Heat Shock Protein Research Articles

Correlation of Immunological Variables of Interleukin-17 and Heat Shock Protein-70 In Ethnic Women with Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is a hormonal imbalance resulting from high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in females, leading to immature eggs, ovarian cysts, irregular menstrual cycles, infertility, excessive facial hair growth, and acne. Objective: This study was conducted to follow up the therapeutic effect on some blood, hormonal, and immune variables of samples consisting of 35 patients with polycystic ovary syndrome (PCOS) from women suffering from infertility and infertility, and who visited Azadi Teaching Hospital and private laboratories in Kirkuk city, their ages ranged between (18 - 40 years). Materials and Methods: Sample collection and follow-up began by observing some clinical signs in addition to verifying the results of ultrasound examinations from early February 2023 to early November 2023. Each patient’s examinations were followed up before treatment and three months after taking the treatment. The results we obtained after three months of treatment were compared with the results of the examinations of the patients in the pre-treatment stage and the control group. The treatment plan was based on modifying the patient's dietary lifestyle by following a healthy diet and giving treatment consisting of oral contraceptives, fertility drugs and the use of sugar-reducing drugs such as Glucophage or Metformin, in addition to nutritional supplements such as antioxidants. Result: The results of the therapeutic effect on the patients' diagnostic clinical signs showed a significant decrease in their percentages after three months of treatment compared to the pre-treatment stage such as (ovulation disorders - menstrual disorders - obesity - hirsutism - acne -). The results of the statistical analysis of the study showed that the therapeutic effect showed a significant difference in the body mass index (BMI) after three months of treatment compared to the pre-treatment stage and the control group. The therapeutic effect of the immune factors for each Hast Shock protein 70 and Interleukin-17 also showed a significant decrease at the level (0.000 > p) respectively after three months of taking the treatment compared to the pre-treatment stage and the control group. It was found that there is a significant positive correlation between the level of Heat Shock Protein 70 and the cellular kinetic IL-17.

Heat-shock protein 27 (HSP27) not just a biomarker of cardiac and renal diseases

Heat-shock protein 27 (HSP27) not just a biomarker of cardiac and renal diseases

Selection of Reference Genes and HSP17.9A Expression Profiling in Heat-Stressed Grapevine Varieties

Background: “Touriga Franca” (TF) and “Touriga Nacional” (TN) are grapevine varieties cultivated in the ‘Douro Superior’ subregion (Northern Portugal) that experience stressful environmental conditions during the summer. Objectives: Aiming to profile the expression of stress-responsive genes by quantitative real-time PCR (qPCR) in TF and TN plants growing naturally, three candidate reference genes were first tested under controlled conditions. Methods: To simulate a summer’s day, TF and TN in vitro plants were exposed to 32 °C–3 h (heat acclimation) and 42 °C–1 h (severe heat stress, HS) followed by two recovery periods (32 °C–3 h and 24 °C–24 h). Leaf samples were collected at the end of each phase. Control plants were kept at 24 °C. Results: Among the candidate reference genes, the UBC and VAG pair showed the highest stability. The suitability of these genes for qPCR was validated by heat shock protein 17.9A (HSP17.9A) gene profiling. The HSP17.9A expression was up-regulated in both varieties and all experimental phases except in TF control plants. TN showed the highest HSP17.9A relative expression ratio after severe HS. Conclusions: TN responded faster than TF to the induced heat shocks. The UBC, VAG, and HSP17.9A genes revealed to be suitable for further qPCR assays in TF and TN grapevine varieties.

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.

