Heat Shock Protein Research Articles

Effect of Heat Stress on the Expression of Circulating Cyto(chemo)kine and Inflammatory Markers in Broiler Chickens Selected for High- or Low-water Efficiency.

Water scarcity is a current, significant global concern that will only increase under the pressure of climate change. Improving water efficiency of poultry is a new and promising area to help temper agriculture's future impact on fresh water availability. Here, we explored the effects of acute heat stress (HS) on circulating stress and inflammatory markers in 2 lines of broilers divergently selected for water efficiency. Male chicks from low (LWE) and high water efficient (HWE) lines were raised in 12 environmental chambers (2 pens/chamber, 6 chambers/line, 20 birds/pen) under normal conditions until day 28. On day 29, birds were subjected to thermoneutral (TN, 25 °C) or HS (36 °C) conditions, resulting in four treatments (2 lines × 2 environmental conditions). After 3 h of HS, whole blood was collected (8 birds per line × environment) and analyzed for target gene expression and plasma cytokine levels. Data were analyzed by 2-way ANOVA, with line, environment, and their interaction as main factors, and means were compared using Tukey's multiple range test. Gene expression of heat shock protein (HSP) 27, HSP70, interleukin (IL)-6, IL-18, c-reactive protein (CRP), tumor necrosis factor-α (TNFα), C-C motif chemokine ligand 4 (CCL4), CCL20, nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3), NLR family CARD domain containing 5 (NLRC5), and NLR family member X1 (NLRX1) were increased by HS, with no differences between the lines. HSP70, IL-10, and NLRC3 were lower in the HWE as compared to the LWE lines. Additionally, there were interactive effects between line and environment for HSP90, IL-4, and CCL4, where HS induced HSP90 expression in the LWE only, and IL-4 and CCL4 in HWE only. Arginine vasopressin (AVP) gene expression was significantly lower in the whole blood of the HWE line; however, plasma protein levels were not different. Overall, most of the effects seen on cyto (chemokines) and inflammatory markers were due to acute HS, with only a few genes differentially regulated between the lines. This likely indicates that the divergent selection for water efficiency for four generations did not elicit changes in inflammation and stress molecular signatures.

Mesenchymal stromal cells deliver H2S-enhanced Nrf2 via extracellular vesicles to mediate mitochondrial homeostasis for repairing hypoxia-ischemia brain damage

Mesenchymal stromal cells (MSCs) are considered a therapeutic approach for neurological diseases via extracellular vesicles (EVs). Modified EVs contain active components with enhanced therapeutic potential. In this study, we aimed to explore the role and underlying mechanism of EVs from MSCs preconditioned by NaHS (an Hydrogen sulfide donor) (H2S-EVs) in hypoxia-ischemia (HI) brain damage. Our results showed that H2S-EVs treatment via the non-invasive intranasal route in HI mice was able to reduce oxidative stress and mitochondrial dysfunction compared to EVs treatment. Mechanistic studies demonstrated that NaHS promoted nuclear factor erythroid-2 related factor 2 (Nrf2) expression in the cytoplasm by inducing Parkinson disease protein 7 (PARK7)‐dependent disintegration of Nrf2/Keap-1 complex in MSCs. In particular, the free Nrf2 was loaded into the EVs as a result of its KFERQ motif being recognized by 70-kDa heat shock proteins and lysosomal-associated membrane protein 2A. Subsequently, H2S-EVs were internalized into neurons in the ipsilateral hemisphere, thus delivering abundant Nrf2 to accumulate in the mitochondria and remodeling mitochondrial function following H2S-EVs treatment in HI mice. Moreover, Nrf2 knockdown in MSCs remarkably impaired H2S-EVs-mediated therapeutic effects on HI mice. In brief, the present study for the first time demonstrated that H2S-modified MSCs significantly accumulated higher Nrf2 in EVs via upregulating PARK7 expression, revealing the mechanism through which antioxidant protein Nrf2 delivered by H2S-EVs protect against mitochondrial dysfunction in HI brain damage.

