Search

Notwithstanding the latest advancements in anticancer therapy, non-small cell lung cancer (NSCLC) remains a prominent contributor to cancer-associated mortality worldwide. Therefore, effective anti-cancer agents are required for the treatment of NSCLC. We previously demonstrated that the natural alkaloid evodiamine efficiently suppressed lung cancer cells and lung cancer stem-like cell populations by suppressing heat shock protein 70 (Hsp70). This finding inspired us to formulate evodiamine-based anti-cancer compounds against NSCLC. In this study, we synthesized a series of evodiamine derivatives with substitutions at the N14 position. EV206 was chosen for further study because it was the most effective among the 22 evodiamine derivatives at stopping H1299 cell growth. EV206 treatment efficiently suppressed cell viability and colony formation in both attached cells and in soft agar, even in those carrying drug resistance, by inducing apoptosis. The effectiveness of EV206 is approximately ten times greater than that of evodiamine. Normal cell viability was marginally affected by EV206 treatment. Additionally, EV206 efficiently decreased the cancer stem cell (CSC) population in the NSCLC cells. EV206 reduced the growth of H460 xenograft tumors without exhibiting toxic effects. These data implied that EV206 has the potential to be an effective Hsp70-targeting anticancer drug with low toxicity. [ABSTRACT FROM AUTHOR]

Objective To investigate the diagnostic value of serum programmed cell death protein 4 (PDCD4) and heat shock protein 70 (HSP70) levels in lymph node metastasis (LNM) of early cervical cancer, in order to provide more evidence for the diagnosis of LNM of early cervical cancer. Methods A total of 132 patients with early cervical cancer (observation group) were selected, and sentinel lymph node biopsy was performed during the operation. Histopathological examination was performed to determine whether LNM occurred, and 60 healthy female volunteers (control group) were selected during the same period. Fasting peripheral venous blood of all subjects was collected and serum was retained by centrifugation. Serum PDCD4 and HSP70 levels were detected by ELISA. The clinical data of patients with early cervical cancer were collected and the risk factors for LNM of early cervical cancer were analyzed by multivariate Logistic regression model. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of serum PDCD4 and HSP70 levels in LNM of early cervical cancer. Results The serum PDCD4 level in the observation group was lower than that in the control group, and the serum HSP70 level was higher than that in the control group (both P<0. 05). Among 132 patients with early cervical cancer, 25 had LNM and 107 did not have LNM. Univariate analysis showed that maximum tumor diameter, depth of cervical interstitial infiltration, FIGO stage and serum PDCD4 and HSP70 levels might be related to LNM of early cervical cancer (all P<0. 05). Multivariate Logistic regression analysis showed that cervical interstitial infiltration depth ≥1/2 cervical muscle wall, FIGO stage IIA and increased serum HSP70 level were independent risk factors for LNM of early cervical cancer, while increased serum PDCD4 level was independent protective factor (all P<0. 05). ROC curve analysis showed that the area under the curve (AUC) of serum PDCD4 and HSP70 levels alone and combined in predicting LNM of early cervical cancer were 0. 810, 0. 817 and 0. 876, respectively, and the AUC of serum PDCD4 and HSP70 levels combined in predicting LNM of early cervical cancer was greater than that of the two alone (both P<0. 05). Conclusions The decrease of serum PDCD4 level and the increase of serum HSP70 level are closely related to LNM of early cervical cancer. Serum PDCD4 and HSP70 levels have certain diagnostic value for early cervical cancer LNM, and their combined diagnosis value is higher. [ABSTRACT FROM AUTHOR]