Isolation and Characterization of Heat Shock Protein 70-Ipek 1 from Toxoplasma gondii

Toxoplasma gondii is a common intracellular parasite that causes the toxoplasmosis. Heat shock proteins (Hsps) have a critical role in pathogenesis of toxoplasmosis. Hsps are highly conserved proteins in evolution among living organisms. This protein family responsible for a wide range of biological processes such as protein folding, protein translocation, protein aggregation. In the present study, Hsp70, a member of the Hsp family, was isolated from T. gondii and its sequence and motifs were determined by PCR, cloning, sequencing and homology modelling analysis. ATP hydrolysis, luciferase folding, and luciferase aggregation experiments were performed for determination of its chaperone activity while the stability and secondary structure of the Hsp70 were discovered by using biophysical experiments (FTIR, florescence and quenching experiment). In addition, in silico analysis were used to determine the physicochemical characteristics of Hsp70. The results revealed that Hsp70 protein obtained from T. gondii (Hsp70-IPEK1) is similar to Hsp70s from other organisms. Also, the chaperone activity, stability and secondary structure of Hsp70-IPEK1 were determined. Hsp70-IPEK1 together with other chaperones in the presence of nucleotide were dramatically increased protein folding and aggregation. According to these results, it is thought that Hsp70 has a potential to contribute many research areas such as pharmaceutical analysis

An integrative strategy used by the aphid Uroleucon formosanum to counter host sesquiterpene lactone defense: Insights from combined genomic and transcriptomic analysis.

Insect herbivores adapt and develop strategies to counteract plant chemical defenses. The aphid Uroleucon formosanum is a serious sap-sucking pest that infests lettuces containing toxic sesquiterpene lactones (STLs). Herein, we employed a combination of genome sequencing and RNA-seq transcriptome profiling to understand the mechanisms underlying phytotoxin tolerance in U.formosanum. We generated the first chromosome-level genome assembly for U.formosanum, with a total size of 453.26Mb and a scaffold N50 of 33.22Mb. Comparative genomic analyses revealed an enrichment of signals for positive selection and gene family expansion in immune-related pathways. Specifically, the expanded set of heat shock protein70 (HSP70) genes showed upregulation after treatment with lactucin, suggesting that they may play a role in the immune response against STLs. The expression of takeout-like genes and cuticle-associated genes was also significantly increased in the lactucin-treated samples. Additionally, 53 cytochrome P450 monooxygenase, 30 carboxylesterase, 19 glutathione S-transferase, 32 uridine diphosphate glycosyltransferase and 63 ATP-binding cassette (ABC) transporter genes were identified in the U.formosanum genome. CYP4C1, CYP6A13 and 7 ABC genes were strongly upregulated in response to lactucin treatment, indicating the involvement of detoxifying enzymes in the tolerance of U.formosanum to STLs. Our findings suggest that the cuticle barrier, immune response and enzyme-mediated metabolic detoxification jointly enhance the tolerance of U.formosanum to phytotoxins and promote its adaptation to host plants. This study presents a valuable genomic resource and provides insights into insect adaptation to plant chemical challenges and future technological developments for pest management.

Comparative analysis of transcriptomics of Fasciola hepatica at different developmental stages.

This study explored the transcriptome differences in Fasciola hepatica at different developmental stages and identified functional genes related to growth and development during juvenile stages. DNBSEQ eukaryotic strand-specific transcriptome resequencing technology was used to sequence the transcriptomes of Fasciola hepatica eggs, juveniles, and adults. Additionally, the genes that were highly expressed during the juvenile stage were validated using qRT-PCR. The Q20 values of all three phases of sequencing were above 98%, and the Q30 values were above 94%. The differentially expressed genes (DEGs) in pairwise comparisons were analyzed by GO functional classification and the KEGG pathway database. Many immune-, growth-, and development-related pathways were found, which might be related to cell proliferation, development, and host immune evasion by Fasciola hepatica. In addition, five DEGs with high expression levels during the juvenile stage were identified: Cathepsin B, Glutathione S-transferase mu, heat shock protein 67B2, Kunitz-CH, and Legumain. Validation analyses revealed that these genes play key roles in maintaining normal growth, development, and immunological processes in liver Fasciola hepatica. RNA-seq was used to analyze the biological characteristics of the DEGs at different developmental stages concerning GO functional classification and KEGG metabolic pathways. Five DEGs with high expression during the juvenile stage were identified. These genes are related to the growth, development, and immune function of Fasciola hepatica, which provides a theoretical basis for subsequent research on the proteomics of Fasciola hepatica and the screening of candidate genes for early diagnosis.

Acute exposure to mercury drives changes in gene expression in Drosophila melanogaster.