Reengineering of Donor-Acceptor-Donor Structured Near-Infrared II Aggregation-Induced Emission Luminogens for Starving-Photothermal Antitumor and Inhibition of Lung Metastasis.

Electron acceptor possessing strong electron-withdrawing ability and exceptional stability is crucial for developing donor-acceptor-donor (D-A-D) structured aggregation-induced emission luminogens (AIEgens) with second near-infrared (NIR-II) emission. Although 6,7-diphenyl-[1,2,5] thiadiazolo [3,4-g] quinoxaline (PTQ) and benzobisthiadiazole (BBT) are widely employed as NIR-II building blocks, they still suffer from limited electron-withdrawing capacity or inadequate chemo-stability under alkaline conditions. Herein, a boron difluoride formazanate (BFF) acceptor is utilized to construct NIR-II AIEgen, which exhibits a better overall performance in terms of NIR-II emission and chemo-stability compared to the PTQ- and BBT-derived fluorophores. With finely tuned intramolecular motions and strong D-A interaction strength, TPE-BFF simultaneously exhibits high molar extinction coefficient (ε= 4.31 × 104 M-1cm-1), strong NIR-II emission (Φ = 0.49%) and photothermal effect (η = 58.5%), as well as high stability. Thanks to these merits, the thermosensitive nanoparticles constructed by integrating TPE-BFF and the antiglycolytic agent 2-deoxy-d-glucose (2DG) are successfully utilized for imaging-guided photothermal antitumor lung metastasis by regulating glycolysis and reducing ATP-dependent heat shock proteins. Combining experimental results and theoretical calculations, BFF proves to be an outstanding electron acceptor for the design of versatile NIR-II AIEgens. Overall, this study offers a promising alternative for developing multifunctional NIR-II AIEgens in biomedical applications.

DNAJC13 influences responses of the extended reward system to conditioned stimuli: a genome-wide association study.

Reward system dysfunction is implicated in the pathogenesis of major psychiatric disorders. We conducted a genome-wide association study (GWAS) to identify genes that influence activation strength of brain regions within the extended reward system in humans. A homogeneous sample of 214 participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All subjects performed the 'desire-reason dilemma' (DRD) paradigm allowing systematic investigation of systems-level mechanisms of reward processing in humans. As a main finding, we identified the single nucleotide variant rs113408797 in the DnaJ Heat Shock Protein Family Member C13 gene [DNAJC13], alias Receptor-Mediated Endocytosis 8 [RME-8], that was associated with the activation strength of the ventral tegmental area (VTA; p = 2.50E-07) and the nucleus accumbens (NAcc; p = 5.31E-05) in response to conditioned reward stimuli. Moreover, haplotype analysis assessing the information across the entire DNAJC13 locus demonstrated an impact of a five-marker haplotype on VTA activation (p = 3.21E-07), which further corroborates a link between this gene and reward processing. The present findings provide first direct empirical evidence that genetic variation of DNAJC13 influences neural responses within the extended reward system to conditioned stimuli. Further studies are required to investigate the role of this gene in the pathogenesis and pathophysiology of neuropsychiatric disorders.

Impact of Platelet-Rich Plasma on Sciatic Nerve Injury in Rats: HSP 70 Expression and Histological Changes in the Anterior Horn of the Spinal Cord

Peripheral nerve injuries are a significant and growing cause of disability worldwide, as reported by the World Health Organization (WHO). These injuries initiate complex cellular and molecular responses, including the activation of protective pathways that upregulate proteins such as Heat Shock Protein 70 (HSP 70), which plays a crucial role in neuroprotection and the inhibition of neuronal apoptosis. This study investigates the effects of Platelet-Rich Plasma (PRP) on peripheral nerve regeneration, focusing on neuron density, Nissl body presence, and HSP 70 expression as key indicators of recovery. The study utilized 36 rat spinal cord samples, divided into two main groups based on the evaluation time points, day 7 and day 42 post-injury. Each time point group was further subdivided into three: control, sciatica injury, and sciatica injury treated with PRP. Results demonstrated that PRP treatment significantly enhances peripheral nerve regeneration. This was evidenced by increased neuron density, improved Nissl body formation, and a modulation of HSP 70 expression levels, leading to accelerated recovery of motor function, particularly noticeable by day 7 post-injury. These findings suggest that PRP could be a promising therapeutic option for enhancing nerve regeneration and functional recovery after peripheral nerve injuries.

