Expression Of Heat Shock Protein Research Articles

Diethylhexyl phthalate induces immune dysregulation and is an environmental immune disruptor

Diethylhexyl phthalate (DEHP) is the most abundant phthalate compound in the environment, and has been linked with multiple human diseases. The immune system is closely associated with the occurrence and progression of various diseases. However, minimal research has addressed the impact of DEHP on the immune system. In this study, single-cell RNA sequencing was performed using spleen tissue of mice to comprehensively determine alterations of the immune system in response to DEHP. The results showed that DEHP exposure reduced the absolute number of peripheral white blood cells (WBCs), including lymphocytes, monocytes, eosinophils, basophils, and neutrophils in mice. In addition, scRNA-seq analyses showed that inflammatory signaling and the expression of heat shock proteins (HSPs) were reduced in all peripheral immune cell populations. Furthermore, we established a mice cecal ligation and puncture (CLP) model, and showed that DEHP exacerbated sepsis-induced immunosuppression and organ damage. These results suggest that DEHP is an environmental immune disruptor that undermines the immune system, exacerbating acute infections and organ damage. Our findings offer a novel perspective on the hazards of DEHP to human health.

MMP-2 Responsive Gold Nanorods Loaded with HSP-70 siRNA for Enhanced Photothermal Tumor Therapy.

Gold nanorods (Au NRs) are a valuable photothermal nanomaterial for tumor therapy. However, when treated with Au NRs for photothermal therapy, the expression of heat shock proteins in tumors will increase, which will induce heat resistance in tumor cells and reduce the photothermal therapeutic effect of Au NRs. By RNA interference, the expression of heat shock proteins would be effectively inhibited to improve the efficasy of tumor photothermal therapy. However, deep and noninvasive tissue penetration remains a great obstacle to applying siRNA successfully. Thus, the nanoplatform AGC/HSP-70 siRNA was designed for enhanced photothermal tumor therapy by RNA interference. In the AGC/HSP-70 siRNA complex, the Au-S bond modified the matrix metalloproteinase-2 (MMP-2)-sensitive peptide GPLGLAG on the surface of gold nanorods. Moreover, the natural basic polysaccharide (chitosan) was reacted with the peptide by an amide bond for delivering heat shock protein 70 silencing siRNA (HSP-70 siRNA). Modifying the MMP-2-sensitive linker could cause more Au NRs to accumulate in tumors to exert a photothermal effect and promote the penetration of HSP-70 siRNA and chitosan complexes into deep tumor tissues. In vitro experiments indicated that the enzymolysis of the MMP-2-sensitive linker for AGC/HSP-70 siRNA could promote the cellular uptake and perinuclear distribution of HSP-70 siRNA in tumor cells, which may be due to the smaller size and positive electricity of the complexes. All of these results ensured the efficient gene silencing effect of HSP-70 siRNA to enhance the photothermal therapeutic effect of Au NRs in tumor tissues, as demonstrated by the gene silencing and cellular apoptotic experiments. In vivo experiments further proved that the AGC/HSP-70 siRNA nanoplatform efficiently improved the photothermal effect of Au NRs. In summary, this work proved that AGC/HSP-70 siRNA is a promising drug delivery strategy for enhancing the photothermal therapy of tumors by regulating the photothermal sensitivity of deep tumor cells as well as retaining more Au NRs in tumor tissues, and also provides a novel strategy for tumor photothermal therapy.

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.

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.

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.

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.

Adaptation and carry over effects of extreme sporadic heat stress in Culex mosquitoes