We quantified the effect of acute exposure to a high dosage of inorganic mercury on gene expression in Drosophila melanogaster using RNA-sequencing of whole adult females. We found 119 genes with higher gene expression following treatment (including all 5 Drosophila metallothionine genes and a number of heat shock protein genes), and 31 with lower expression (several of which are involved in egg formation). Our results highlight biological processes and genetic pathways impacted by exposure to this toxic metal, and provide motivation for future studies to understand the genetic basis of response to mercury.

Chitosan-Zinc-Ligated Hydroxychloroquine: Molecular Docking, Synthesis, Characterization, and Trypanocidal Activity against Trypanosoma evansi

The existing treatments against Trypanosoma evansi are faced with several drawbacks, such as limited drug options, resistance, the relapse of infection, toxicity, etc., which emphasizes the necessity for new alternatives. We synthesized novel metal-based antiparasitic compounds using chitosan, hydroxychloroquine (HC), and ZnO nanoparticles (NPs) and characterized them for size, morphology, chemical interactions, etc. Molecular docking and protein interaction studies were performed in silico to investigate the inhibitory effects of HC, zinc-ligated hydroxychloroquine (HCZnONPs), and chitosan-zinc-ligated hydroxychloroquine (CsHCZnONPs) for two key proteins, i.e., heat shock protein 90 (Hsp90) and trypanothione reductase associated with T. evansi. In vitro trypanocidal activity and the uptake of zinc ions by T. evansi parasites were observed. The formulation was successfully synthesized, as indicated by its size, stability, morphology, elemental analysis, and functional groups. CsHCZnO nanoparticles strongly inhibit both Hsp90 and trypanothione reductase proteins. The inhibition of Hsp90 by these nanoparticles is even stronger than that of trypanothione reductase when compared to HC and HCZnONPs. This suggests that the presence of polymer chitosan enhances the nanoparticles’ effectiveness against the parasite. For the first time, CsHCZnO nanoparticles exhibited trypanocidal activity against T. evansi, with complete growth inhibition being observed at various concentrations after 72 h of treatment. Fluorescent microscopy using FluoZin-3 on T. evansi culture confirmed the presence of zinc on the surface of parasites. This innovative approach has shown promising results in the quest to develop improved antiparasitic compounds against T. evansi with enhanced effectiveness and safety, highlighting their potential as therapeutic agents against trypanosomiasis.

HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.

Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.

Relationship between Protein, MicroRNA Expression in Extracellular Vesicles and Rice Seed Vigor.

Plant extracellular vesicles are non-self-replicating particles released by living plant cells and delimited by a lipid bilayer. They contain a large amount of lipids, RNA, and proteins. Seed vigor plays an important role in agricultural production and preservation of germplasm resources. Extracellular vesicles with cross-species communication with bioactive molecules can resist pathogens, exhibit anti-aging properties, and perform other functions; however, its potential influence on seed vigor has not been reported. In this study, rice seeds with different germination percentages were used to extract extracellular vesicles, endogenous proteins, and RNA. Protein qualitative identification and miRNA differential analysis were performed to analyze the regulatory mechanism of extracellular vesicles on seed vigor. Results: The profiles of four miRNA families were found to be significantly different: osa-miR164, osa-miR168, osa-miR166, and osa-miR159. Protein correlation analysis predicted that extracellular vesicles might mediate the synthesis of the seed cell wall; glyoxic acid cycle and tricarboxylic acid cycle; non-specific lipid transfer; mitochondrial quality control; and other biological processes to regulate rice seed viability. In addition, cupin protein, phospholipase D, aldehyde dehydrogenase, seven heat shock proteins (especially BiP1 and BiP2), protein disulfide isomerase-like (PDI), thioredoxin, calnexin and calreticulin, glutathione transferase, and other proteins found in extracellular vesicles were closely related to seed vigor. This provides a novel direction for the study of the regulation mechanism of seed vigor.