Brain-derived neurotrophic factor in older adults exposed to simulated indoor overheating.

Brain-derived neurotrophic factor (BDNF) is a neuroprotective growth factor that increases in young adults during short, intense bouts of passive heat stress. However, this may not reflect the response in heat-vulnerable populations exposed to air temperatures more consistent with indoor overheating during hot weather and heatwaves, especially as the BDNF response to acute stressors may diminish with increasing age.We therefore evaluated the ambient and body temperature-dependent responses of BDNF inolder adults during daylong passive heating. Sixteenolder adults (6 females; aged 66-78years) completed 8-h exposure to four randomized ambient conditions simulating those experienced indoors during hot weather and heatwaves in continental climates: 22°C (air-conditioning; control), 26°C (health-agency-recommended indoor temperature limit), 31°C, and 36°C (non-airconditioned home); all 45% relative humidity. To further investigate upstream mechanisms of BDNF regulation during thermal strain, we also explored associations between BDNF and circulating heat shock protein 70 (HSP70; taken as an indicator of the heat shock response). Circulating BDNF was elevated by ~ 28% (1139 [95%CI: 166, 2112] pg/mL) at end-exposure in the 36°C compared to the 22°C control condition (P = 0.026; 26°C-and 31°C-22°C differences: P ≥ 0.090), increasing 90 [22, 158] pg/mL per 1°C rise in ambient temperature (linear trend: P = 0.011). BDNF was also positively correlated with mean body temperatures (P = 0.013), which increased 0.12 [0.10, 0.13]°C per 1°C rise in ambient temperature (P < 0.001). By contrast, serum HSP70 did not change across conditions (P ≥ 0.156), nor was it associated with BDNF (P = 0.376). Our findings demonstrate a progressive increase in circulating BDNF during indoor overheating in older adults.

Heat shock responsive genes in Brassicaceae: genome-wide identification, phylogeny, and evolutionary associations within and between genera.

Heat stress affects the growth and development of Brassicaceae crops. Plant breeders aim to mitigate the effects of heat stress by selecting for heat stress tolerance, but the genes responsible for heat stress in Brassicaceae remain largely unknown. During heat stress, heat shock proteins (HSPs) function as molecular chaperones to aid in protein folding, and heat shock transcription factors (HSFs) serve as transcriptional regulators of HSP expression. We identified 5002 heat shock related genes, including HSPs and HSFs, across 32 genomes in Brassicaceae. Among these, 3347 genes were duplicated, with segmented duplication primarily contributing to their expansion. We identified 466 physical gene clusters, including 240 homogenous clusters and 226 heterogeneous clusters, shedding light on the organization of heat shock related genes. Notably, 37 genes were co-located with published thermotolerance quantitative trait loci, which supports their functional role in conferring heat stress tolerance. This study provides a comprehensive resource for the identification of functional Brassicaceae heat shock related genes, elucidates their clustering and duplication patterns and establishes the genomic foundation for future heat tolerance research. We hypothesise that genetic variants in HSP and HSF genes in certain species have potential for improving heat stress tolerance in Brassicaceae crops.