Mosquitoes, as temperature-sensitive ectothermic vectors, exhibit temperature-dependence. This study investigates Culex pipiens pallens (Cx. pallens) responses to abrupt temperature increases and their implications on mosquito physiology.First instar larvae (24hr post hatching) and newly enclosed adults (24hr post emergence) were separately exposed to heat shock regimes of 33 °C, 37 °C, and 42 °C for 3 days alongside a control temperature of 27 °C. Results showed that mortality was triggered at 42 °C within a day. Adult male mosquitoes were less tolerant to all temperatures than larvae and adult females (p < 0.05). Exposing larvae to constant temperatures for 3 days significantly decreased larvae's development time, growth rate and adult emergence (p < 0.05). Reproductive fitness was significantly reduced (p < 0.05) in males emerging from larvae exposed to 37 °C. Life table parameters showed significant increased mortality rate, kill power and decreased life expectancy at the embryonic stage (p < 0.05). Furthermore, heatwaves deactivated the Transient receptor protein ankyrin 1 at 37 °C (p < 0.05) in larvae but not adults. Calmodium, Heat shock protein 90, and small heat shock protein expression were significantly decreased in larvae at 37 °C (p < 0.05) as compared to larvae raised at 33 °C and 27 °C.In conclusion, we classified the heat waves into three categories: adaptable (33 °C), critical (37 °C), and fatal (42 °C). Prolonged exposure of Culex pallens larvae to extreme heat affects the male reproductive output. These findings may serve as an important reference for forecasting vector and pest dynamics and used to tailor mosquito prevention and control measures.

Association between physiological responses and heat shock protein 70 (HSP70) expressions in the vulnerable populations of Kuala Lumpur

ABSTRACT Continued heat exposure can cause physiological and cellular responses. This study investigated the association between physiological responses and heat shock protein 70 (HSP70) expressions in Kuala Lumpur’s urban vulnerable population. We conducted a cross-sectional study involving 54 participants from four areas classified as experiencing moderate to strong heat stress. Physiological measurements included core body temperature, heart rate, and diastolic and systolic blood pressure. RT-qPCR and ELISA were also performed on blood samples to assess HSP70 gene and protein expressions. Despite indoor heat stress, participants maintained normal physiological parameters while there were significant indications of HSP70 expression at both the gene and protein levels. However, our study found no significant correlation (p > 0.05) between physiological responses and HSP70 expressions. This study shows no interaction between physiological responses and HSP70 expressions in the study population, revealing the complex mechanisms of indoor heat stress in vulnerable individuals.

Microbial response to seasonal variation in arctic biocrusts with a focus on fungi and cyanobacteria

Biocrusts are crucial components of Arctic ecosystems, playing significant roles in carbon and nitrogen cycling, especially in regions where plant growth is limited. However, the microbial communities within Arctic biocrusts and their strategies for surviving the harsh conditions remain poorly understood. In this study, the microbial profiles of Arctic biocrusts across different seasons (summer, autumn, and winter) were investigated in order to elucidate their survival strategies in extreme conditions. Metagenomic and metatranscriptomic analyses revealed significant differences in microbial community composition among the sites located in different elevations. The bacterial communities were dominated by Actinobacteria and Proteobacteria, while the fungal communities were mainly represented by Ascomycota and Basidiomycota, with lichenized and saprotrophic traits prevailing. Cyanobacteria were primarily composed of heterocystous cyanobacteria. Furthermore, the study identified molecular mechanisms underlying cold adaptation, including the expression of heat shock proteins and cold-inducible RNA helicases in cyanobacteria and fungi. Overall, the microbial communities appear to be permanently well adapted to the extreme environment.

Biomimetic Nanomodulators With Synergism of Photothermal Therapy and Vessel Normalization for Boosting Potent Anticancer Immunity.

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC).

Expression of TWEAK/Fn14 axis in the context of metabolic dysfunction associated-fatty liver disease: an approach in liver regeneration

Background: One of the pathways involved in liver regeneration processes is TWEAK/Fn14 (tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14), which has been proposed to act directly and selectively on hepatic progenitor cells; however, its role in the regeneration of steatotic liver metabolic dysfunction associated fatty liver disease has not been fully elucidated. Objective: To evaluate the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals as biochemical cues for possible liver regeneration in MAFLD. Materials and methods: A prospective study was carried out where the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals were observed as biochemical indications of a possible liver regeneration in a condition of tissue damage caused by excessive lipid accumulation. The expression of TWEAK, Fn14 and heat shock proteins in hepatic steatosis of non-alcoholic origin was assessed using immunohistochemistry and western blotting. Results: The histological classification of the tissues under study corresponded to microvesicular steatosis. We report a high level of expression of heat shock proteins in the cytoplasm. The expression of TWEAK and Fn14 in liver tissue affected by lipid accumulation was localized in the cytoplasm of hepatocytes, showing a higher intensity of reactivity for Fn14 compared to its ligand TWEAK. Conclusion: The expression of TWEAK/Fn14 axis was positive suggesting reactivity of the signaling pathway in metabolic dysfunction associated fatty liver disease.

