Search Results (163)

Chrysanthemum species represent an economically important group of flowering plants. Many species also present a medicinal interest, notably for the treatment of inflammatory pathologies. This is the case for Chrysanthemum boreale Makino, endemic to Japan and widespread in Eastern Asia. This perennial plant has long been used in folk medicine to treat inflammatory diseases and bacterial infections. An extensive review of the scientific literature pertaining to C. boreale has been performed to analyze the origin of the plant, its genetic traits, the traditional usages, and the properties of aqueous or organic plant extracts and essential oils derived from this species. Aqueous extracts and the associated flavonoids, such as acacetin and glycoside derivatives, display potent antioxidant activities. These aqueous extracts and floral waters are used mainly as cytoprotective agents. Organic extracts, in particular those made from methanol or ethanol, essentially display antioxidant and anti-inflammatory properties useful to protect organs from oxidative damage. They can be used for neuroprotection. Essential oils from C. boreale have been used as cytoprotective or antibacterial agents. The main bioactive natural products isolated from the plant include flavonoids such as acacetin and related glycosides (notably linarin), and diverse sesquiterpene lactones (SLs). Among monomeric SLs, cumambrins and borenolide are the main products of interest, with cumambrin A targeting covalently the transcription factor NF-κB to regulate proinflammatory gene expression to limit osteoclastic bone resorption. The dimeric SL handelin, which is characteristic of C. boreale, exhibits a prominent anti-inflammatory action, with a capacity to target key proteins like kinase TAK1 and chaperone Hsp70. A few other natural products isolated from the plant (tulipinolide, polyacetylenic derivatives) are discussed. Altogether, the review explores all medicinal usages of the plant and the associated phytochemical panorama, with the objective of promoting further botanical and chemical studies of this ancestral medicinal species. Full article

Understanding the mechanisms of immune activation and deactivation is paramount. A host must initiate effective immunity against pathogenic infections while avoiding triggering immunity against self-antigens, which can lead to detrimental autoimmune disorders. Host immunological pathways can be categorized as Immunoglobulin (Ig)G-dominant eradicable immune reactions and IgA-dominant tolerable immune reactions. Eradicable immune reactions include Th1, Th2, Th22, and Thαβ immune responses against four different types of pathogens. Tolerable immune reactions include Th1-like, Th9, Th17, and Th3 immune responses against four different types of pathogens. Here, we try to determine the mechanisms of activation and deactivation of host immune reactions. The spleen and liver play contrasting roles in mediating immune responses: the spleen is primarily involved in immune activation, whereas the liver is responsible for immune deactivation. Similarly, the sympathetic and parasympathetic nervous systems have opposing functions in immune modulation, with the sympathetic system promoting pro-inflammatory responses and the parasympathetic system facilitating anti-inflammatory processes. Furthermore, adrenocorticotropic hormone (ACTH) and glucocorticosteroids exhibit contrasting effects on immune regulation: ACTH is involved in activating adaptive immunity while inhibiting innate immunity, whereas glucocorticosteroids activate natural IgM antibody associated with innate immunity while inhibiting adaptive immunity. Heat shock proteins, particularly molecular chaperones induced by fever, play pivotal roles in immune activation. Conversely, IgD B cells and gamma/delta T cells contribute to immune deactivation through mechanisms such as clonal anergy. Understanding these mechanisms provides insights into immunological pathways, aiding in the better management of infectious diseases and autoimmune disorders. Full article

Eukaryotic transcription involves a complex interplay of protein factors that dynamically engage with chromatin at distinct stages. Among these, the histone chaperone FACT (Facilitates Chromatin Transcription) plays a unique role in nucleosome disassembly and reassembly during transcription, replication, and repair. While its functional importance is well established, the underlying structural mechanisms involved in these activities remain incompletely understood. The remarkable functional versatility of FACT in regulating genetic information processing likely stems from its distinctive structural and mechanical properties. This review focuses on the structural organization of FACT and analysis of the mechanisms involved in chromatin reorganization by this unusual histone chaperone. Full article