Effect of cuproptosis on acute kidney injury after cardiopulmonary bypass in diabetic patients

BACKGROUND Cardiopulmonary bypass (CPB) is a common procedure in cardiac surgery. CPB is a high-risk factor for acute kidney injury (AKI), and diabetes is also such a factor. Diabetes can lead to copper overload. It is currently unclear whether AKI after CPB in diabetic patients is related to copper overload. AIM To explore whether the occurrence of CPB-AKI in diabetic patients is associated with cuproptosis. METHODS Blood and urine were collected from clinical diabetic and non-diabetic patients before and after CPB. Levels of copper ion, lactate, glucose, heat shock protein-70 (HSP-70), and dihydrolipoamide dehydrogenase (DLAT) were determined. A diabetic rat model was established and CPB was performed. The rats were assessed for the development of CPB-AKI, and for the association of AKI with cuproptosis by detecting copper levels, iron-sulfur cluster proteins and observation of mitochondrial structure by electron microscopy. RESULTS CPB resulted in elevations of copper, lactate, HSP-70 and DLAT in blood and urine in both diabetic and non-diabetic patients. CPB was associated with pathologic and mitochondrial damage in the kidneys of diabetic rats. Cuproptosis-related proteins also appeared to be significantly reduced. CONCLUSION CPB-AKI is associated with cuproptosis. Diabetes mellitus is an important factor aggravating CPB-AKI and cuproptosis.

Comprehensive Transcriptomic Analysis Reveals Defense-Related Genes and Pathways of Rice Plants in Response to Fall Armyworm (Spodoptera frugiperda) Infestation.

Rice (Oryza sativa L.) serves as a substitute for bread and is a staple food for half of the world's population, but it is heavily affected by insect pests. The fall armyworm (Spodoptera frugiperda) is a highly destructive pest, threatening rice and other crops in tropical regions. Despite its significance, little is known about the molecular mechanisms underlying rice's response to fall armyworm infestation. In this study, we used transcriptome analysis to explore the global changes in gene expression in rice leaves during a 1 h and 12 h fall armyworm feeding. The results reveal 2695 and 6264 differentially expressed genes (DEGs) at 1 and 12 h post-infestation, respectively. Gene Ontology (GO) and KEGG enrichment analyses provide insights into biological processes and pathways affected by fall armyworm feeding. Key genes associated with hormone regulation, defense metabolic pathways, and antioxidant and detoxification processes were upregulated, suggesting the involvement of jasmonic acid (JA) signaling, salicylic acid biosynthesis pathways, auxin response, and heat shock proteins in defense during 1 h and 12 h after fall armyworm infestation. Similarly, key genes involved in transcriptional regulation and defense mechanisms reveal the activation of calmodulins, transcription factors (TFs), and genes related to secondary metabolite biosynthesis. Additionally, MYB, WRKY, and ethylene-responsive factors (ERFs) are identified as crucial TF families in rice's defense response. This study provides a comprehensive understanding of the molecular dynamics in rice responding to fall armyworm infestation, offering valuable insights for developing pest-resistant rice varieties and enhancing global food security. The identified genes and pathways provide an extensive array of genomic resources that can be used for further genetic investigation into rice herbivore resistance. This also suggests that rice plants may have evolved strategies against herbivorous insects. It also lays the groundwork for novel pest-resistance techniques for rice.

MC-LR disrupts dopamine synthesis in the substantia nigra of midbrain by enhancing the chaperone-mediated autophagy pathway through direct binding to ERK2

Microcystins are environmental toxins produced by freshwater cyanobacteria. Microcystin-LR (MC-LR) is one of the most abundant and harmful isomers. MC-LR poses a serious threat to human health. MC-LR could penetrate the blood-brain barrier of mice and accumulate in the substantia nigra (SN) of the midbrain, leading to a reduction in dopamine levels and Parkinson's disease (PD)-like motor dysfunction in mice. The reduction in dopamine levels is a key factor contributing to movement disorders in humans with PD. Dopamine is synthesized in the dopaminergic neurons of the SN by the actions of tyrosine hydroxylase (TH) and dihydroxyphenylalanine decarboxylase (DDC). In this study, we found that MC-LR could enter dopaminergic neurons in the SN and directly bound to extracellular signal-regulated kinase 2 (ERK2), enhancing ERK2 stability. ERK2 further enhanced the transcriptional activity of Heat Shock Protein Family A Member 8 (HSPA8) and promoted the expression of Heat shock cognate 71 kDa protein (HSC70), which in turn amplified the chaperone-mediated autophagy (CMA) pathway and accelerated the degradation of TH and DDC. This affected the dopamine synthesis process, resulting in a significant reduction in dopamine levels. The study is the first to reveal that ERK2 was a direct target of MC-LR, and further enhanced CMA affecting dopamine synthesis, which has important theoretical and practical significance for environmental safety management.

