Search Results (92)

Recent insights into the p53-MDM2 nexus have advanced deeper understanding of their regulation and potent impact on cancer heterogeneity. The roles of nuclear phosphoinositide (PIP_ns) in modulating this pathway are emerging as a key mechanism. Here, we dissect the molecular mechanisms by which nuclear PIP_ns stabilize p53 through the recruitment of small heat shock proteins (sHSPs), activate the nuclear phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade, and modulate MDM2 function to regulate the p53-MDM2 interaction. We propose potential mechanisms by which nuclear PIP_ns coordinate signaling with nuclear p53, AKT, and MDM2. Ultimately, we highlight that nuclear PIP_ns serve as a ‘third messenger’ within the p53-MDM2 axis, expanding the current framework of non-canonical nuclear signaling in cancer biology. Full article

Small heat shock proteins (sHsps) play crucial roles in organismal adaptation to stress tolerance. Sitodiplosis mosellana, a devastating insect wheat pest, undergoes long obligatory larval diapause to survive temperature extremes during summer and winter. To elucidate the function of sHsps in this process, two sHsp-encoding genes (SmHsp22.2 and SmHsp26.7) were characterized from S. mosellana, and their responsiveness to diapause and thermal stress, as well as their roles in cold stress, was analyzed. Both SmHsp22.2 and SmHsp26.7 possessed the canonical α-crystallin domain and lacked introns. Quantitative PCR indicated significant upregulation of SmHsp22.2 and SmHsp26.7 during diapause, especially in summer and winter. Notably, SmHsp22.2 exhibited higher expression in summer relative to winter, whereas SmHsp26.7 showed the opposite profile. Moreover, short-term heat shock (≥35 °C) in over-summering larvae or cold shock (≤−10 °C) in over-wintering larvae was found to trigger transcriptional upregulation of both genes, while prolonged temperature extremes (i.e., 45–50 °C or −15 °C) did not elicit a comparable response. RNA interference-mediated knockdown of both genes significantly increased the mortality of S. mosellana larvae under cold stress. These findings indicate the importance of both SmHsps in diapause and environmental adaptation in S. mosellana. Full article

Small heat shock proteins (sHsps) are ubiquitous low-molecular-weight chaperones that prevent protein aggregation under cellular stress conditions. In the absence of stress, they assemble into large oligomers. In response to stress, such as elevated temperatures, they undergo conformational changes that expose hydrophobic surfaces, allowing them to interact with denatured proteins. At heat shock temperatures in bacteria, large sHsp oligomers disassemble into smaller oligomeric forms. Methanogens are a diverse group of microorganisms, ranging from thermophilic to psychrophilic and halophilic species. Accordingly, their sHsps exhibit markedly different temperature dependencies based on their optimal growth temperatures. In this study, we characterized sHsps from both hyperthermophilic and mesophilic methanogens to investigate the mechanisms underlying their temperature-dependent behavior. Using analytical ultracentrifugation, we observed the dissociation of sHsps from a mesophilic methanogen into dimers. The dissociation equilibrium of these oligomers was found to be dependent not only on temperature but also on protein concentration. Furthermore, by generating various mutants, we identified the specific amino acid residues responsible for the temperature dependency observed. The C-terminal region containing the IXI/V motif and the α-crystallin domain were found to be the primary determinants of oligomer stability and its temperature dependence. Full article

Background: Small heat shock proteins (sHsps), particularly Hsp20 family members, are pivotal for plant thermotolerance and abiotic stress adaptation. However, their evolutionary dynamics and functional roles in Lycium barbarum (goji berry), a commercially significant stress-tolerant crop, remain uncharacterized. This study aims to comprehensively identify LbHsp20 genes, delineate their evolutionary patterns, and decipher their regulatory mechanisms under heat stress to accelerate molecular breeding of resilient cultivars. Methods: Forty-three LbHsp20 genes were identified from the goji genome using HMMER and BLASTP. Phylogenetic relationships were reconstructed via MEGA-X (maximum likelihood, 1000 bootstraps), while conserved motifs and domains were annotated using MEME Suite and InterProScan. Promoter cis-elements were predicted via PlantCARE. Heat-responsive expression profiles of candidate genes were validated by qRT-PCR in two contrasting lines (N7 and 1402) under 42 °C treatment. Results: The LbHsp20 family clustered into 14 subfamilies, predominantly cytoplasmic (subfamilies I–VII). Chromosomal mapping revealed a tandem duplication hotspot on Chr4 (12 genes) and absence on Chr9, suggesting lineage-specific gene loss. All proteins retained the conserved α-crystallin domain (ACD), with 19 members harboring the ScHsp26-like ACD variant. Promoters were enriched in stress-responsive elements (HSE, ABRE, MYC). Heat stress induced significant upregulation (>15-fold in LbHsp17.6A and LbHsp18.3) in N7, whereas 1402 showed weaker induction (<5-fold). Subfamily specific divergence was observed, with cytoplasmic subfamily I genes exhibiting the strongest heat responsiveness. Conclusions: This study unveils the evolutionary conservation and functional diversification of LbHsp20 genes in L. barbarum. The tandem duplication-driven expansion on Chr4 and subfamily specific expression patterns underpin their roles in thermotolerance. These findings establish a foundation for engineering climate-resilient goji varieties. Full article