LEVELS OF HEAT SHOCK PROTEIN HSP70 IN NEURONS OF PARIETAL CORTEX AND HIPPOCAMPUS IN RATS WITH VARIOUS STAGES OF CEREBRAL ISCHEMIA

The paper examines the issue of increasing the body’s resistance to oxygen deficiency and energy deficit under cerebral ischemia. Adaptation to these changes is represented by an increased number of heat shock proteins in brain neurons. Their expression increases with a decrease of oxygen level in the blood. The aim of the paper is to evaluate HSP70 level in the brain of rats with various stages of cerebral ischemia. Materials and Methods. The study was conducted on 27 white outbred male rats weighing 267±16 g. The authors used such models as partial cerebral ischemia, step-by-step 90 % blood flow shutdown, one-time 90 % blood flow shutdown, and complete cerebral ischemia. Results. In the 1st subgroup of step-by-step 90 % blood flow shutdown (7 days between dressings) there was an increase in the HSP70 level by 25 % in the parietal cortex (p<0.05) compared with the control. However, its concentration in the hippocampus did not change (p>0.05). In the 2nd and 3rd subgroups of step-by-step 90 % blood flow shutdown (3 days and 1 day between dressings), the HSP70 level did not change in any of the studied areas (p>0.05) compared with the control. Compared with the 1st subgroup, in the 2nd subgroup HSP70 level in the parietal cortex was lower by 26 % (p<0.05) and in the hippocampus by 20 % (p<0.05), in the 3rd subgroup it was lower by 30 % (p<0.05) and by 23 % (p<0.05), respectively. No differences in HSP70 levels were found between the 2nd and 3rd subgroups (p>0.05). In the group of one-time 90 % blood flow shutdown, the HSP70 level decreased by 29 % in the parietal cortex (p<0.05) and by 18 % in the hippocampus (p<0.05) compared with the control. In group of one-time 90 % blood flow shutdown, the HSP70 level did not differ from those in the 2nd and 3rd subgroups of step-by-step 90 % blood flow shutdown in the hippocampus. In the parietal cortex, the HSP70 level in the 2nd subgroup was 28 % higher (p<0.05), and in the 3rd subgroup by 23 % higher (p<0.05) compared with the group of one-time 90 % blood flow shutdown. In total cerebral ischemia, the most significant decrease in HSP70 level was observed compared to the control: by 35 % in the parietal cortex (p<0.05) and by 36 % in the hippocampus (p<0.05). Conclusion. Thus, in the 1st subgroup with the maximum interval between dressings, the HSP70 level increased, indicating the activation of compensation mechanisms during hypoxia by protecting proteins from premature proteolytic breakdown and promoting the correct polypeptide folding into a tertiary structure.

A potential trade-off between reproduction and enhancement of thermotolerance in Liriomyza trifolii populations driven by thermal acclimation

The invasive pest, Liriomyza trifolii, poses a significant threat to ornamental and vegetable plants. It spreads rapidly and causes large-scale outbreaks with pronounced thermotolerance. In this study, we developed L. trifolii strains adapted to high temperatures (strains designated 35 and 40); these were generated from a susceptible strain (designated S) by long-term thermal acclimation to 35 °C and 40 °C, respectively. Age-stage, two-sex life tables, thermal preferences, critical thermal limits, knockdown behaviors, eclosion and survival rates as well as expression of genes encoding heat shock proteins (Hsps) were compared for the three strains. Our findings indicated that the thermotolerance of L. trifolii was enhanced after long-term thermal acclimation, which suggested an adaptive plastic response to thermal stress. A trade-off between reproduction and thermotolerance was observed under thermal stress, potentially improving survival of the population and fostering adaptionary changes. Acclimation at 35 °C improved reproductive performance and population density of L. trifolii, particularly by enhancing the fecundity of female adults and accelerating the speed of development. Although the 40 strain exhibited the highest developmental speed and greater thermotolerance, it incurred a larger reproductive cost. This study provides a theoretical framework for monitoring and controlling leafminers and understanding their evolutionary adaptation to environmental changes.

DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming.

Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer's signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.

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.