Chronic pain, defined by persistent pain beyond normal healing time, is a pervasive and debilitating condition affecting up to 30–50% of adults globally. In parallel, neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) are characterized by progressive neuronal loss and cognitive or motor decline, often underpinned by pathological protein misfolding and aggregation. Emerging evidence suggests a potential mechanistic link between chronic pain and NDs, with persistent pain contributing to neuroinflammatory states and protein homeostasis disturbances that mirror processes in neurodegeneration. This review explores the hypothesis that protein misfolding and aggregation serve as a mechanistic bridge between chronic pain and neurodegeneration. We systematically examine molecular pathways of protein misfolding, proteostasis dysfunction in chronic pain, and shared neuroimmune mechanisms, highlighting prion-like propagation of misfolded proteins, chronic neuroinflammation, and oxidative stress as common denominators. We further discuss evidence from experimental models and clinical studies linking chronic pain to accelerated neurodegenerative pathology—including tau accumulation, amyloid dysregulation, and microglial activation—and consider how these insights open avenues for novel therapeutics. Targeting protein aggregation, enhancing chaperone function, modulating the unfolded protein response (UPR), and attenuating glial activation are explored as potential strategies to mitigate chronic pain and possibly slow neurodegeneration. Understanding this intersection not only elucidates chronic pain’s role in cognitive decline but also suggests that interventions addressing proteostasis and inflammation could yield dual benefits in pain management and neurodegenerative disease modification. Full article

Atherosclerosis, a chronic inflammatory disease characterized by lipid accumulation and immune cell infiltration, is linked to plaque formation and cardiovascular events. While traditionally associated with lipid metabolism and endothelial dysfunction, recent research highlights the roles of autophagy and clonal hematopoiesis (CH) in its pathogenesis. Autophagy, a cellular process crucial for degrading damaged components, regulates macrophage homeostasis and inflammation, both of which are pivotal in atherosclerosis. In macrophages, autophagy influences lipid metabolism, cytokine regulation, and oxidative stress, helping to prevent plaque instability. Defective autophagy exacerbates inflammation, impairs cholesterol efflux, and accelerates disease progression. Additionally, autophagic processes in endothelial cells and smooth muscle cells further contribute to atherosclerotic pathology. Recent studies also emphasize the interplay between autophagy and CH, wherein somatic mutations in genes like TET2, JAK2, and DNMT3A drive immune cell expansion and enhance inflammatory responses in atherosclerotic plaques. These mutations modify macrophage function, intensifying the inflammatory environment and accelerating atherosclerosis. Chaperone-mediated autophagy (CMA), a selective form of autophagy, also plays a critical role in regulating macrophage inflammation by degrading pro-inflammatory cytokines and oxidized low-density lipoprotein (ox-LDL). Impaired CMA activity leads to the accumulation of these substrates, activating the NLRP3 inflammasome and worsening inflammation. Preclinical studies suggest that pharmacologically activating CMA may mitigate atherosclerosis progression. In animal models, reduced CMA activity accelerates plaque instability and increases inflammation. This review highlights the importance of autophagic regulation in macrophages, focusing on its role in inflammation, plaque formation, and the contributions of CH. Building upon current advances, we propose a hypothesis in which autophagy, programmed cell death, and clonal hematopoiesis form a critical intrinsic axis that modulates the fundamental functions of macrophages, playing a complex role in the development of atherosclerosis. Understanding these mechanisms offers potential therapeutic strategies targeting autophagy and inflammation to reduce the burden of atherosclerotic cardiovascular disease. Full article

Protein misfolding, aggregation, and aberrant aggregate accumulation play a central role in neurodegenerative disease progression. The proteotoxic factors also govern the aging process to a large extent. Molecular chaperones modulate proteostasis and thereby impact aberrant-protein-induced proteotoxicity. These chaperones have a diverse functional spectrum, including nascent protein folding, misfolded protein sequestration, refolding, or degradation. Small heat shock proteins (sHsps) possess an ATP-independent chaperone-like activity that prevents protein aggregation by keeping target proteins in a folding-competent state to be refolded by ATP-dependent chaperones. Due to their near-universal upregulation and presence in sites of proteotoxic stress like diseased brains, sHsps were considered pathological. However, gene knockdown and overexpression studies have established their protective functions. This review provides an updated overview of the sHsp role in protein aggregation amelioration and highlights evidence for sHsp modulation of neurodegenerative disease-related protein aggregation and aging. Full article