Background: Avian malaria is caused by diverse parasite species of the genus Plasmodium, and it affects various bird species. The occurrence of this disease in some wild bird species is sparsely documented due to the scarce availability of samples. Hence the pathogenicity in some hosts is not completely known. In addition, feral birds may act as reservoirs bridging the transmission cycle from wild migratory birds to domestic and zoo-kept bird species. Case presentation: An owner of pigeons adopted a feral pigeon (Columba livia forma domestica) and housed it together with his other pet-pigeons. The bird died unexpectedly a few weeks after a surgical procedure and necropsy revealed a severely anaemic carcass, with pale organs and hydropericardium. Histopathologic analysis revealed inflammatory infiltrates in the lung and liver, and monocytes and Kupffer cells contained haemozoin pigment indicative of phagocytosis of Plasmodium-infected erythrocytes. A high erythrocytic infection rate of 18% was evident in tissues and blood vessels in various organs. Furthermore, the thyroid had masses classified as thyroid carcinomas. Immunohistochemistry with anti- Plasmodium falciparum HSP70 antibody revealed positive signals in erythrocytes and intravascular leucocytes. Further microscopy analysis using a Hemacolor-stained impression smear revealed a high parasitaemia with an asynchronous infection showing all erythrocytic stages. Molecular diagnosis by PCR identified Plasmodium relictum, lineage GRW11 as the aetiological agent. The bird presented died most likely due to an acute infection as evidenced by the high blood parasitaemia, leading to major erythrocyte destruction. Further analyses of feral pigeons (n = 22) did not reveal any additional cases of Plasmodium infections. Conclusion: This study reports the first mortality associated with P. relictum lineage GRW11. The study supports previous studies, suggesting that Plasmodium infections are not frequent in pigeons. Host conditions like immunosuppression due to the tumour may have influenced the infection outcome in this fatal case. Use of anti-P. falciparum HSP70 antibody for detection of P. relictum antigens for immune assays in blood and tissue samples will be a useful tool for future studies. [ABSTRACT FROM AUTHOR]

Background: Mycoplasmal pneumonia of sheep and goats (MPSG) is an important infectious disease that threatens sheep and goat production worldwide, and Mycoplasma ovipneumoniae (Movi) is one of the major aetiological agents causing MPSG. The aim of this study was to investigate the immunological activity of the Hsp70‒P113 fusion protein derived from Movi and to develop a serological assay for the detection of Movi. Methods: This study involved codon optimization of the dominant antigenic regions of Movi heat shock protein 70 (Hsp70) and adhesin P113. Afterwards, the optimized sequences were inserted into the prokaryotic expression vector pET-30a(+) through tandem linking with the aid of a linker. Once a positive recombinant plasmid (pET-30a-rHsp70-P113) was successfully generated, the expression conditions were further refined. The resulting double gene fusion target protein (rHsp70‒P113) was subsequently purified using ProteinIso® Ni–NTA resin, and the reactivity of the protein was confirmed via SDS‒PAGE and Western blot analysis. An indirect enzyme-linked immunosorbent assay (i-ELISA) technique was developed to detect Movi utilizing the fusion protein as the coating antigen. The specificity, sensitivity, and reproducibility of all methods were assessed after each reaction parameter was optimized. Results: The resulting rHsp70-P113 protein had a molecular weight of approximately 51 kDa and was predominantly expressed in the supernatant. Western blot analysis demonstrated its favourable reactivity. The optimal parameters for the i-ELISA technique were as follows: the rHsp70-P113 protein was encapsulated at a concentration of 5 μg/mL; the serum was diluted at a ratio of 1:50; the HRP-labelled donkey anti-goat IgG was diluted at a ratio of 1:6,000. The results of the cross-reactivity assays revealed that the i-ELISA was not cross-reactive with other goat-positive sera against Mycoplasma mycodies subsp. capri (Mmc), Mycoplasma capricolum subsp. capripneumoniae (Mccp), Mycoplasma arginini (Marg), orf virus (ORFV) or enzootic nasal tumour virus of goats (ENTV-2). The sensitivity of this method is high, with a maximum dilution of up to 1:640. The results of the intra- and inter-batch replication tests revealed that the coefficients of variation were both less than 10%, indicating excellent reproducibility. The analysis of 108 clinical serum samples via i-ELISA and indirect haemagglutination techniques yielded significant findings. Among these samples, 43 displayed positive results, whereas 65 presented negative results, resulting in a positivity rate of 39.8% for the i-ELISA method. In contrast, the indirect haemagglutination technique identified 20 positive samples and 88 negative samples, resulting in a positivity rate of 18.5%. Moreover, a comparison between the two methods revealed a conformity rate of 78.7%. Conclusion: The results obtained in this study lay the groundwork for advancements in the use of an Movi antibody detection kit, epidemiological inquiry, and subunit vaccines. [ABSTRACT FROM AUTHOR]