The molecular impact of sonoporation: A transcriptomic analysis of gene regulation profile

Sonoporation has long been known to disrupt intracellular signaling, yet the involved molecules and pathways have not been identified with clarity. In this study, we employed whole transcriptome shotgun sequencing (RNA-seq) to profile sonoporation-induced gene responses after membrane resealing has taken place. Sonoporation was achieved by microbubble-mediated ultrasound (MB-US) exposure in the form of 1 MHz ultrasound pulsing (0.50 MPa peak negative pressure, 10 % duty cycle, 30 s exposure period) in the presence of microbubbles (1:1 cell-to-bubble ratio). Using propidium iodide (PI) and calcein respectively as cell viability and cytoplasmic uptake labels, post-exposure flow cytometry was performed to identify three viable cell populations: 1) unsonoporated cells, 2) sonoporated cells with low uptake, and 3) sonoporated cells with high uptake. Fluorescence-activated cell sorting was then conducted to separate the different groups followed by RNA-seq analysis of the gene expressions in each group of cells. We found that sonoporated cells with low or high calcein uptake showed high similarity in the gene responses, including the activation of multiple heat shock protein (HSP) genes and immediate early response genes mediating apoptosis and transcriptional regulation. In contrast, unsonoporated cells exhibited a more extensive gene expression alteration that included the activation of more HSP genes and the upregulation of diverse apoptotic mediators. Four oxidative stress-related and three immune-related genes were also differentially expressed in unsonoporated cells. Our results provided new information for understanding the intracellular mobilization in response to sonoporation at the molecular level, including the identification of new molecules in the sonoporation-induced apoptosis regulatory network. Our data also shed light on the innovative therapeutic strategy which could potentially leverage the responses of viable unsonoporated cells as a synergistic effector in the microenvironment to favor tumor treatment.

Effects of Alkalinity Stress on Amino Acid Metabolism Profiles and Oxidative-Stress-Mediated Apoptosis/Ferroptosis in Hybrid Sturgeon (Huso dauricus ♀ × Acipenser schrenckii ♂) Livers

Alkaline water is toxic to cultured aquatic animals that frequently live in pH-neutral freshwater. Overfishing and habitat destruction have contributed to the decline in the wild sturgeon population; consequently, the domestic hybrid sturgeon has become an increasingly important commercial species in China. Hybrid sturgeons are widely cultured in alkaline water, but little is known about the effects of alkalinity stress on hybrid sturgeon liver tissues. We exposed hybrid sturgeons to four alkaline concentrations (3.14 ± 0.02 mmol/L, 7.57 ± 0.08 mmol/L, 11.78 ± 0.24 mmol/L and 15.46 ± 0.48 mmol/L). Histopathology, biochemical index assessment, gene expression level detection and metabolomics analysis were used to investigate the negative effects on liver functions following exposure to NaHCO3. Livers exposed to alkaline stress exhibited severe tissue injury and clear apoptotic characteristics. With increased exposure concentrations, the hepatic superoxide dismutase, catalase, glutathione peroxidase and alkaline phosphatase activities significantly decreased in a dose-dependent manner. NaHCO3 exposure up-regulated the transcriptional levels of apoptosis/ferroptosis-related genes in livers. Similarly, the expression trends of interleukin-1β and heat shock protein genes also increased in high-alkalinity environments. However, the expression levels of complement protein 3 significantly decreased (p < 0.05). Hepatic untargeted metabolomics revealed the alteration conditions of various metabolites associated with the antioxidant response, the ferroptosis process and amino acid metabolism (such as beta-alanine metabolism; alanine, aspartate and glutamate metabolism; and glycine, serine and threonine metabolism). These data provided evidence that NaHCO3 impaired immune functions and the integrity of hybrid sturgeon liver tissues by mediating oxidative-stress-mediated apoptosis and ferroptosis. Our results shed light on the breeding welfare of domestic hybrid sturgeons and promote the economic development of fisheries in China.

New Pyrazole/Pyrimidine-Based Scaffolds as Inhibitors of Heat Shock Protein 90 Endowed with Apoptotic Anti-Breast Cancer Activity.

