and cancer. Cylindromatosis (CYLD), initially identified as a gene linked to familial cylindromatosis, has a well-established and increasingly well-characterized function in tumor inhibition and anti-inflammatory processes. Nevertheless, burgeoning evidence suggests that CYLD, as a conserved deubiquitination enzyme, also plays a pivotal role in various key signaling pathways and is implicated in the pathogenesis of numerous diseases driven by oxidative stress. In this review, we systematically examine the current research on the function and pathogenesis of CYLD in diseases instigated by oxidative stress. Therapeutic interventions targeting CYLD may hold significant promise for the treatment and management of oxidative stress-induced human diseases. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with increasing prevalence worldwide. The genetic and molecular background of NAFLD pathogenesis is not yet clear. The vitamin D/vitamin D receptor (VDR) axis is significantly associated with the development and progression of NAFLD. Gene polymorphisms may influence the regulation of the VDR gene, although their biological significance remains to be elucidated. VDR gene polymorphisms are associated with the presence and severity of NAFLD, as they may influence the regulation of adipose tissue activity, fibrosis, and hepatocellular carcinoma (HCC) development. Vitamin D binds to the hepatic VDR to exert its biological functions, either by activating VDR transcriptional activity to regulate gene expression associated with inflammation and fibrosis or by inducing intracellular signal transduction through VDR-mediated activation of Ca2+ channels. VDR activity has protective and detrimental effects on hepatic steatosis, a characteristic feature of NAFLD. Vitamin D-VDR signaling may control the progression of NAFLD by regulating immune responses, lipotoxicity, and fibrogenesis. Elucidation of the genetic and molecular background of VDR in the pathophysiology of NAFLD will provide new therapeutic targets for this disease through the development of VDR agonists, which already showed promising results in vivo. [ABSTRACT FROM AUTHOR]

The intestine is considered to be a vital digestive organ to absorb nutrients and is the largest immune organ, while numerous microorganisms coexist with the host. It is well known that the complex interactions between the gut microbiota and the host's immune system inevitably affect the function of other organs, creating an "axis" between them. During the past few years, a new technique based mainly on microfluidics and cell biology has been developed to emulate the structure, function, and microenvironment of the human gut, called the "gut-on-chip". This microfluidic chip provides insight into key aspects of gut function in health and disease, such as the gut–brain axis, gut–liver axis, gut–kidney axis, and gut–lung axis. In this review, we first describe the basic theory of the gut axis and the various composition and parameter monitoring of the gut microarray systems, as well as summarize the development and emerging advances in the gut–organ-on-chip, with a focus on the host-gut flora and nutrient metabolism, and highlight their role in pathophysiological studies. In addition, this paper discusses the challenges and prospects for the current development and further use of the gut–organ-on-chip platform. [ABSTRACT FROM AUTHOR]

Senescence is a cellular aging process in all multicellular organisms. It is characterized by a decay in cellular functions and proliferation, resulting in increased cellular damage and death. This condition plays an essential role in the aging process and significantly contributes to the development of age-related complications. On the other hand, ferroptosis is a systemic cell death pathway characterized by excessive iron accumulation followed by the generation of reactive oxygen species (ROS). Oxidative stress is a common trigger of this condition and may be induced by various factors such as toxins, drugs, and inflammation. Ferroptosis is linked to numerous disorders, including cardiovascular disease, neurodegeneration, and cancer. Senescence is believed to contribute to the decay in tissue and organ functions occurring with aging. It has also been linked to the development of age-related pathologies, such as cardiovascular diseases, diabetes, and cancer. In particular, senescent cells have been shown to produce inflammatory cytokines and other pro-inflammatory molecules that can contribute to these conditions. In turn, ferroptosis has been linked to the development of various health disorders, including neurodegeneration, cardiovascular disease, and cancer. Ferroptosis is known to play a role in the development of these pathologies by promoting the death of damaged or diseased cells and contributing to the inflammation often associated. Both senescence and ferroptosis are complex pathways that are still not fully understood. Further research is needed to thoroughly investigate the role of these processes in aging and disease, and to identify potential interventions to target such processes in order to prevent or treat age-related conditions. This systematic review aims to assess the potential mechanisms underlying the link connecting senescence, ferroptosis, aging, and disease, and whether they can be exploited to block or limit the decay of the physiological functions in elderly people for a healthy longevity. [ABSTRACT FROM AUTHOR]