Abstract Notwithstanding the latest advancements in anticancer therapy, non-small cell lung cancer (NSCLC) remains a prominent contributor to cancer-associated mortality worldwide. Therefore, effective anti-cancer agents are required for the treatment of NSCLC. We previously demonstrated that the natural alkaloid evodiamine efficiently suppressed lung cancer cells and lung cancer stem-like cell populations by suppressing heat shock protein 70 (Hsp70). This finding inspired us to formulate evodiamine-based anti-cancer compounds against NSCLC. In this study, we synthesized a series of evodiamine derivatives with substitutions at the N14 position. EV206 was chosen for further study because it was the most effective among the 22 evodiamine derivatives at stopping H1299 cell growth. EV206 treatment efficiently suppressed cell viability and colony formation in both attached cells and in soft agar, even in those carrying drug resistance, by inducing apoptosis. The effectiveness of EV206 is approximately ten times greater than that of evodiamine. Normal cell viability was marginally affected by EV206 treatment. Additionally, EV206 efficiently decreased the cancer stem cell (CSC) population in the NSCLC cells. EV206 reduced the growth of H460 xenograft tumors without exhibiting toxic effects. These data implied that EV206 has the potential to be an effective Hsp70-targeting anticancer drug with low toxicity.

Abstract Background Avian malaria is caused by diverse parasite species of the genus Plasmodium, and it affects various bird species. The occurrence of this disease in some wild bird species is sparsely documented due to the scarce availability of samples. Hence the pathogenicity in some hosts is not completely known. In addition, feral birds may act as reservoirs bridging the transmission cycle from wild migratory birds to domestic and zoo-kept bird species. Case presentation An owner of pigeons adopted a feral pigeon (Columba livia forma domestica) and housed it together with his other pet-pigeons. The bird died unexpectedly a few weeks after a surgical procedure and necropsy revealed a severely anaemic carcass, with pale organs and hydropericardium. Histopathologic analysis revealed inflammatory infiltrates in the lung and liver, and monocytes and Kupffer cells contained haemozoin pigment indicative of phagocytosis of Plasmodium-infected erythrocytes. A high erythrocytic infection rate of 18% was evident in tissues and blood vessels in various organs. Furthermore, the thyroid had masses classified as thyroid carcinomas. Immunohistochemistry with anti- Plasmodium falciparum HSP70 antibody revealed positive signals in erythrocytes and intravascular leucocytes. Further microscopy analysis using a Hemacolor-stained impression smear revealed a high parasitaemia with an asynchronous infection showing all erythrocytic stages. Molecular diagnosis by PCR identified Plasmodium relictum, lineage GRW11 as the aetiological agent. The bird presented died most likely due to an acute infection as evidenced by the high blood parasitaemia, leading to major erythrocyte destruction. Further analyses of feral pigeons (n = 22) did not reveal any additional cases of Plasmodium infections. Conclusion This study reports the first mortality associated with P. relictum lineage GRW11. The study supports previous studies, suggesting that Plasmodium infections are not frequent in pigeons. Host conditions like immunosuppression due to the tumour may have influenced the infection outcome in this fatal case. Use of anti-P. falciparum HSP70 antibody for detection of P. relictum antigens for immune assays in blood and tissue samples will be a useful tool for future studies.