The antibiotic resistance of pathogenic microorganisms is currently one of most major medical problems, causing a few million deaths every year worldwide due to untreatable bacterial infections. Unfortunately, the prognosis is even worse, as over 8 million deaths associated with antibiotic resistance are expected to occur in 2050 if no new effective antibacterial treatments are discovered. The Hfq protein has been discovered as a bacterial RNA chaperone. However, subsequent studies have indicated that this small protein (composed of 102 amino acid residues in Escherichia coli) has more activities, including binding to DNA and influencing its compaction, interaction with biological membranes, formation of amyloid-like structures, and others. Although Hfq is known to participate in many cellular processes, perhaps surprisingly, only reports from recent years have demonstrated its role in bacterial antibiotic resistance. The aim of this narrative review is to discuss how can Hfq affects antibiotic resistance in bacteria and propose how this knowledge may facilitate developing new therapeutic strategies against pathogenic bacteria. We indicate that the mechanisms by which the Hfq protein modulates the response of bacterial cells to antibiotics are quite different, from the regulation of the expression of genes coding for proteins directly involved in antibiotic transportation or action, through direct effects on membranes, to controlling the replication or transposition of mobile genetic elements bearing antibiotic resistance genes. Therefore, we suggest that Hfq could be considered a potential target for novel antimicrobial compounds. We also discuss difficulties in developing such drugs, but since Hfq appears to be a promising target for drugs that may enhance the efficacy of antibiotics, we propose that works on such potential therapeutics are encouraged. Full article

Background/Objectives: The Sigma-1 receptor (Sigmar1), an intracellular chaperone protein, is ubiquitously expressed throughout the body, but its role in peripheral organs, such as the kidneys, remains unclear. Here, we investigated the protective effects and molecular mechanisms of SA4503, a selective Sigmar1 agonist, on Adriamycin (ADR)-induced renal glomerular injury. Methods: Using in vitro and in vivo models, we evaluated the effects of SA4503 on ADR-induced podocyte injury, including podocyte survival, albumin permeability, urinary albumin levels, and Sigmar1-nephrin interactions. NE-100, a Sigmar1 antagonist, was co-administered to validate the specificity of the effects of SA4503. Results: Sigmar1 was highly expressed in podocytes and mouse kidney tissues. SA4503 significantly reduced ADR-induced podocyte injury and urinary albumin leakage in mice. Mechanistically, SA4503 preserved Sigmar1-nephrin interactions, which were disrupted in ADR-treated kidneys. This protective effect was abolished by NE-100 co-treatment, confirming the Sigmar1-dependency of SA4503’s action. Conclusions: These findings demonstrate that the activation of Sigmar1 by SA4503 protects against ADR-induced podocyte injury and glomerular damage, likely by stabilizing Sigmar1-nephrin interactions. Therefore, Sigmar1 represents a promising therapeutic target for glomerular diseases such as nephrotic syndrome. Full article

Aggregation is intricately linked to protein folding, necessitating a precise understanding of their relationship. Traditionally, aggregation has been viewed primarily as a sequential consequence of protein folding and misfolding. However, this conventional paradigm is inherently incomplete and can be deeply misleading. Remarkably, it fails to adequately explain how intrinsic and extrinsic factors, such as charges and cellular macromolecules, prevent intermolecular aggregation independently of intramolecular protein folding and structure. The pervasive inconsistencies between protein folding and aggregation call for a new framework. In all combined reactions of molecules, both intramolecular and intermolecular rate (or equilibrium) constants are mutually independent; accordingly, intrinsic and extrinsic factors independently affect both rate constants. This universal principle, when applied to protein folding and aggregation, indicates that they should be treated as two independent yet interconnected processes. Based on this principle, a new framework provides groundbreaking insights into misfolding, Anfinsen’s thermodynamic hypothesis, molecular chaperones, intrinsic chaperone-like activities of cellular macromolecules, intermolecular repulsive force-driven aggregation inhibition, proteome solubility maintenance, and proteinopathies. Consequently, this paradigm shift not only refines our current understanding but also offers a more comprehensive view of how aggregation is coupled to protein folding in the complex cellular milieu. Full article