Increasingly popular, recreational diving is a physical activity that takes place under extreme environmental conditions, which include hyperoxia, hyperbaria and exposure to cold water. The effects of these factors on the human body induce increased levels of reactive oxygen and nitrogen species in divers’ bodies, which may modulate damage-associated molecular pattern (DAMPs), their receptors and the antioxidant response. This study involved 21 divers who descended to a depth of 40 metres. Determinations of selected intracellular DAMPs (high-mobility group box protein 1,HMGB1, S100 calcium-binding proteins A9 and A8, S100A8 and S100A9, heat shock protein family A member 1A, HSPA1A (Hsp70), heat shock protein family B, (small) member 1, HSPB1(Hsp27), thioredoxin, TXN), their receptors (Toll-like receptor 4, TLR4 and receptors for advanced glycation end products, RAGE), nuclear factor-κB (NF-κB) and antioxidant defence markers were performed before, after and 1 h after the dive. A significant transient reduction in HMGB1 expression was observed immediately after the dive at both the mRNA and protein levels. We noted an increase in S100A9 expression, which occurred 1 h post-dive compared to the post-dive time point, and a post-dive decrease in TLR4 expression only at the mRNA level. Diving also influenced the expression of genes encoding key enzymes associated with glutathione synthesis, (glutamate-cysteine ligase, catalytic subunit, GCLC and glutathione synthetase, GSS), and reduced plasma glutathione levels. However, no significant changes were observed in the expression of NF-κB, nitric oxide synthase 2 (NOS2) or circulating DAMP receptors (TLR4 and RAGE). The findings suggest an adaptive response to diving-induced oxidative stress, which appears to be a protective mechanism against an excessive inflammatory response. To our knowledge, this is the first study to analyse the role of intracellular DAMPs in recreational divers. Full article

The heat shock protein B8 (HSPB8) is one of the small heat shock proteins (sHSP or HSPB) and is a ubiquitous protein in various organisms, including humans. It is highly expressed in skeletal muscle, heart, and neurons. It plays a crucial role in identifying misfolding proteins and participating in chaperone-assisted selective autophagy (CASA) for the removal of misfolded and damaged, potentially cytotoxic proteins. Mutations in HSPB8 can cause distal hereditary motor neuropathy (dHMN), Charcot–Marie–Tooth (CMT) disease type 2L, or myopathy. The disease can manifest from childhood to mid-adulthood. Most missense mutations in the N-terminal and α-crystallin domains of HSPB8 lead to dHMN or CMT2L. Frameshift mutations in the C-terminal domain (CTD), resulting in elongation of the HSPB8 C-terminal, cause myopathy with myofibrillar pathology and rimmed vacuoles. Myopathy and motor neuropathy can coexist. HSPB8 frameshift mutations in the CTD result in HSPB8 mutant aggregation, which weakens the CASA ability to direct misfolded proteins to autophagic degradation. Cellular and animal models indicate that HSPB8 mutations drive pathogenesis through a toxic gain-of-function mechanism. Currently, no cure is available for HSPB8-associated neuromuscular disorders, but numerous therapeutic strategies are under investigation spanning from small molecules to RNA interference to exogenous HSPB8 delivery. Full article