Abstract Background Mycoplasmal pneumonia of sheep and goats (MPSG) is an important infectious disease that threatens sheep and goat production worldwide, and Mycoplasma ovipneumoniae (Movi) is one of the major aetiological agents causing MPSG. The aim of this study was to investigate the immunological activity of the Hsp70‒P113 fusion protein derived from Movi and to develop a serological assay for the detection of Movi. Methods This study involved codon optimization of the dominant antigenic regions of Movi heat shock protein 70 (Hsp70) and adhesin P113. Afterwards, the optimized sequences were inserted into the prokaryotic expression vector pET-30a( +) through tandem linking with the aid of a linker. Once a positive recombinant plasmid (pET-30a-rHsp70-P113) was successfully generated, the expression conditions were further refined. The resulting double gene fusion target protein (rHsp70‒P113) was subsequently purified using ProteinIso® Ni–NTA resin, and the reactivity of the protein was confirmed via SDS‒PAGE and Western blot analysis. An indirect enzyme-linked immunosorbent assay (i-ELISA) technique was developed to detect Movi utilizing the fusion protein as the coating antigen. The specificity, sensitivity, and reproducibility of all methods were assessed after each reaction parameter was optimized. Results The resulting rHsp70-P113 protein had a molecular weight of approximately 51 kDa and was predominantly expressed in the supernatant. Western blot analysis demonstrated its favourable reactivity. The optimal parameters for the i-ELISA technique were as follows: the rHsp70-P113 protein was encapsulated at a concentration of 5 μg/mL; the serum was diluted at a ratio of 1:50; the HRP-labelled donkey anti-goat IgG was diluted at a ratio of 1:6,000. The results of the cross-reactivity assays revealed that the i-ELISA was not cross-reactive with other goat-positive sera against Mycoplasma mycodies subsp. capri (Mmc), Mycoplasma capricolum subsp. capripneumoniae (Mccp), Mycoplasma arginini (Marg), orf virus (ORFV) or enzootic nasal tumour virus of goats (ENTV-2). The sensitivity of this method is high, with a maximum dilution of up to 1:640. The results of the intra- and inter-batch replication tests revealed that the coefficients of variation were both less than 10%, indicating excellent reproducibility. The analysis of 108 clinical serum samples via i-ELISA and indirect haemagglutination techniques yielded significant findings. Among these samples, 43 displayed positive results, whereas 65 presented negative results, resulting in a positivity rate of 39.8% for the i-ELISA method. In contrast, the indirect haemagglutination technique identified 20 positive samples and 88 negative samples, resulting in a positivity rate of 18.5%. Moreover, a comparison between the two methods revealed a conformity rate of 78.7%. Conclusion The results obtained in this study lay the groundwork for advancements in the use of an Movi antibody detection kit, epidemiological inquiry, and subunit vaccines.

Background and Aim: The productivity of sheep in humid tropical plantation areas relies on their ability to adapt. Oil palm plantations serve as potential grazing lands for livestock. This study aimed to identify Garut sheep adaptations in oil palm and rubber plantations of the Garut district, West Java, Indonesia. Materials and Methods: The total number of sheep used was 103 as the object of this study. Each individual of sheep was used for several different observations, including: Physiological assessment using 24 sheep of various ages, molecular analysis of heat stress using 31 sheep, worm egg count using 59 sheep, and for morphological assessment using 98 sheep. A general linear model was employed to analyze rectal temperature (RT), heart rate (HR), respiratory rate, number of eggs in each gram of sample feces, body weight (BW), body condition score, and morphometric measurements according to age and sex. Forage was compared between oil palm and rubber plantations during the vegetation analysis. Results: RT, HR, and panting frequency were significantly (p < 0.05) affected by the age and sex of the sheep. The mutation was found in the coding region of the HSP70 gene, which is approximately 232 bp long. Fecal eggs were found in 99% of the fecal samples, consisting of 100% Strongyle eggs and 1.75% Moniezia eggs. BW, body condition score, shoulder height, body length, pelvic height, chest circumference, and number of eggs were significantly affected (p < 0.05) by the age and sex of the sheep. The average fresh matter of vegetation under the plantation was 248.69 ± 120.94 g/m2 and 718.15 ± 249.93 g/m2 for oil palm and rubber plantations, respectively. Conclusion: Garut sheep were adapted to oil palm and rubber plantations in the humid tropical region. Plantations are potential sources of sheep grazing and roughage. Further research is needed regarding the consumption of forages in oil palm and rubber plantations.