Enhancement of Triple-Negative Breast Cancer-Specific Induction of Cell Death by Silver Nanoparticles by Combined Treatment with Proteotoxic Stress Response Inhibitors.

Metal nanoparticles have been tested for therapeutic and imaging applications in pre-clinical models of cancer, but fears of toxicity have limited their translation. An emerging concept in nanomedicine is to exploit the inherent drug-like properties of unmodified nanomaterials for cancer therapy. To be useful clinically, there must be a window between the toxicity of the nanomaterial to cancer and toxicity to normal cells. This necessitates identification of specific vulnerabilities in cancers that can be targeted using nanomaterials without inducing off-target toxicity. Previous studies point to proteotoxic stress as a driver of silver nanoparticle (AgNPs) toxicity. Two key cell stress responses involved in mitigating proteotoxicity are the heat shock response (HSR) and the integrated stress response (ISR). Here, we examine the role that these stress responses play in AgNP-induced cytotoxicity in triple-negative breast cancer (TNBC) and immortalized mammary epithelial cells. Furthermore, we investigate HSR and ISR inhibitors as potential drug partners to increase the anti-cancer efficacy of AgNPs without increasing off-target toxicity. We showed that AgNPs did not strongly induce the HSR at a transcriptional level, but instead decreased expression of heat shock proteins (HSPs) at the protein level, possibly due to degradation in AgNP-treated TNBC cells. We further showed that the HSR inhibitor, KRIBB11, synergized with AgNPs in TNBC cells, but also increased off-target toxicity in immortalized mammary epithelial cells. In contrast, we found that salubrinal, a drug that can sustain pro-death ISR signaling, enhanced AgNP-induced cell death in TNBC cells without increasing toxicity in immortalized mammary epithelial cells. Subsequent co-culture studies demonstrated that AgNPs in combination with salubrinal selectively eliminated TNBCs without affecting immortalized mammary epithelial cells grown in the same well. Our findings provide additional support for proteotoxic stress as a mechanism by which AgNPs selectively kill TNBCs and will help guide future efforts to identify drug partners that would be beneficial for use with AgNPs for cancer therapy.

Expression of Heat Shock Protein 90 in Testicular Cancer: A Retrospective Cohort Study.

The HSP90 marker is believed to play a constructive role in facilitating neoplastic transformation mainly via interaction with multiple pro-survival proteins. Welldesigned studies are needed to elucidate the role of HSP90 as a diagnostic marker and therapeutic target in testicular tumors. The current study aimed to investigate the expression of HSP90 in various types of testicular cancer and highlight its expression in embryonal testicular cancer. Immunohistochemical staining for HSP90 in 84 male patients, with nonmetastatic testicular cancer, who underwent orchiectomy from 2000 to 2023, was retrospectively performed at the Laboratory Department of General Hospital of Nikaia in Greece. A total of 84 males, with a mean age of 36.2 years, who have undergone high-cord radical orchiectomy, were included in this study. Out of the included males, 28.57% had embryonal carcinoma, 23.81% had seminoma, 19.05% had yolk sac tumor, 11.9% had mature teratoma, 9.52% had immature teratoma, and 7.14% had choriocarcinoma. HSP90b was positive in all embryonal carcinoma, seminoma, and choriocarcinoma cases, while it was positive in 75% of the yolk sac tumor, 75% of mature teratoma, and 75% of immature teratoma specimens. HSP90 was found negative in all choriocarcinoma, mature teratoma, and immature teratoma specimens, while it was positive in 25% of yolk sac tumor, 8.33% of embryonal carcinoma, and 10% of seminoma cases. Concerning the expression of HSP90b, a statistically significant relationship was found between excised tumor specimens and normal parenchyma specimens, especially in sac cases (p <0.001). Regarding HSP90a expression, a statistically significant relationship (OR=21.5, p =0.021) was found between excised tumor specimens and normal parenchyma specimens, especially in embryonal carcinoma cases (p <0.001). HSP90b is highly expressed in the majority of the types of testicular tumors, both in tumor and normal parenchyma specimens, while HSP90a staining is negative in resected specimens. Further well-designed studies are needed to elucidate the role of HSP90 as a diagnostic marker and therapeutic target in testicular tumors.