Background: Within the past few years, many new therapies have emerged for psoriasis and psoriatic arthritis (PsA). Current topical therapies—including corticosteroids, vitamin D analogs, tapinarof, and roflumilast—remain the mainstay for mild disease, while oral systemic and biologic options are for moderate to severe cases. Biologics—such as Tumor necrosis factor-alpha (TNF-alpha), Interleukin 12/23 (IL-12/23), Interleukin-17 (IL-17), and Interleukin-23 (IL-23)—have revolutionized care by providing highly effective and safer alternatives. Oral small molecules, including Janus kinase (JAK) and tyrosine kinase 2 (TYK2) inhibitors, further expand the therapeutic options. Objectives: The goal for this review article was to examine current and latest treatments for psoriasis and PsA and discuss whether these emerging therapeutic options address the unmet needs of current treatments. Methods: The search for this review article included PubMed, Google Scholar, and ClinicalTrials.gov for relevant articles and current clinical trials using keywords. Results: A wide range of novel psoriatic and PsA therapies are currently undergoing clinical trials. These include selective JAK inhibitors, TYK2 inhibitors, retinoic acid-related orphan receptor (RORγT) inhibitors, oral IL-23 receptor inhibitors, oral IL-17A inhibitors, nanobody products, sphingosine-1-phosphate (S1P1R) antagonists, A3 adenosine receptor (A3AR) agonists, heat shock protein (HSP) 90 inhibitors, and rho-associated protein kinases (ROCK-2) inhibitors. Conclusions: These different mechanisms of action not only expand treatment options but may offer potential solutions for patients who do not achieve adequate response with existing therapies. However, the safety and contraindications of these newer agents remain an important consideration to ensure appropriate patient selection and minimize potential risks. Certain mechanisms may pose increased risks for infection, cardiovascular manifestations, malignancy, or other immune-related adverse events, necessitating careful monitoring and individualized treatment decisions. Ongoing clinical research aims to address unmet needs for patients who do not respond to previous agents to achieve sustained remission, monitor long-term safety outcomes, and assess patient preferences for delivery, including a preference for oral delivery. Oral IL-23 inhibitors hold potential due to their robust safety profiles. In contrast, oral IL-17 inhibitors and TYK-2 inhibitors are effective but may present side effects that could impact their acceptability. It is essential to balance efficacy, safety, and patient preferences to guide the selection of appropriate therapies. 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

Heat shock proteins (HSPs) are essential molecular chaperones that protect cells by aiding in protein folding and preventing aggregation under stress conditions. Small heat shock proteins (sHSPs), which include members from HSPB1 to HSPB10, are particularly important for cellular stress responses. These proteins share a conserved α-crystallin domain (ACD) critical for their chaperone function, with flexible N- and C-terminal extensions that facilitate oligomer formation. Phosphorylation, a key post-translational modification (PTM), plays a dynamic role in regulating sHSP structure, oligomeric state, stability, and chaperone function. Unlike other PTMs such as deamidation, oxidation, and glycation—which are often linked to protein destabilization—phosphorylation generally induces structural transitions that enhance sHSP activity. Specifically, phosphorylation promotes the disaggregation of sHSP oligomers into smaller, more active complexes, thereby increasing their efficiency. This disaggregation mechanism is crucial for protecting cells from stress-induced damage, including apoptosis, inflammation, and other forms of cellular dysfunction. This review explores the role of phosphorylation in modulating the function of sHSPs, particularly HSPB1, HSPB4, and HSPB5, and discusses how these modifications influence their protective functions in cellular stress responses. Full article