Background and Aim: The productivity of sheep in humid tropical plantation areas relies on their ability to adapt. Oil palm plantations serve as potential grazing lands for livestock. This study aimed to identify Garut sheep adaptations in oil palm and rubber plantations of the Garut district, West Java, Indonesia. Materials and Methods: The total number of sheep used was 103 as the object of this study. Each individual of sheep was used for several different observations, including: Physiological assessment using 24 sheep of various ages, molecular analysis of heat stress using 31 sheep, worm egg count using 59 sheep, and for morphological assessment using 98 sheep. A general linear model was employed to analyze rectal temperature (RT), heart rate (HR), respiratory rate, number of eggs in each gram of sample feces, body weight (BW), body condition score, and morphometric measurements according to age and sex. Forage was compared between oil palm and rubber plantations during the vegetation analysis. Results: RT, HR, and panting frequency were significantly (p < 0.05) affected by the age and sex of the sheep. The mutation was found in the coding region of the HSP70 gene, which is approximately 232 bp long. Fecal eggs were found in 99% of the fecal samples, consisting of 100% Strongyle eggs and 1.75% Moniezia eggs. BW, body condition score, shoulder height, body length, pelvic height, chest circumference, and number of eggs were significantly affected (p < 0.05) by the age and sex of the sheep. The average fresh matter of vegetation under the plantation was 248.69 ± 120.94 g/m² and 718.15 ± 249.93 g/m² for oil palm and rubber plantations, respectively. Conclusion: Garut sheep were adapted to oil palm and rubber plantations in the humid tropical region. Plantations are potential sources of sheep grazing and roughage. Further research is needed regarding the consumption of forages in oil palm and rubber plantations. [ABSTRACT FROM AUTHOR]

Introduction: Prion diseases are deadly neurodegenerative disorders in both animals and humans, causing the destruction of neural tissue and inducing behavioral manifestations. Heat shock proteins (Hsps), act as molecular chaperones by supporting the appropriate folding of proteins and eliminating the misfolded proteins as well as playing a vital role in cell signaling transduction, cell cycle, and apoptosis control. SW02 is a potent activator of Hsp 70 kDa (Hsp70). Methods: In the current study, the protective effects of SW02 against prion protein 106-126 (PrP106-126)-induced neurotoxicity in human neuroblastoma cells (SH-SY5Y) were investigated. In addition, the therapeutic effects of SW02 in ME7 scrapie-infected mice were evaluated. Results: The results showed that SW02 treatment significantly increased Hsp70 mRNA expression levels and Hsp70 ATPase activity (p < 0.01). SW02 also significantly inhibited cytotoxicity and apoptosis induced by PrP106-126 (p < 0.01) and promoted neurite extension. In vivo, intraperitoneal administration of SW02 did not show a statistically significant difference in survival time (p = 0.16); however, the SW02-treated group exhibited a longer survival time of 223.6 ± 6.0 days compared with the untreated control group survival time of 217.6 ± 5.4 days. In addition, SW02 reduced the PrPSc accumulation in ME7 scrapie-infected mice at 5 months post-injection (p < 0.05). A significant difference was not observed in GFAP expression, an astrocyte marker, between the treated and untreated groups. Conclusion: In conclusion, the potential therapeutic role of the Hsp70 activator SW02 was determined in the present study and may be a novel and effective drug to mitigate the pathologies of prion diseases and other neurodegenerative diseases. Further studies using a combination of two pharmacological activators of Hsp70 are required to maximize the effectiveness of each intervention. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancerrelated mortality worldwide, necessitating improved diagnostic and prognostic markers. Immunohistochemical (IHC) markers such as alpha-fetoprotein (AFP), glypican-3 (GPC3), heat shock protein 70 (HSP70), and cytokeratin 19 (CK19) have shown promise in HCC detection and prognosis. However, their utility in clinical practice remains to be fully elucidated. Materials and Methods: We conducted a retrospective study analyzing 129 HCC tissue samples for the expression of AFP, GPC3, HSP70, and CK19 using IHC staining. Clinicopathological parameters, including tumor size, grade, presence of cirrhosis, and patient survival, were correlated with marker expression. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Results: Our analysis revealed variable expression patterns for AFP, GPC3, HSP70, and CK19 in HCC tissues. AFP and GPC3 exhibited moderate to high expression levels, while HSP70 showed moderate expression, and CK19 demonstrated lower expression. Positive correlations were observed between marker expression and tumor size, grade, and the presence of cirrhosis (p < 0.05). Additionally, higher expression levels of AFP, GPC3, and HSP70 were associated with shorter overall survival and lower survival rates at 1 year and 3 years (p < 0.001). In contrast, lower expression levels of CK19 were associated with better overall survival and higher survival rates. Conclusion: Our study highlights the diagnostic and prognostic potential of AFP, GPC3, HSP70, and CK19 in HCC. These markers exhibit distinct expression patterns and associations with clinicopathological parameters and patient outcomes, underscoring their utility in guiding clinical management decisions. Further validation studies in larger cohorts are warranted to confirm our findings and facilitate the integration of these markers into routine clinical practice. [ABSTRACT FROM AUTHOR]