High temperature induces oxidative stress in spotted seabass (Lateolabrax maculatus) and leads to inflammation and apoptosis

Our study aims to examine the changes of long-term high temperature on the mortality and health status of spotted seabass (Lateolabrax maculatus), as well as to screen suitable biomarkers to determine whether the spotted seabass is under heat stress. In this study, 360 juvenile spotted seabass were evenly distributed into three temperature-controlled systems at 27 °C (N, normal temperature), 31 °C (M, moderate temperature), and 35 °C (H, high temperature) for an 8-week aquaculture experiment. The results revealed that 35 °C water temperature significantly increased the mortality and the MDA content in tissues (P < 0.05). Meanwhile, 35 °C water temperature significantly increased the activity of SOD enzyme and T-AOC capacity in tissues, as well as the expression of hsp60, hsp70, and hsp90 (P < 0.05). Additionally, the expression of nrf2, il1β, il8, caspase3, caspase9, and bax in the liver significantly increased (P < 0.05), while the expression of keap1, il10, tgfβ, and bcl2 decreased significantly (P < 0.05). These results indicate that 35 °C water temperature induces oxidative stress in spotted seabass, leading to tissue oxidative damage, promoting inflammation and apoptosis in liver, and increasing mortality. However, the organism compensates by heightening its antioxidant capacity via the Nrf2-Keap1 signaling pathway and inducing high expression of heat shock proteins for self-protection. Furthermore, the alterations in the mRNA level of hsp70 and MDA content in the liver, muscle, and kidney can serve as indicators for evaluating spotted seabass under prolonged heat stress.

Esculetin Attenuates Doxorubicin-Induced Kidney Damage By Reducing Heat Shock Proteins Expression Levels

The effectiveness of Doxorobucin (DOX), a commonly used anti-cancer and immunosuppressive medication, is hindered by its potential for organ toxicity. Prolonged use of DOX is associated with severe hepatocellular toxicity. This study reveals fresh insights into the therapeutic impact of esculetin (E) on DOX-induced kidney cell damage. Esculetin demonstrates its remedial effects by modulating heat shock protein signaling pathways. In our research, we explored the impact of DOX and E on the expression of the 70 kDa HSP gene family, including Hspa1a, Hspa4, and Hspa5, which are small stress proteins in Rattus norvegicus. The study involved the assignment of five different groups (Control, DOX, E50 mg/kg, E100 mg/kg, DOX+ E50 mg/kg, and DOX+ E100 mg/kg). Subsequently, kidney tissues were collected from rats, and cDNA libraries were generated at the conclusion of the application process. The Real-Time PCR method was employed using these libraries to detect HSP70 genes. Analyses conducted on Hspa1a, Hspa4 and Hspa5 expression revealed a statistically significant increase in the DOX group compared to the control group. Additionally, the combination of DOX and esculetin demonstrates a reduction in the increase caused by DOX alone. The study suggests that esculetin could serve as a potential protective agent for shielding kidney tissue from oxidative damage and apoptosis.

Safe concentration, unsafe effects: Impact of BPA on antioxidant function in the hepatopancreas and ovarian gene expression in oriental river prawns (Macrobrachium nipponense)