The receptor transporter protein 4 (RTP4) is a receptor chaperone protein that targets class A G-protein coupled receptor (GPCR)s. Recently, it has been found to play a role in peripheral inflammatory regulation, as one of the interferon-stimulated genes (ISGs). However, the detailed role of RTP4 in response to inflammatory stress in the central nervous system has not yet been fully understood. While we have previously examined the role of RTP4 in the brain, particularly in neuronal cells, this study focuses on its role in microglial cells, immunoreactive cells in the brain that are involved in inflammation. For this, we examined the changes in the RTP4 levels in the microglial cells after exposure to inflammatory stress. We found that lipopolysaccharide (LPS) treatment (0.1~1 µg/mL, 24 h) significantly upregulated the RTP4 mRNA levels in the microglial cell line, SIM-A9. Furthermore, the interferon (IFN)-β mRNA levels and extracellular levels of IFN-β were also increased by LPS treatment. This upregulation was reversed by treatment with neutralizing antibodies targeting either the interferon receptor (IFNR) or toll-like receptor 4 (TLR4), and with a TLR4 selective inhibitor, or a Janus kinase (JAK) inhibitor. On the other hand, the mitogen-activated protein kinase kinase (MEK) inhibitor, U0126, significantly enhanced the increase in RTP4 mRNA following LPS treatment, whereas the PKC inhibitor, calphostin C, had no effect. These findings suggest that in microglial cells, LPS-induced inflammatory stress activates TLR4, leading to the production of type I IFN, the activation of IFN receptor and JAK, and finally, the induction of RTP4 gene expression. Based on these results, we speculate that RTP4 functions as an inflammation-responsive molecule in the brain. However, further research is needed to fully understand its role. Full article

Water exists in the beginning and hydrates all matter. Life emerged in water, requiring three essential components in compartmentalized spaces: (1) universal energy sources driving biochemical reactions and processes, (2) molecules that store, encode, and transmit information, and (3) functional players carrying out biological activities and structural organization. Phosphorus has been selected to create adenosine triphosphate (ATP) as the universal energy currency, nucleic acids for genetic information storage and transmission, and phospholipids for cellular compartmentalization. Meanwhile, proteins composed of 20 α-amino acids have evolved into extremely diverse three-dimensional forms, including folded domains, intrinsically disordered regions (IDRs), and membrane-bound forms, to fulfill functional and structural roles. This review examines several unique findings: (1) insoluble proteins, including membrane proteins, can become solubilized in unsalted water, while folded cytosolic proteins can acquire membrane-inserting capacity; (2) Hofmeister salts affect protein stability by targeting hydration; (3) ATP biphasically modulates liquid–liquid phase separation (LLPS) of IDRs; (4) ATP antagonizes crowding-induced protein destabilization; and (5) ATP and triphosphates have the highest efficiency in inducing protein folding. These findings imply the following: (1) hydration might be encoded in protein sequences, central to manifestation and modulation of protein structures, dynamics, and functionalities; (2) phosphate anions have a unique capacity in enhancing μs-ms protein dynamics, likely through ionic state exchanges in the hydration shell, underpinning ATP, polyphosphate, and nucleic acids as molecular chaperones for protein folding; and (3) ATP, by linking triphosphate with adenosine, has acquired the capacity to spacetime-specifically release energy and modulate protein hydration, thus possessing myriad energy-dependent and -independent functions. In light of the success of AlphaFolds in accurately predicting protein structures by neural networks that store information as distributed patterns across nodes, a fundamental question arises: Could cellular networks also handle information similarly but with more intricate coding, diverse topological architectures, and spacetime-specific ATP energy supply in membrane-compartmentalized aqueous environments? Full article

Agricultural and industrial activities are increasing pollution of water bodies with low doses of xenobiotics that have detrimental effects on aquaculture. The aim of this work was to determine the possibility of using Levilactobacillus brevis 47f culture in fish aquaculture under the influence of low doses of xenobiotics as an adaptogen. An increase in the survival of Danio rerio individuals exposed to the xenobiotic bisphenol A solution and fed with the L. brevis 47f was shown compared to control groups and, at the same time, the cytokine profile in the intestinal tissues of Danio rerio was also investigated. Analysis of differential gene expression of the L. brevis 47f grown under the action of high concentrations of bisphenol A showed changes in mRNA levels of a number of genes, including genes of various transport proteins, genes involved in fatty acid synthesis, genes of transcriptional regulators, genes of the arabinose operon, and the oppA gene. The identification of L. brevis 47f proteins from polyacrylamide gel by mass spectrometry revealed L-arabinose isomerase, Clp chaperone subunit, ATP synthase subunits, pentose phosphate pathway and glycolysis enzyme proteins, which are likely part of the L. brevis 47f strain’s anti-stress response, but probably do not affect its adaptogenic activity toward Danio rerio. Full article