The heat shock protein 70 (HSP70) gene family plays a crucial role in the response of organisms to environmental stress. However, it has not been systematically characterized in shrimp. In this study, we identified 25 PcHsp70 genes in the Penaeus chinensis genome. The encoded proteins were categorized into six subgroups based on phylogenetic relationships. Tandem duplication was the main driver of amplification in the PcHsp70 family, and the genes have experienced strong purifying selection during evolution. Transcriptome data analysis revealed that the 25 PcHsp70 members have different expression patterns in shrimp under conditions of low temperature, low salinity, and white spot syndrome virus infection. Among them, PcHsp70.11 was significantly induced under all three stress conditions, suggesting that this gene plays an important role in response to environmental stress in P. chinensis. To the best of our knowledge, this is the first study to systematically analyze the Hsp70 gene family in shrimp. The results provide important information on shrimp Hsp70s, contributing to a better understanding of the role of these genes in environmental stress and providing a basis for further functional studies.

Background: Cellular stress caused by noise-induced hearing loss can be observed through the damage of cochlear hair cells, mechanically and metabolically. SNR value on the DPOAE examination assesses the sensory function of cochlear outer hair cells. HSP70 as marker of cellular stress can be identified from its levels in blood and its expression in the cochlea. Methods: Three groups of rats were used for the noise intervention: Group 1 was the control group, Group 2 had a noise exposure of 100 dB, and Group 3 received a noise exposure of 110 dB. DPOAE examination was then conducted, blood samples from rats' tail were collected after a noise treatment, followed by the measurement of HSP70 levels by ELISA readings. Rats were terminated afterwards and immunohistochemical examination of the cochlear organ of Corti was performed to calculate the expression of HSP70. The data obtained were analyzed using SPSS. Results: A decrease occurred in the values of SNR and an increase occurred in HSP70 levels in blood along with its expression in the cochlea of noise model Rattus norvegicus, and there is a correlation between the three. Conclusion: The decrease in SNR values, increase in HSP70 levels in blood, and increase in HSP70 expression in the cochlear organ of Corti of Rattus norvegicus, proves that noise-induced hearing loss triggers the production of HSP70 as a cytoprotective agent in preventing inner ear damage. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Heat shock protein 70(HSP70) is a protein that can inhibit cell protein denaturation or expansion under stress or high temperature. It plays a key role in the expression of inflammatory factors, inhibition of apoptosis, and inhibition of protein aggregation. HSP70 is a protein that can inhibit cell protein denaturation or expansion under stress or high temperature. It plays a key role in the expression of inflammatory factors, inhibition of apoptosis, and inhibition of protein aggregation. This paper expounds the close relationship between heat shock protein 70 and the pathogenesis of lung diseases such as lung cancer, pneumonia, pulmonary tuberculosis and asthma, and provides a new idea for the rapid diagnosis of lung diseases. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are central components of the innate immunity system against cancers. Since tumor cells have evolved a series of mechanisms to escape from NK cells, developing methods for increasing the NK cell antitumor activity is of utmost importance. It is previously shown that an ex vivo stimulation of patient‐derived NK cells with interleukin (IL)‐2 and Hsp70‐derived peptide TKD (TKDNNLLGRFELSG, aa450‐461) results in a significant upregulation of activating receptors including CD94 and CD69 which triggers exhausted NK cells to target and kill malignant solid tumors expressing membrane Hsp70 (mHsp70). Considering that TKD binding to an activating receptor is the initial step in the cytolytic signaling cascade of NK cells, herein this interaction is studied by