Expression analysis of the apple HSP70 gene family in abiotic stress and phytohormones and expression validation of candidate MdHSP70 genes

Heat shock protein 70 (HSP70) is one kind of molecular chaperones which are widely found in organisms, and its members are highly conserved among each other, with important roles in plant growth and development. In this study, 56 HSP70 genes were identified from the apple genome database. Analysis of gene duplication events showed that tandem and segmental duplication events play an important role in promoting the amplification of the MdHSP70 gene family. Collinearity analysis showed that HSP70 family members of apple were more closely related to HSP70 family members of Arabidopsis, tomato and soybean. The promoter region of the apple HSP70 genes contains a large number of cis-acting elements in response to hormones and stress. Tissue-specific expression analysis showed that some of the genes were associated with various stages of the apple growth process. Codon preference analysis showed small differences between codon bases 1 and 3 in the apple HSP70 genome, and the codon base composition had a small effect on codon usage preference. The multiple expression patterns of the MdHSP70 gene suggested that MdHSP70 gene members play important roles in growth and development and in response to hormonal and abiotic stresses. The yeast two-hybrid (Y2H) demonstrated that MdHSP70-53 interacts with MdDVH24_032563. The qRT-PCR analysis showed that most MdHSP70 members’ hormonal and abiotic stresses (MdHSP70-6, MdHSP70-26 and MdHSP70-45) appeared to be highly expressed. To further elucidate the function of MdHSP70 (6, 26, 45), we introduced them into tobacco to confirm subcellular locations and noted that these genes are located in the cytoplasm and cell membrane. This study serves as a theoretical basis for further studies of the MdHSP70 gene and helps to further investigate the functional characterization of MdHSP70 gene.

Genotype-phenotype correlation in recessive DNAJB4 myopathy.

Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547C > T, p.R183*; c.775C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181A > G, p.R61G). All patients were homozygous. All affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype-phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J-domain may predict a more severe phenotype.

The arylbipyridine platinum (II) complex increases the level of ROS and induces lipid peroxidation in glioblastoma cells.

Here we present the biological properties of the arylbipyridine platinum (II) complex (arylbipy-Pt) and describe the potential mechanism of its antitumor action which differs from that of the well-known cisplatin. Leading to the oxidative stress and lipid peroxidation, the arylbipyridine platinum (II) complex showcases the significant cytotoxicity against the glioblastoma cells as shown by the MTT test. Using the 5-ethyl-2-deoxyuridine we study the proliferative activity of glioblastoma cells to affirm that arylbipyridine platinum (II) complex does not impede cell division or DNA replication. Staining by the MitoCLox dye and 2',7'-dichlorodihydrofluorescein diacetate demonstrates that the glioblastoma cells treated with arylbipy-Pt exhibit a strong increase of the lipid peroxidation and the stimulation of the reactive oxygen species formation. The hypothesis that arylbipy-Pt promotes oxidative death of tumor cells is confirmed by control experiments using N-acetyl-L-cysteine as an antioxidant. Further evidence for the oxidative mechanism of action is provided by real-time PCR, which shows high expression levels for genes associated with the heat shock proteins HSP27 and HSP70, which can be used as markers of tumor cell ferroptosis. To elucidate the chemical nature of the arylbipy-Pt complex activity, we perform 195Pt NMR spectroscopy and cyclic voltammetry measurements under biologically relevant conditions. The results obtained clearly indicate the structural transformation of the arylbipy-Pt complex in the DMSO-saline mixture, which is crucial for its further antitumor activity via the oxidative pathway. The found correlation between the molecular structure of arylbipy-Pt and its effect on the tumor cell cycle paves the way for the rational design of Pt complexes possessing the alternative mechanism of antitumor activity as compared to DNA intercalation, providing possible solutions to the major problems such as toxicity and drug resistance.