Acute gastroenteritis (AGE) is a disease of global public health importance. Recent studies show that children with AGE have an altered gut microbiota relative to non-AGE controls. Yet, how the gut microbiota differs in Ghanaian children with and without AGE remains unclear. Here, we explore the 16S rRNA gene-based faecal microbiota profiles of Ghanaian children five years of age and younger, comprising 57 AGE cases and 50 healthy controls. We found that AGE cases were associated with lower microbial diversity and altered microbial sequence profiles relative to the controls. The faecal microbiota of AGE cases was enriched for disease-associated bacterial genera, including Enterococcus, Streptococcus, and Staphylococcus. In contrast, the faecal microbiota of controls was enriched for potentially beneficial genera, including Faecalibacterium, Prevotella, Ruminococcus, and Bacteroides. Lastly, distinct microbial correlation network characteristics were observed between AGE cases and controls, thereby supporting broad differences in faecal microbiota structure. Altogether, we show that the faecal microbiota of Ghanaian children with AGE differ from controls and are enriched for bacterial genera increasingly associated with diseases. [ABSTRACT FROM AUTHOR]

Exosome, a subpopulation of extracellular vesicles, plays diverse roles in various biological processes. As one of the most abundant components of exosomes, exosomal proteins have been revealed to participate in the development of many diseases, such as carcinoma, sarcoma, melanoma, neurological disorders, immune responses, cardiovascular diseases, and infection. Thus, understanding the functions and mechanisms of exosomal proteins potentially assists clinical diagnosis and targeted delivery of therapies. However, current knowledge about the function and application of exosomal proteins is still limited. In this review, we summarize the classification of exosomal proteins, and the roles of exosomal proteins in exosome biogenesis and disease development, as well as in the clinical applications. [ABSTRACT FROM AUTHOR]

As the last step of the OXPHOS system, mitochondrial ATP synthase (or complex V) is responsible for ATP production by using the generated proton gradient, but also has an impact on other important functions linked to this system. Mutations either in complex V structural subunits, especially in mtDNA-encoded ATP6 gene, or in its assembly factors, are the molecular cause of a wide variety of human diseases, most of them classified as neurodegenerative disorders. The role of ATP synthase alterations in cancer development or metastasis has also been postulated. In this work, we reported the generation and characterization of the first mt-Atp6 pathological mutation in mouse cells, an m.8414A>G transition that promotes an amino acid change from Asn to Ser at a highly conserved residue of the protein (p.N163S), located near the path followed by protons from the intermembrane space to the mitochondrial matrix. The phenotypic consequences of the p.N163S change reproduce the effects of MT-ATP6 mutations in human diseases, such as dependence on glycolysis, defective OXPHOS activity, ATP synthesis impairment, increased ROS generation or mitochondrial membrane potential alteration. These observations demonstrate that this mutant cell line could be of great interest for the generation of mouse models with the aim of studying human diseases caused by alterations in ATP synthase. On the other hand, mutant cells showed lower migration capacity, higher expression of MHC-I and slightly lower levels of HIF-1α, indicating a possible reduction of their tumorigenic potential. These results could suggest a protective role of ATP synthase inhibition against tumor transformation that could open the door to new therapeutic strategies in those cancer types relying on OXPHOS metabolism. [ABSTRACT FROM AUTHOR]

Niclosamide is an FDA-approved anthelmintic drug for the treatment of parasitic infections. However, over the past few years, increasing evidence has shown that niclosamide could treat diseases beyond parasitic diseases, which include metabolic diseases, immune system diseases, bacterial and viral infections, asthma, arterial constriction, myopia, and cancer. Therefore, we systematically reviewed the pharmacological activities and therapeutic prospects of niclosamide in human disease and cancer and summarized the related molecular mechanisms and signaling pathways, indicating that niclosamide is a promising therapeutic player in various human diseases, including cancer. [ABSTRACT FROM AUTHOR]

Cell-surface-localized pattern recognition receptors (PRRs) and intracellular nucleotide-binding domain and leucine-rich repeat receptors (NLRs) are plant immune proteins that trigger an orchestrated downstream signaling in response to molecules of microbial origin or host plant origin. Historically, PRRs have been associated with pattern-triggered immunity (PTI), whereas NLRs have been involved with effector-triggered immunity (ETI). However, recent studies reveal that such binary distinction is far from being applicable to the real world. Although the perception of plant pathogens and the final mounting response are achieved by different means, central hubs involved in signaling are shared between PTI and ETI, blurring the zig-zag model of plant immunity. In this review, we not only summarize our current understanding of PRR- and NLR-mediated immunities in plants, but also highlight those signaling components that are evolutionarily conserved across the plant kingdom. Altogether, we attempt to offer an overview of how plants mediate and integrate the induction of the defense responses that comprise PTI and ETI, emphasizing the need for more evolutionary molecular plant–microbe interactions (EvoMPMI) studies that will pave the way to a better understanding of the emergence of the core molecular machinery involved in the so-called evolutionary arms race between plants and microbes. [ABSTRACT FROM AUTHOR]