Ovarian torsion (OT) is a rare gynaecological emergency that requires a prompt diagnosis for optimal patient management. To determine whether there were any biomarkers suitable for the non-invasive detection of OT, two independent reviewers performed systematic searches of five literature databases (PubMed, Medline, Scopus, Cochrane, and CINAHL) from inception until October 1st, 2023. Following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, the search included patients with OT that had quantified biomarker expression with no age, geographical location, publication date, language, or setting restrictions. Articles were excluded if OT was found incidentally, was based on qualitative analyses, or were not primary research articles. Full texts of 23 selected articles were assessed for risk of bias and quality assurance using a modified Newcastle–Ottawa Scale (NOS) for clinical studies and SYRCLE’s risk of bias tool for the assessment of pre-clinical (animal) studies. A total of 11 articles described studies on animals and all described serum biomarkers comparing results between OT versus a sham operation, a control group, or readings before and after OT. Ischaemia-modified albumhumin (IMA), serum D-dimer (s-DD), heat shock protein-70 (hsp-70), Pentraxin-3 (PTX3), and c-reactive protein (CRP) each showed the most promise, with p-values for the difference between OT and control groups achieving ≤ 0.001. In studies of humans, the biomarkers ranged from 16.4 to 92.3% sensitivity and 77–100% specificity. The most promising biomarkers for the early prediction of OT in patients included s-DD, interleukin-6 (IL-6), IMA, and tumour necrosis factor-alpha (TNF-α). Signal peptide, CUB domain, and EGF-like domain-containing 1 (SCUBE1) had a high specificity at 93.3%, second only to s-DD and a positive likelihood ratio (LR) > 10. IMA was the only other biomarker that also had a positive LR > 10, making it a promising diagnostic biomarker. The studies identified by this systematic literature review each analysed small patient groups but IMA, DD, and SCUBE1 nevertheless showed promise as serum biomarkers with a pooled LR > 10. However, further well-designed studies are needed to identify and evaluate individual markers or diagnostic panels to help clinicians manage this important organ-threatening condition. Full article

Cotton fiber is one of the most important natural fiber sources in the world, and lipid metabolism plays a critical role in its development. However, the specific role of lipid molecules in fiber development and the impact of fatty acid alterations on fiber quality remain largely unknown. In this study, we demonstrate that the downregulation of GhROD1, a gene encoding phosphatidylcholine diacylglycerol cholinephosphotransferase (PDCT), results in an improvement of fiber fineness. We found that GhROD1 downregulation significantly increases the proportion of linoleic acid (18:2) in cotton fibers, which subsequently upregulates genes encoding small heat shock proteins (sHSPs). This, in turn, reduces H₂O₂ production, thus delaying secondary wall deposition and leading to finer fibers. Our findings reveal how alterations in linoleic acid influence cellulose synthesis and suggest a potential strategy to improve cotton fiber quality by regulating lipid metabolism pathways. Full article

High temperatures during the crop growing season are becoming more frequent and unpredictable, resulting in reduced crop productivity and quality. Heat stress disrupts plant metabolic processes that affect cell membrane composition and integrity. Cell membrane permeability, ion leakage, and heat shock proteins have been evaluated to screen for heat tolerance in plants. In potatoes, it is unclear whether leaf membrane stability under heat stress is correlated with underground tuber productivity and quality. The main goal of this study was to evaluate if leaf membrane relative electrolyte conductivity (REC) under high temperatures could be used to identify heat-tolerant potato genotypes. Electrolyte leakage assays, correlation estimations, and genome-wide association studies were carried out in 215 genotypes. Expression levels of small heat shock protein 18 (sHSP18) were evaluated in the heat-sensitive potato variety Russet Burbank and compared with those of the heat-tolerant variety Vanguard Russet using Western blotting. Significant differences were observed among genotypes for leaf membrane REC under extreme heat (50°C); REC values ranged from 47.0–99.5%. Leaf membrane REC was positively correlated with tuber external and internal defects and negatively correlated with yield. REC was negatively correlated with the content of several tuber minerals, such as nitrogen, magnesium, and manganese. Eleven quantitative trait loci (QTLs) were identified for leaf membrane REC, explaining up to 13.8% of the phenotypic variance. Gene annotation in QTL areas indicated associations with genes controlling membrane solute transport and plant responses to abiotic stresses. Vanguard Russet had lower leaf REC and higher expression of sHSP18 under high-temperature stress. Our findings indicate that leaf membrane REC under high temperatures can be used as an indicator of potato heat tolerance. Full article