Background/Objectives: Supported by a comparative study between conventional, grinding, and microwave techniques, a mild and versatile method based on the [1 + 3] cycloaddition of 2-((3-nitrophenyl)diazenyl)malononitrile to tether pyrazole and pyrimidine derivatives in good yields was used. Methods: The newly synthesized compounds were analyzed with IR, 13C NMR, 1H NMR, mass, and elemental analysis methods. The products show interesting precursors for their antiproliferative anti-breast cancer activity. Results: Pyrimidine-containing scaffold compounds 9 and 10 were the most active, achieving IC50 = 26.07 and 4.72 µM against the breast cancer MCF-7 cell line, and 10.64 and 7.64 µM against breast cancer MDA-MB231-tested cell lines, respectively. Also, compounds 9 and 10 showed a remarkable inhibitory activity against the Hsp90 protein with IC50 values of 2.44 and 7.30 µM, respectively, in comparison to the reference novobiocin (IC50 = 1.14 µM). Moreover, there were possible apoptosis and cell cycle arrest in the G1 phase for both tested compounds (supported by CD1, caspase-3,8, BAX, and Bcl-2 studies). Also, the binding interactions of compound 9 were confirmed through molecular docking, and simulation studies displayed a complete overlay into the Hsp90 protein pocket. Conclusions: Compounds 9 and 10 may have apoptotic antiproliferative action as Hsp90 inhibitors.

LncRNA HAR1A inhibits non-small cell lung cancer growth by downregulating c-MYC transcripts and facilitating its proteasomal degradation

Non-small cell lung cancer (NSCLC) is a primary cause of cancer-related mortality on a global scale. Research increasingly shows that long non-coding RNAs (lncRNAs) play crucial regulatory roles and serve as biomarkers for diagnosis, prognosis, therapy monitoring, and druggable targets in NSCLC. We previously identified HAR1A as a tumor-suppressing lncRNA in NSCLC, with its loss also observed in oral and hepatocellular carcinoma. This study aimed to expand the understanding of the functional role of HAR1A in NSCLC and uncover its underlying mechanisms. Our results demonstrated that elevating HAR1A levels impeded NSCLC cell proliferation and migration but promoted apoptosis, thereby boosting their susceptibility to cisplatin. Subsequently, we discovered that HAR1A enhanced cisplatin’s cytotoxicity in NSCLC cells by curbing adaptive autophagy through the downregulation of MYC. Further analysis revealed that HAR1A suppresses MYC by both lowering its transcript levels and promoting protein ubiquitination and degradation, thereby restricting tumor cell proliferation, migration, and adaptive autophagy. In exploring MYC’s targets, we observed that MYC upregulated the transcription of heat shock protein 90 alpha family class B member 1 (HSP90AB1/HSP90β) gene. Rescue experiments verified that HAR1A mitigated NSCLC cell proliferation and migration and induced apoptosis through the MYC/HSP90β axis. Finally, we confirmed that HAR1A overexpression increased cisplatin efficacy in nude mouse NSCLC xenograft models.In conclusion, the findings suggest that HAR1A could be a promising therapeutic target in treating NSCLC and biomarkers for predicting chemotherapy outcomes. This study provides new insights into the molecular mechanisms of chemoresistance in NSCLC and underscores the potential of lncRNA-based strategies in cancer therapy.

Analysis of the immune transcriptome of the invasive pest spotted wing drosophila infected by Steinernema carpocapsae.

Drosophila suzukii is a pest of global concern due to its great impact on several crops. The entomopathogenic nematode Steinernema carpocapsae was highly virulent to the larvae of the fly although some immune mechanisms were triggered along the infection course. Thus, to understand the gene activation profile we performed a comparative transcriptome of D. suzukii larvae infected with S. carpocapsae and Xenorhabdus nematophila to map the differentially expressed genes involved in the defence response. The analysis exposed the induction of genes involved in the humoral response such as the antimicrobial peptides and pattern-recognition receptors while there was a suppression of the cellular defence. Besides, genes involved in melanisation, and clot formation were downregulated hindering the encapsulation response and wound healing. After the infection, larvae were in a stress condition with an enrichment of metabolic and transport functionalities. Concerning the stress response, we observed variations of the heat-shock proteins, detoxification, and peroxidase enzymes. These findings set a genetical comprehensive knowledge of the host-pathogen relation of D. suzukii challenged with S. carpocapsae which could support further comparative studies with entomopathogenic nematodes.