Homeostasis is a self-regulatory dynamic process that maintains a stable internal environment in the human body. These regulations are essential for the optimal functioning of enzymes necessary for human health. Homeostasis elucidates disrupted mechanisms leading to the development of various pathological conditions caused by oxidative stress. In our work, we discuss redox homeostasis and salivary antioxidant activity during healthy periods and in periods of disease: dental carries, oral cavity cancer, periodontal diseases, cardiovascular diseases, diabetes mellitus, systemic sclerosis, and pancreatitis. The composition of saliva reflects dynamic changes in the organism, which makes it an excellent tool for determining clinically valuable biomarkers. The oral cavity and saliva may form the first line of defense against oxidative stress. Analysis of salivary antioxidants may be helpful as a diagnostic, prognostic, and therapeutic marker of not only oral, but also systemic health. [ABSTRACT FROM AUTHOR]

It is estimated that up to 80% of the human genome is transcribed into RNA molecules but less than 2% of the genome encodes the proteins, and the rest of the RNA transcripts that are not translated into protein are called non-coding RNAs (ncRNAs). Many studies have revealed that ncRNAs have biochemical activities as epigenetic regulators at the post-transcriptional level. Growing evidence has demonstrated that transposable elements (TEs) contribute to a large percentage of ncRNAs' transcription. The TEs inserted into certain parts of the genome can act as alternative promoters, enhancers, and insulators, and the accumulation of TEs increases genetic diversity in the human genome. The TEs can also generate microRNAs, so-called miRNA-derived from transposable elements (MDTEs), and are also implicated in disease progression, such as infectious diseases and cancer. Here, we analyzed the origin of ncRNAs and reviewed the published literature on MDTEs related to disease progression. [ABSTRACT FROM AUTHOR]

Xanthomonas oryzae pv. oryzae (Xoo) strains that cause bacterial leaf blight (BLB) limit rice (Oryza sativa) production and require breeding more resistant varieties. Transcription activator-like effectors (TALEs) activate transcription to promote leaf colonization by binding to specific plant host DNA sequences termed effector binding elements (EBEs). Xoo major TALEs universally target susceptibility genes of the SWEET transporter family. TALE-unresponsive alleles of clade III OsSWEET susceptibility gene promoter created with genome editing confer broad resistance on Asian Xoo strains. African Xoo strains rely primarily on the major TALE TalC, which targets OsSWEET14. Although the virulence of a talC mutant strain is severely impaired, abrogating OsSWEET14 induction with genome editing does not confer equivalent resistance on African Xoo. To address this contradiction, we postulated the existence of a TalC target susceptibility gene redundant with OsSWEET14. Bioinformatics analysis identified a rice locus named ATAC composed of the INCREASED LEAF INCLINATION 2 (ILI2) gene and a putative lncRNA that are shown to be bidirectionally upregulated in a TalC-dependent fashion. Gain-of-function approaches with designer TALEs inducing ATAC sequences did not complement the virulence of a Xoo strain defective for SWEET gene activation. While editing the TalC EBE at the ATAC loci compromised TalC-mediated induction, multiplex edited lines with mutations at the OsSWEET14 and ATAC loci remained essentially susceptible to African Xoo strains. Overall, this work indicates that ATAC is a probable TalC off-target locus but nonetheless documents the first example of divergent transcription activation by a native TALE during infection. [ABSTRACT FROM AUTHOR]