Novel ultrathin ferrous sulfide nanosheets: Towards replacing black phosphorus in anticancer nanotheranostics

Biodegradable two-dimensional nanomaterials could be a significant breakthrough in the field of oncology nanotheranostic agents, which are rapidly emerging as promising candidates for tumor theranostic applications. Herein, a novel biodegradable ferrous sulfide nanosheet (FeS NS) is developed. Compared to the traditional photothermal material, black phosphorus nanosheet (BP NS), FeS demonstrates superior degradability and enhanced photothermal performance, and making it ideal for efficient photothermal therapy (PTT) of tumors. In the acidic tumor microenvironment, FeS degrades and releases H2S, which inhibits mitochondrial respiration and ATP production. This process leads to a reduction in heat shock protein expression, lowering the resistance of tumor cells to photothermal stimulation, and improving the efficacy of PTT. The released Fe2+ exhibits efficient peroxidase activity, triggering ferroptosis in tumor cells. Furthermore, due to its superparamagnetic nature, FeS NSs could accumulate at the tumor site and provide a strong magnetic resonance imaging (MRI) signal for imaging-guided tumor therapy. Overall, as a promising alternative to BP, the FeS NSs are a potentially innovative nanotheranostic agent of tumors, offering a synergistic approach to ferroptosis−PTT with MRI guidance.

Implications of Lead (Pb)-Induced Transcriptomic and Phenotypic Alterations in the Aged Zebrafish (Danio rerio).

Lead (Pb) is a well-known neurotoxin with established adverse effects on the neurological functions of children and younger adults, including motor, learning, and memory abilities. However, its potential impact on older adults has received less attention. Using the zebrafish model, our study aims to characterize the dose-response relationship between environmentally relevant Pb exposure levels and their effects on changes in behavior and transcriptomics during the geriatric periods. We exposed two-year-old zebrafish to waterborne lead acetate (1, 10, 100, 1000, or 10,000 µg/L) or a vehicle (DMSO) for 5 days. While lower concentrations (1-100 µg/L) reflect environmentally relevant Pb levels, higher concentrations (1000-10,000 µg/L) were included to assess acute toxicity under extreme exposure scenarios. We conducted adult behavior assessment to evaluate the locomotor activity following exposure. The same individual fish were subsequently sacrificed for brain dissection after a day of recovery in the aquatic system. RNA extraction and sequencing were then performed to evaluate the Pb-induced transcriptomic changes. Higher (1000-10,000 ug/L) Pb levels induced hyperactive locomotor patterns in aged zebrafish, while lower (10-100 ug/L) Pb levels resulted in the lowest locomotor activity compared to the control group. Exposure to 100 µg/L led to the highest number of differentially expressed genes (DEGs), while 10,000 µg/L induced larger fold changes in both directions. The neurological pathways impacted by Pb exposure include functions related to neurotransmission, such as cytoskeletal regulation and synaptogenesis, and oxidative stress response, such as mitochondrial dysfunction and downregulation of heat shock protein genes. These findings emphasize a U-shape dose-response relationship with Pb concentrations in locomotor activity and transcriptomic changes in the aging brain.