This study investigated the effects of Bisphenol A (BPA), a common endocrine-disrupting chemical, on the antioxidant enzyme activities in the hepatopancreas and the expression of genes related to ovarian development in oriental river prawns (Macrobrachium nipponense). The 24hLC50 and 48hLC50 values for BPA were 80.59 mg/L and 63.90 mg/L, respectively, with a safe concentration of 12.06 mg/L. Prawns were exposed to low (4.85 mg/L), safe (12.06 mg/L), and high (30.00 mg/L) concentrations of BPA for 10 days to measure enzyme activities, and for 20 days followed by 7 days in BPA-free water to measure gene expression.Short-term exposure (12 h, 1d, 3d) to low concentration BPA did not significantly affect superoxide dismutase (SOD) activity in the hepatopancreas (P > 0.05), but long-term exposure (6d, 10d) significantly reduced SOD activity (P < 0.05). Catalase (CAT) activity showed no significant changes throughout the low concentration exposure period (P > 0.05). At safe and high concentrations, SOD and CAT activities significantly decreased after 12 h of exposure (P < 0.05).BPA affected heat shock protein 90 (HSP90) expression in the ovary, with low concentration BPA significantly upregulating HSP90 after 1 day (P < 0.05), but returning to normal levels after 10 and 20 days. At the safe concentration, HSP90 was significantly upregulated at all three sampling points (1d, 10d, 20d) (P < 0.05), while high concentration exposure led to significant upregulation only on day 10 (P < 0.05).Low concentration BPA had no significant effect on Cathepsin B (CB) and Cathepsin L (CL) gene expression in the ovaries (P > 0.05). However, safe concentration exposure promoted CB expression on days 1, 10, and 20 (P < 0.05), while high concentration exposure significantly increased CB expression on day 1 (P < 0.05), with levels returning to normal on days 10 and 20. CL expression significantly increased after 20 days of exposure to both safe and high concentrations (P < 0.05). Gene expression levels in the ovaries returned to normal after transfer to BPA-free water, with HSP90 and CB normalizing by day 1, and CL by day 7.These results indicate that even safe concentrations of BPA impose stress on the hepatopancreas and increase the expression of HSP90, CB, and CL genes in the ovaries, affecting ovarian development. And, these effects are reversible within a certain period after the removal of BPA.

TRPA1 Influences Staphylococcus aureus Skin Infection in Mice and Associates with HIF-1a and MAPK Pathway Modulation.

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major public health burden. Emerging antibiotic resistance has heightened the need for new treatment approaches for MRSA infection such as developing novel antimicrobial agents and enhancing the host's defense response. The thermo-ion channels Transient Receptor Potential (TRP-) A1 and V1 have been identified as modulators of S. aureus quorum sensing in cell culture models. However, their effects on in vivo infection control are unknown. In this study, we investigated the therapeutic effect of natural TRP ion channel inhibitors on MRSA skin infection in mice. While deletion of TRPV1 did not affect lesion size or inflammatory markers, TRPA1-/- mice demonstrated significantly reduced infection severity and abscess size. Treatment with natural inhibitors of TRPA1 with or without blockade of TRPV1 also reduced abscess size. Tissue transcriptomic data coupled with immunohistochemistry revealed that TRPA1 inhibition impacted heat shock protein expression (HSP), modulated the HIF-1a and MAPK pathways, and reduced IL4 expression. Additionally, metabolomics data showed an impact on purine and glycosaminoglycan pathways. Multi-omic integration of transcriptomic and metabolic data revealed that diacylglycerol metabolism was the likely bridge between metabolic and immunological impacts. Our findings suggest that TRPA1 antagonism could provide a promising and cost-effective therapeutic approach for reducing the severity of MRSA infection, and presents a novel underlying molecular mechanism.

From Nature to Treatment: The Impact of Pterostilbene on Mitigating Retinal Ischemia-Reperfusion Damage by Reducing Oxidative Stress, Inflammation, and Apoptosis.

Retinal ischemia-reperfusion (I/R) injury is a critical pathogenic mechanism in various eye diseases, and an effective therapeutic strategy remains unresolved. Natural derivatives have recently reemerged; therefore, in our present study, we examined the potential therapeutic effects of a stilbenoid that is chemically related to resveratrol. Pterostilbene, recognized for its anti-inflammatory, anti-carcinogenic, anti-diabetic, and neuroprotective properties, counteracts oxidative stress during I/R injury through various mechanisms. This study explored pterostilbene as a retinoprotective agent. Male Sprague Dawley rats underwent retinal I/R injury and one-week reperfusion and were treated with either vehicle or pterostilbene. After this functional electroretinographical (ERG) measurement, Western blot and histological analyses were performed. Pterostilbene treatment significantly improved retinal function, as evidenced by increased b-wave amplitude on ERG. Histological studies showed reduced retinal thinning and preserved the retinal structure in the pterostilbene-treated groups. Moreover, Western blot analysis revealed a decreased expression of glial fibrillary acidic protein (GFAP) and heat shock protein 70 (HSP70), indicating reduced glial activation and cellular stress. Additionally, the expression of pro-apoptotic and inflammatory markers, poly(ADP-ribose) polymerase 1 (PARP1) and nuclear factor kappa B (NFκB) was significantly reduced in the pterostilbene-treated group. These findings suggest that pterostilbene offers protective effects on the retina by diminishing oxidative stress, inflammation, and apoptosis, thus preserving retinal function and structure following I/R injury. This study underscores pterostilbene's potential as a neuroprotective therapeutic agent for treating retinal ischemic injury and related disorders.