Strigolactones are low-molecular-weight phytohormones that play several roles in plants, such as regulation of shoot branching and interactions with arbuscular mycorrhizal fungi and parasitic weeds. Recently, strigolactones have been shown to be involved in plant responses to abiotic and biotic stress conditions. Herein, we analyzed the effects of strigolactones on systemic acquired resistance induced through salicylic acid-mediated signaling. We observed that the systemic acquired resistance inducer enhanced disease resistance in strigolactone-signaling and biosynthesis-deficient mutants. However, the amount of endogenous salicylic acid and the expression levels of salicylic acid-responsive genes were lower in strigolactone signaling-deficient max2 mutants than in wildtype plants. In both the wildtype and strigolactone biosynthesis-deficient mutants, the strigolactone analog GR24 enhanced disease resistance, whereas treatment with a strigolactone biosynthesis inhibitor suppressed disease resistance in the wildtype. Before inoculation of wildtype plants with pathogenic bacteria, treatment with GR24 did not induce defense-related genes; however, salicylic acid-responsive defense genes were rapidly induced after pathogenic infection. These findings suggest that strigolactones have a priming effect on Arabidopsis thaliana by inducing salicylic acid-mediated disease resistance. [ABSTRACT FROM AUTHOR]

With the development of psychology and medicine, more and more diseases have found their psychological origins and associations, especially ulceration and other mucosal injuries, within the digestive system. However, the association of psychological factors with lesions of the oral mucosa, including oral squamous cell carcinoma (OSCC), burning mouth syndrome (BMS), and recurrent aphthous stomatitis (RAS), have not been fully characterized. In this review, after introducing the association between psychological and nervous factors and diseases, we provide detailed descriptions of the psychology and nerve fibers involved in the pathology of OSCC, BMS, and RAS, pointing out the underlying mechanisms and suggesting the clinical indications. [ABSTRACT FROM AUTHOR]

Nutraceuticals are bioactive or chemical compounds acclaimed for their valuable biological activities and health-promoting effects. The global community is faced with many health concerns such as cancers, cardiovascular and neurodegenerative diseases, diabetes, arthritis, osteoporosis, etc. The effect of nutraceuticals is similar to pharmaceuticals, even though the term nutraceutical has no regulatory definition. The usage of nutraceuticals, to prevent and treat the aforementioned diseases, is limited by several features such as poor water solubility, low bioavailability, low stability, low permeability, low efficacy, etc. These downsides can be overcome by the application of the field of nanotechnology manipulating the properties and structures of materials at the nanometer scale. In this review, the linear and cyclic dextrin, formed during the enzymatic degradation of starch, are highlighted as highly promising nanomaterials- based drug delivery systems. The modified cyclic dextrin, cyclodextrin (CD)-based nanosponges (NSs), are well-known delivery systems of several nutraceuticals such as quercetin, curcumin, resveratrol, thyme essential oil, melatonin, and appear as a more advanced drug delivery system than modified linear dextrin. CD-based NSs prolong and control the nutraceuticals release, and display higher biocompatibility, stability, and solubility of poorly water-soluble nutraceuticals than the CD-inclusion complexes, or uncomplexed nutraceuticals. In addition, the well-explored CD-based NSs pathways, as drug delivery systems, are described. Although important progress is made in drug delivery, all the findings will serve as a source for the use of CD-based nanosystems for nutraceutical delivery. To sum up, our review introduces the extensive literature about the nutraceutical concepts, synthesis, characterization, and applications of the CD-based nano delivery systems that will further contribute to the nutraceutical delivery with more potent nanosystems based on linear dextrins. [ABSTRACT FROM AUTHOR]

Saliva is a complex body fluid that comprises secretions from the major and minor salivary glands, which are extensively supplied by blood. Therefore, molecules such as proteins, DNA, RNA, etc., present in plasma could be also present in saliva. Many studies have reported that saliva body fluid can be useful for discriminating several oral diseases, but also systemic diseases including cancer. Most of these studies revealed messenger RNA (mRNA) and proteomic biomarker signatures rather than specific non-coding RNA (ncRNA) profiles. NcRNAs are emerging as new regulators of diverse biological functions, playing an important role in oncogenesis and tumor progression. Indeed, the small size of these molecules makes them very stable in different body fluids and not as susceptible as mRNAs to degradation by ribonucleases (RNases). Therefore, the development of a non-invasive salivary test, based on ncRNAs profiles, could have a significant applicability to clinical practice, not only by reducing the cost of the health system, but also by benefitting the patient. Here, we summarize the current status and clinical implications of the ncRNAs present in human saliva as a source of biological information.