Promising predictors of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus

BackgroundDiabetic peripheral neuropathy (DPN) in children and adolescents with type 1 diabetes mellitus (T1DM) is a growing issue, with controversial data in the terms of prevalence and evaluation timelines. Currently, there are no clear standards for its early detection. Therefore, our aim was to assess the contribution of the Michigan neuropathy screening instrument (MNSI), lipid profile, serum neuron specific enolase (NSE), and serum heat shock protein 27 (HSP 27) to the prediction of DPN in children and adolescents with T1DM.MethodsIn this case-control study, fifty children diagnosed with T1DM for at least five years were enrolled and evaluated through complete neurological examination, MNSI, and nerve conduction study (NCS). Additionally, HbA1c, lipid profile, serum NSE, and serum HSP 27 levels were measured for patients and controls.ResultsThe prevalence of DPN in our study was 24% by NCS, and electrophysiological changes showed a statistically significant lower conduction velocity for the posterior tibial and sural nerves, as well as a prolonged latency period for the common peroneal and sural nerves in neuropathic patients. In these patients, older age, earlier age of diabetes onset, longer disease duration, higher total cholesterol, triglycerides, low density lipoprotein cholesterol, HbA1c, serum NSE, and HSP27 levels were observed. The MNSI examination score ≥ 1.5 cutoff point had an area under the curve (AUC) of 0.955, with 75% sensitivity and 94.74% specificity, according to receiver operating characteristic curve analysis. However, the questionnaire’s cutoff point of ≥ 5 had an AUC of 0.720, 75% sensitivity, and 63% specificity, with improved overall instrument performance when combining both scores. Regarding blood biomarkers, serum NSE had greater sensitivity and specificity in discriminating neuropathic patients than HSP27 (92% and 74% versus 75% and 71%, respectively). Regression analysis revealed a substantial dependency for MNSI and serum NSE in predicting DPN in patients.ConclusionsDespite limited research in pediatrics, MNSI and serum NSE are promising predictive tools for DPN in children and adolescents with T1DM, even when they are asymptomatic. Poor glycemic control and lipid profile changes may play a critical role in the development of DPN in these patients, despite conflicting results in various studies.

Improving the diffraction quality of heat-shock protein 47 crystals.

Heat-shock protein 47 (HSP47) is a potential target for inhibitors that ameliorate fibrosis by reducing collagen assembly. In an effort to develop a structure-based drug-design system, it was not possible to replicate a previous literature result (PDB entry 4au4) for apo dog HSP47; instead, crystal forms were obtained in which pairs of dog HSP47 molecules interacted through a noncleavable C-terminal His-tag to build up tetramers, all of which had multiple molecules of HSP47 in the asymmetric unit and none of which diffracted as wellas the literature precedent. To overcome these difficulties, a two-pronged approach was followed: (i) the His-tag was moved from the C-terminus to the N-terminus and was made cleavable, and (ii) Adnectin (derived from the tenth domain of human fibronectin type III) crystallization chaperones were developed. Both approaches provided well diffracting crystals, but the latter approach yielded crystal forms with only one or two HSP47 complexes per asymmetric unit, which made model building less onerous.

Precision Photothermal Therapy at Mild Temperature: NIR-II Imaging-Guided, H2O2-Responsive Stealth Nanobomb.

The therapeutic efficacy of photothermal therapy (PTT) under mild temperatures (<45°C) is hindered as cancer cells can activate heat shock proteins (HSPs) to mend fever-type cellular damage swiftly. The previous attempt fabricated first-generation nanobombs (nanobomb1G) by self-assembly of polymeric NIR-II AIEgens and carbon monoxide (CO) carrier polymer mPEG(CO) to inhibit the expression of HSPs after intratumor injection. A new generation nanobomb (Stealth NanoBomb (SNB)) is developed by self-assembling small molecular NIR-II AIEgens with CO carrier polymer PLGA(CO) coated by PEG-lipid. This design allows for intravenous administration, enabling the SNB to circulate safely in the bloodstream and selectively target cancer cells. Upon accumulation in tumors, the SNB releases CO to effectively suppress HSP expression, enhancing the therapeutic efficacy of mild-temperature PTT. Compared to the previous generation, the SNB offers a safer, more stable, and more efficient CO gas/drug co-delivery system for cancer treatment. This work represents a significant advancement in PTT, providing a promising strategy for enhanced antitumor therapy with reduced systemic toxicity.