Chickpeas (Cicer arietinum L.) are an important legume crop known for their rich nutrient content, including proteins, carbohydrates, and minerals. Thus, they are enjoyed by people worldwide. In recent years, the production scale of chickpeas has been growing gradually. The planting area of chickpeas represents roughly 35–36% of the total planting area, and the output of the beans is roughly 47–48%. However, the growth and development process of chickpeas is limited by a number of factors, including high temperature, drought, salt stress, and so forth. In particular, high temperatures can reduce the germination rate, photosynthesis, seed setting rate, and filling rate of chickpeas, restricting seed germination, plant growth, and reproductive growth. These changes lead to a decrease in the yield and quality of the crop. Heat shock proteins (HSPs) are small proteins that play an important role in plant defense against abiotic stress. Therefore, in the present study, HSP20 gene family members were identified based on the whole-genome data of chickpeas, and their chromosomal positions, evolutionary relationships, promoter cis-acting elements, and tissue-specific expression patterns were predicted. Subsequently, qRT-PCR was used to detect and analyze the expression characteristics of HSP20 genes under different temperature stress conditions. Ultimately, we identified twenty-one HSP20 genes distributed on seven chromosomes, and their gene family members were found to be relatively conserved, belonging to ten subfamilies. We also found that CaHSP20 promoter regions have many cis-acting elements related to growth and development, hormones, and stress responses. In addition, under high-temperature stress, the relative expression of CaHSP20-17, CaHSP20-20, CaHSP20-7, CaHSP20-3, and CaHSP20-12 increased hundreds or even thousands of times as the temperature increased from 25 °C to 42 °C. Among them, excluding CaHSP20-5, the other five genes all contain 1-2 ABA cis-regulatory elements. This finding indicates that CaHSP20s are involved in the growth and development of chickpeas under heat stress, and the mechanisms of their responses to high-temperature stress may be related to hormone regulation. The results of the present study lay the foundation for exploring HSP20 gene family resources and the molecular mechanisms of heat resistance in chickpeas. Our results can also provide a theoretical basis for breeding high-temperature-resistant chickpea varieties and provide valuable information for the sustainable development of the global chickpea industry. Full article

Forty castrated Holstein calves underwent an adrenocorticotropic hormone (ACTH) challenge to assess the effects of premortem stress on the longissimus lumborum (LL) following harvest. LL biopsies were collected before the challenge, at different harvest times (2, 12, 24, and 48 h; n = 10), and after 14 d aging. The expression of small heat shock proteins (SHSPs), deglycase 1 (DJ-1), and troponin were analyzed. Blood was analyzed throughout the ACTH challenge and at harvest for cortisol, oxidative stress, and complete blood count (CBC). Color and myofibrillar fragmentation index (MFI) were measured in aged samples. Unexpectedly, calves from different harvest times differed (p = 0.05) in cortisol response. Calves were divided into two different cortisol response groups (high or low; n = 20). Statistical analysis assessed the effects of cortisol response (n = 20), harvest time (n = 10), and their interaction. Harvest time altered SHSPs (p = 0.03), DJ-1 (p = 0.002), and troponin (p = 0.02) expression. Harvest time and cortisol response impacted steak color (p < 0.05), and harvest time altered steak pH (p < 0.0001). Additionally, various CBCs were changed (p < 0.05) by harvest time. Harvest time changed (p = 0.02) MFI. These data demonstrate that the protein expression, color, and MFI of the LL may be influenced by premortem stress. Full article

The diagnosis of cardiovascular disease (CVD) is still limited. Therefore, this study demonstrates the presence of human ether-a-go-go-related gene 1 (hERG1) and heat shock protein 47 (Hsp47) on the surface of small extracellular vesicles (sEVs) in human peripheral blood and their association with CVD. In this research, 20 individuals with heart failure and 26 participants subjected to cardiac stress tests were enrolled. The associations between hERG1 and/or Hsp47 in sEVs and CVD were established using Western blot, flow cytometry, electron microscopy, ELISA, and nanoparticle tracking analysis. The results show that hERG1 and Hsp47 were present in sEV membranes, extravesicularly exposing the sequences ⁴³⁰AFLLKETEEGPPATE⁴⁴⁵ for hERG1 and ¹⁶⁹ALQSINEWAAQTT- DGKLPEVTKDVERTD¹⁹⁶ for Hsp47. In addition, upon exposure to hypoxia, rat primary cardiomyocytes released sEVs into the media, and human cardiomyocytes in culture also released sEVs containing hERG1 (EV-hERG1) and/or Hsp47 (EV-Hsp47). Moreover, the levels of sEVs increased in the blood when cardiac ischemia was induced during the stress test, as well as the concentrations of EV-hERG1 and EV-Hsp47. Additionally, the plasma levels of EV-hERG1 and EV-Hsp47 decreased in patients with decompensated heart failure (DHF). Our data provide the first evidence that hERG1 and Hsp47 are present in the membranes of sEVs derived from the human cardiomyocyte cell line, and also in those isolated from human peripheral blood. Total sEVs, EV-hERG1, and EV-Hsp47 may be explored as biomarkers for heart diseases such as heart failure and cardiac ischemia. Full article