The orchestration of cellular metabolism and redox balance is a complex, multifaceted process crucial for maintaining cellular homeostasis. Lipid droplets (LDs), once considered inert storage depots for neutral lipids, are now recognized as dynamic organelles critical in lipid metabolism and energy regulation. Mitochondria, the powerhouses of the cell, play a central role in energy production, metabolic pathways, and redox signaling. The physical and functional contacts between LDs and mitochondria facilitate a direct transfer of lipids, primarily fatty acids, which are crucial for mitochondrial β-oxidation, thus influencing energy homeostasis and cellular health. This review highlights recent advances in understanding the mechanisms governing LD-mitochondria interactions and their regulation, drawing attention to proteins and pathways that mediate these contacts. We discuss the physiological relevance of these interactions, emphasizing their role in maintaining energy and redox balance within cells, and how these processes are critical in response to metabolic demands and stress conditions. Furthermore, we explore the pathological implications of dysregulated LD-mitochondria interactions, particularly in the context of metabolic diseases such as obesity, diabetes, and non-alcoholic fatty liver disease, and their potential links to cardiovascular and neurodegenerative diseases. Conclusively, this review provides a comprehensive overview of the current understanding of LD-mitochondria interactions, underscoring their significance in cellular metabolism and suggesting future research directions that could unveil novel therapeutic targets for metabolic and degenerative diseases.

The term “pharmacological chaperone” was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein. [ABSTRACT FROM AUTHOR]

Small heat shock proteins (sHsps) are a family of ATP-independent molecular chaperones that function as "holdases" and prevent protein aggregation due to changes in temperature, pH, or oxidation state. sHsps have a conserved α-crystallin domain (ACD), which forms the dimer building block, flanked by variable N- and C-terminal regions. sHsps populate various oligomeric states as a function of their sequestrase activity, and these dynamic structural features allow the proteins to interact with a plethora of cellular substrates. However, the molecular mechanisms of their dynamic conformational assembly and the interactions with various substrates remains unclear. Therefore, it is important to gain insight into the underlying physicochemical properties that influence sHsp structure in an effort to understand their mechanism(s) of action. We evaluated several disease-relevant mutations, D109A, F113Y, R116C, R120G, and R120C, in the ACD of HspB5 for changes to in vitro chaperone activity relative to that of wildtype. Structural characteristics were also evaluated by ANS fluorescence and CD spectroscopy. Our results indicated that mutation Y113F is an efficient holdase, while D109A and R120G, which are found in patients with myofibrillar myopathy and cataracts, respectively, exhibit a large reduction in holdase activity in a chaperone-like light-scattering assay, which indicated alterations in substrate-sHsp interactions. The extent of the reductions in chaperone activities are different among the mutants and specific to the substrate protein, suggesting that while sHsps are able to interact with many substrates, specific interactions provide selectivity for some substrates compared to others. This work is consistent with a model for chaperone activity where key electrostatic interactions in the sHsp dimer provide structural stability and influence both higher-order sHsp interactions and facilitate interactions with substrate proteins that define chaperone holdase activity.

Long interspersed element-1 (LINE-1; L1s) are mobile genetic elements that comprise nearly 20% of the human genome. L1s have been shown to have important functions in various biological processes, and their dysfunction is thought to be linked with diseases and cancers. However, the roles of the repetitive elements are largely not understood. While the CRISPR activation (CRISPRa) system based on catalytically deadCas9 (dCas9) is widely used for genome-wide interrogation of gene function and genetic interaction, few studies have been conducted on L1s. Here, we report using the CRISPRa method to efficiently activate L1s in human L02 cells, a derivative of the HeLa cancer cell line. After CRISPRa, the young L1 subfamilies such as L1HS/L1PA1 and L1PA2 are found to be expressed at higher levels than the older L1s. The L1s with high levels of transcription are closer to full-length and are more densely occupied by the YY1 transcription factor. The activated L1s can either be mis-spliced to form chimeric transcripts or act as alternative promoters or enhancers to facilitate the expression of neighboring genes. The method described here can be used for studying the functional roles of young L1s in cultured cells of interest.

Genome wide studies based on conventional molecular tools and upcoming omics technologies are beginning to gain functional applications in the control and prevention of diseases in teleosts fish. Herein, we provide insights into current progress and prospects in the use genomics studies for the control and prevention of fish diseases. Metagenomics has emerged to be an important tool used to identify emerging infectious diseases for the timely design of rational disease control strategies, determining microbial compositions in different aquatic environments used for fish farming and the use of host microbiota to monitor the health status of fish. Expounding the use of antimicrobial peptides (AMPs) as therapeutic agents against different pathogens as well as elucidating their role in tissue regeneration is another vital aspect of genomics studies that had taken precedent in recent years. In vaccine development, prospects made include the identification of highly immunogenic proteins for use in recombinant vaccine designs as well as identifying gene signatures that correlate with protective immunity for use as benchmarks in optimizing vaccine efficacy. Progress in quantitative trait loci (QTL) mapping is beginning to yield considerable success in identifying resistant traits against some of the highly infectious diseases that have previously ravaged the aquaculture industry. Altogether, the synopsis put forth shows that genomics studies are beginning to yield positive contribution in the prevention and control of fish diseases in aquaculture. [ABSTRACT FROM AUTHOR]