Stress-inducible heat shock protein 70 (Hsp70), which functions as a molecular chaperone and is frequently overexpressed in different cancer cell types, is present on the cell surface of tumor cells and is actively released into the circulation in free and extracellular lipid vesicle-associated forms. Since the exact pathomechanism of endometriosis has not yet been elucidated (although it has been associated with the development of endometrial and ovarian cancer), we asked whether extracellular Hsp70 and circulating endometriotic cells (CECs) reflect the presence and development of endometriosis. Therefore, circulating levels of free and lipid microvesicle-associated Hsp70 were measured using the Hsp70-exo ELISA, and the presence of circulating CECs in the peripheral blood of patients with endometriosis was determined using membrane Hsp70 (mHsp70) and EpCAM monoclonal antibody (mAb)-based bead isolation approaches. Isolated CECs were further characterized by immunofluorescence using reagents directed against cytokeratin (epithelial marker), CD45 (leukocyte marker), CD105/CD44 (mesenchymal stemness markers) and by comparative RNA analysis. Similar to the situation in patients with cancer, the levels of circulating Hsp70 were elevated in the blood of patients with histologically proven endometriosis compared to a healthy control cohort, with significantly elevated Hsp70 levels in endometriosis patients with lesions outside the uterine cavity. Moreover, CECs could be isolated using the cmHsp70.1 mAb-based, and to a lesser extent EpCAM mAb-based, bead approach in all patients with endometriosis, with the highest counts obtained using the mHsp70-targeting procedure in patients with extra-uterine involvement. The longevity in cell culture and the expression of the cytokeratins CD105 and CD44, together with differentially expressed genes related to epithelial-to-mesenchymal transition (EMT), revealed similarities between mHsp70-expressing CECs and circulating tumor cells (CTCs) and suggest a mesenchymal stem cell origin. These findings support the involvement of mHsp70-positive stem cell-like cells in the development of endometriotic lesions. In summary, elevated levels of Hsp70 and CECs in the circulation could serve as liquid biopsy markers for endometriosis with extra-uterine involvement and help to elucidate the underlying pathomechanism of the disease. Full article

Klotho is an anti-aging protein whose deletion significantly reduces lifespan in mice, while its over-expression increases lifespan. Klotho is a type-I transmembrane protein that is N-glycosylated at eight positions within its ectodomain. Our study demonstrates that N-glycosylation or mutation at position N614, but not at N161, N285, or N346 in mouse Klotho, is critically involved in the transport of Klotho out of the endoplasmic reticulum (ER). Consequently, while wild-type Klotho-EGFP as well as the N-glycosylation mutants N161Q, N285Q, and N346Q were present at the plasma membrane (PM), only small amounts of the N614Q Klotho-EGFP were present at the PM, with most of the protein accumulating in the ER. Protein interactome analysis of Klotho-EGFP N614Q revealed increased interactions with proteasome-related proteins and proteins involved in ER protein processing, like heat shock proteins and protein disulfide isomerases, indicative of impaired protein folding. Co-immunoprecipitation experiments confirmed the interaction of Klotho-EGFP N614Q with ER chaperons. Interestingly, despite the low amounts of Klotho-EGFP N614Q at the PM, it efficiently induced FGF receptor-mediated ERK activation in the presence of FGF23, highlighting its efficacy in triggering downstream signaling, even in limited quantities at the PM. Full article

The unique chaperone-like properties of C19orf53, discovered in 2020 as a “hero” protein, make it an intriguing subject for research in relation to ischemic stroke (IS). Our pilot study aimed to investigate whether C19orf53 SNPs are associated with IS. DNA samples from 2138 Russian subjects (947 IS and 1308 controls) were genotyped for 7 C19orf53 SNPs using probe-based PCR. Dominant (D), recessive (R), and log-additive (A) regression models in relation to the effect alleles (EA) were used to interpret associations. An increased risk of IS was associated with rs10104 (EA G; P_bonf(R) = 0.0009; P_bonf(A) = 0.0004), rs11666524 (EA A; P_bonf(R) = 0.003; P_bonf(A) = 0.02), rs346158 (EA C; P_bonf(R) = 0.006; P_bonf(A) = 0.045), and rs2277947 (EA A; P_bonf(R) = 0.002; P_bonf(A) = 0.01) in patients with obesity; with rs11666524 (EA A; P_bonf(R) = 0.02), rs346157 (EA G; P_bonf(R) = 0.036), rs346158 (EA C; P_bonf(R) = 0.005), and rs2277947 (EA A; P_bonf(R) = 0.02) in patients with low fruit and vegetable intake; and with rs10104 (EA G; P_bonf(R) = 0.03) and rs11666524 (EA A; P_bonf(R) = 0.048) in patients with low physical activity. In conclusion, our pilot study provides comprehensive genetic and bioinformatic evidence of the involvement of C19orf53 in IS risk. Full article