Unveiling the impact of SUMOylation at K298 site of heat shock factor 1 on glioblastoma malignant progression

BackgroundGlioblastoma (GBM) poses a significant medical challenge due to its aggressive nature and poor prognosis. Mitochondrial unfolded protein response (UPRmt) and the heat shock factor 1 (HSF1) pathway play crucial roles in GBM pathogenesis. Post-translational modifications, such as SUMOylation, regulate the mechanism of action of HSF1 and may influence the progression of GBM. Understanding the interplay between SUMOylation-modified HSF1 and GBM pathophysiology is essential for developing targeted therapies. MethodsWe conducted a comprehensive investigation using cellular, molecular, and in vivo techniques. Cell culture experiments involved establishing stable cell lines, protein extraction, Western blotting, co-immunoprecipitation, and immunofluorescence analysis. Mass spectrometry was utilized for protein interaction studies. Computational modeling techniques were employed for protein structure analysis. Plasmid construction and lentiviral transfection facilitated the manipulation of HSF1 SUMOylation. In vivo studies employed xenograft models for tumor growth assessment. ResultsOur research findings indicate that HSF1 primarily undergoes SUMOylation at the lysine residue K298, enhancing its nuclear translocation, stability, and downstream heat shock protein expression, while having no effect on its trimer conformation. SUMOylated HSF1 promoted the UPRmt pathway, leading to increased GBM cell proliferation, migration, invasion, and reduced apoptosis. In vivo studies have confirmed that SUMOylation of HSF1 enhances its oncogenic effect in promoting tumor growth in GBM xenograft models. ConclusionThis study elucidates the significance of SUMOylation modification of HSF1 in driving GBM progression. Targeting SUMOylated HSF1 may offer a novel therapeutic approach for GBM treatment. Further investigation into the specific molecular mechanisms influenced by SUMOylated HSF1 is warranted for the development of effective targeted therapies to improve outcomes for GBM patients.

Ultrathin BSA-Stabilized Black Phosphorous Nanoreactor Boosts Mild-Temperature Photothermal Therapy Through Modulation of Cellular Self-Defense Fate.

Mild-temperature photothermal therapy (mild-PTT, 42-45°C) offers a higher level of biosafety. However, its therapeutic effects are compromised by the heat shock response (HSR), a cellular self-defense mechanism, which triggers the overexpression of heat shock proteins (HSPs) with the capacity of repairing the damaged tumor cells. Herein, this work fabricates a novel nanoreactor by incorporating up-conversion nanoparticles (UCNPs), chlorin e6 (Ce6), and glucose oxidase (GOx) onto the ultrathin black phosphorus nanosheet (BPNS) (denoted as GOx-BUC). This nanoreactor amplifies mild-PTT effects under irradiation with an 808nm laser, modulating HSPs-mediated cellular self-defense fate. On one hand, upon irradiation with a 980nm laser, UCNPs can transfer energy to excite Ce6, leading to the generation of ROS burst, which achieves indiscriminate damage to HSPs activity in deeper tumor tissues. On the other hand, GOx can consume glucose, thereby depleting the ATP energy supply and further suppressing HSPs expression. Consequently, GOx-BUC exhibits excellent anti-tumor efficacy under mild temperature in a human colorectal cancer mouse model, resulting in complete tumor inhibition with negligible side effects. This black phosphorous nanoreactor, featuring dual-track HSPs destruction functionality, introduces novel perspectives for enhancing mild-PTT effectiveness while maintaining high biosafety.