The CDKN1C gene encodes the p57Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27Kip1 and p21Cip1. In analogy with these proteins, p57Kip2 is able to bind tightly and inhibit cyclin/cyclin-dependent kinase complexes and, in turn, modulate cell division cycle progression. For a long time, the main function of p57Kip2 has been associated only to correct embryogenesis, since CDKN1C-ablated mice are not vital. Accordingly, it has been demonstrated that CDKN1C alterations cause three human hereditary syndromes, characterized by altered growth rate. Subsequently, the p57Kip2 role in several cell phenotypes has been clearly assessed as well as its down-regulation in human cancers. CDKN1C lies in a genetic locus, 11p15.5, characterized by a remarkable regional imprinting that results in the transcription of only the maternal allele. The control of CDKN1C transcription is also linked to additional mechanisms, including DNA methylation and specific histone methylation/acetylation. Finally, long non-coding RNAs and miRNAs appear to play important roles in controlling p57Kip2 levels. This review mostly represents an appraisal of the available data regarding the control of CDKN1C gene expression. In addition, the structure and function of p57Kip2 protein are briefly described and correlated to human physiology and diseases. [ABSTRACT FROM AUTHOR]

The commands that control animal movement are transmitted from motor neurons to their target muscle cells at the neuromuscular junctions (NMJs). The NMJs contain many protein species whose role in transmission depends not only on their inherent properties, but also on how they are distributed within the complex structure of the motor nerve terminal and the postsynaptic muscle membrane. These molecules mediate evoked chemical transmitter release from the nerve and the action of that transmitter on the muscle. Human NMJs are among the smallest known and release the smallest number of transmitter "quanta". By contrast, they have the most deeply infolded postsynaptic membranes, which help to amplify transmitter action. The same structural features that distinguish human NMJs make them particularly susceptible to pathological processes. While much has been learned about the molecules which mediate transmitter release and action, little is known about the molecular processes that control the growth of the cellular and subcellular components of the NMJ so as to give rise to its mature form. A major challenge for molecular biologists is to understand the molecular basis for the development and maintenance of functionally important aspects of NMJ structure, and thereby to point to new directions for treatment of diseases in which neuromuscular transmission is impaired. [ABSTRACT FROM AUTHOR]

Retromer complexes mediate protein trafficking from the endosomes to the trans-Golgi network (TGN) or through direct recycling to the plasma membrane. In yeast, they consist of a conserved trimer of the cargo selective complex (CSC), Vps26-Vps35-Vps29 and a dimer of sorting nexins (SNXs), Vps5-Vps17. In mammals, the CSC interacts with different kinds of SNX proteins in addition to the mammalian homologues of Vps5 and Vps17, which further diversifies retromer functions. The retromer complex plays important roles in many cellular processes including restriction of invading pathogens. In this review, we summarize some recent developments in our understanding of the physiological and pathological functions of the retromer complex. [ABSTRACT FROM AUTHOR]

Approximately 1 billion people smoke worldwide, and the burden placed on society by primary and secondhand smokers is expected to increase. Smoking is the leading risk factor for myriad health complications stemming from diverse pathogenic programs. First- and second-hand cigarette smoke contains thousands of constituents, including several carcinogens and cytotoxic chemicals that orchestrate chronic inflammatory responses and destructive remodeling events. In the current review, we outline details related to compromised pulmonary and systemic conditions related to smoke exposure. Specifically, data are discussed relative to impaired lung physiology, cancer mechanisms, maternal-fetal complications, cardiometabolic, and joint disorders in the context of smoke exposure exacerbations. As a general unifying mechanism, the receptor for advanced glycation end-products (RAGE) and its signaling axis is increasingly considered central to smoke-related pathogenesis. RAGE is a multi-ligand cell surface receptor whose expression increases following cigarette smoke exposure. RAGE signaling participates in the underpinning of inflammatory mechanisms mediated by requisite cytokines, chemokines, and remodeling enzymes. Understanding the biological contributions of RAGE during cigarette smoke-induced inflammation may provide critically important insight into the pathology of lung disease and systemic complications that combine during the demise of those exposed. [ABSTRACT FROM AUTHOR]