Fluoride stimulates the MAPK pathway to regulate endoplasmic reticulum stress and heat shock proteins to induce duodenal toxicity in chickens

Fluoride is one of the essential trace elements for body. However, excessive fluoride poses a major threat to human and animal health. Fluorosis may cause pathological damage of the duodenum, but the underlying mechanism needs to be further studied. This study was to investigate the effects of long-term exposure to sodium fluoride (0, 500, 1,000, 2,000 mg/kg) on the duodenum of chickens. The results showed that after NaF exposure, intestinal epithelial cells were disarranged, necrotic or even exfoliated, goblet cells and mucus secretion were increased, and inflammatory response was induced in duodenal tissue. Oxidative stress, endoplasmic reticulum stress (ERs), and heat shock proteins (HSPs) are an adaptive response, however long-term, excessive changes are detrimental. Fluorosis activates ERs through IRE1, PERK and ATF6 pathways, increases the expression of HSP60, HSP70 and HSP90, and causes apoptosis and oxidative damage in duodenal tissue. In addition, fluorosis can activate the MAPK signaling pathway. This article can provide a reference for exploring the potential duodenal toxicity of sodium fluoride.

Transcriptomic Analysis of the Response of the Dioryctria abietella Larva Midgut to Bacillus thuringiensis 2913 Infection.

Dioryctria abietella Denis Schiffermuller (Lepidoptera: Pyralidae) is an oligophagous pest that mainly damages Pinaceae plants. Here, we investigated the effects of the Bacillus thuringiensis 2913 strain (Bt 2913), which carries the Cry1Ac, Cry2Ab, and Vip3Aa genes, on the D. abietella midgut transcriptome at 6, 12, and 24 h after infection. In total, 7497 differentially expressed genes (DEGs) were identified from the midgut transcriptome of D. abietella larvae infected with Bt 2913. Among these DEGs, we identified genes possibly involved in Bt 2913-induced perforation of the larval midgut. For example, the DEGs included 67 genes encoding midgut proteases involved in Cry/Vip toxin activation, 74 genes encoding potential receptor proteins that bind to insecticidal proteins, and 19 genes encoding receptor NADH dehydrogenases that may bind to Cry1Ac. Among the three transcriptomes, 88 genes related to metabolic detoxification and 98 genes related to immune defense against Bt 2913 infection were identified. Interestingly, 145 genes related to the 60S ribosomal protein were among the DEGs identified in the three transcriptomes. Furthermore, we performed bioinformatic analysis of zonadhesin, GST, CYP450, and CarE in the D. abietella midgut to determine their possible associations with Bt 2913. On the basis of the results of this analysis, we speculated that trypsin and other serine proteases in the D. abietella larval midgut began to activate Cry/Vip prototoxin at 6 h to 12 h after Bt 2913 ingestion. At 12 h after Bt 2913 ingestion, chymotrypsin was potentially involved in degrading the active core fragment of Vip3Aa toxin, and the detoxification enzymes in the larvae contributed to the metabolic detoxification of the Bt toxin. The ABC transporter and several other receptor-protein-related genes were also downregulated to increase resistance to Bt 2913. However, the upregulation of 60S ribosomal protein and heat shock protein expression weakened the resistance of larvae to Bt 2913, thereby enhancing the expression of NADH dehydrogenase and other receptor proteins that are highly expressed in the larval midgut and bind to activating toxins, including Cry1Ac. At 24 h after Bt 2913 ingestion, many activated toxins were bound to receptor proteins such as APN in the larval midgut, resulting in membrane perforation. Here, we clarified the mechanism of Bt 2913 infection in D. abietella larvae, as well as the larval immune defense response to Bt 2913, which provides a theoretical basis for the subsequent control of D. abietella using B. thuringiensis.