molecular docking and molecular dynamics simulation computational modeling. The in silico results showed a crucial role of the heterodimeric receptor CD94/NKG2A and CD94/NKG2C in the TKD interaction with NK cells. Antibody blocking and CRISPR/Cas9–mediated knockout studies verified the key function of CD94 in the TKD stimulation and activation of NK cells which is characterized by an increased cytotoxic capacity against mHsp70 positive tumor cells via enhanced production and release of lytic granules and pro‐inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Introduction: Psoriasis is a chronic, non-infectious skin disease that affects people of all ages and has no sex preference, which is caused by environmental stressors involving skin cells, immunocytes, and several biologic signaling molecules. Psoriasis has been linked to psychological, metabolic, arthritic, and cardiovascular complications. Heat shock protein 70 (HSP70) is considered the most protective member of the HSP family. HSP70 can regulate protein homeostasis, minimize stress-induced denaturation and aggregation of intracellular proteins and operate as a protective factor in tissue damage. This study aimed to investigate the serum level of HSP70 in patients with psoriasis to assess whether there is an association of HSP70 with psoriasis and to assess the effects of age, gender, body mass index (BMI), waist circumference, and disease duration on the serum level of HSP70. Material and methods: This was a case-control study which recruited 98 patients with psoriasis and 81 apparently healthy age- and sex-matched individuals as controls. Blood samples were collected via venipuncture (5 ml) to estimate the HSP70, random blood sugar, liver enzymes, lipid profile, and complete blood count. Results: The results revealed that the level of HSP70 was significantly higher in psoriasis patients compared to the control group (p-value < 0.05). The level of HSP70 showed a significant association with gender, but a non-significant positive correlation with duration of psoriasis. The level of HSP70 showed a non-significant negative correlation with age, BMI and waist circumference. Conclusions: The study suggested that HSP70 may have a potential role in the pathophysiology of psoriasis and may help to explain the mechanisms behind the development and treatment of psoriatic lesions with different severity. [ABSTRACT FROM AUTHOR]

Rutin (Ru) is a flavonol glycoside, has significant scavenging characteristics against various reactive oxygen species, which exploits for widespread pharmacological activities such as anti-inflammatory and anti-allergic effects. This study aims to improve the bioavailability of iron oxide nanoparticles (IONPs) by coating them with Ru (Ru-IONPs). Considering this, IONPs and Ru-IONPs were prepared and characterized via various physical techniques. In addition, atomic absorption spectroscopy (AAS) has been used to assess the bio-distribution of the prepared formulation in vivo. Results revealed that the prepared IONPs and Ru-IONPs have a spherical shape with an average diameter of about 8 nm and 10 nm, respectively. Their surface potentials were found to be −19 ± 3.9 and −29.5 ± 5.4 mV, respectively. In vivo results revealed that single dose of IV administration of IONPs (16 mg/kg) elevated oxidative stress, indicated by the reduction of GSH in both heart and liver tissues, and increased their MDA contents. Also, IONPs administration resulted in hepatotoxicity characterized by a significant increase in ALT and AST levels in addition to cardiotoxicity characterized by a significant increase in CK-MB and LDH, in addition to the downregulation of heat shock protein 70 (HSP70) expression, while upregulation of TNF-α expression in both heart and liver tissues. Conversely, nearly all of these alterations were significantly ameliorated for animal groups administrated Ru-IONPs and the morphological injury's counteraction in both heart and liver tissues. Therefore, we suggest that Ru could be used to alleviate the harmful effects and damages associated with IONPs administration due to its antioxidant, anti-inflammatory, and free radical scavenging properties. [ABSTRACT FROM AUTHOR]

For marine invertebrates, the disruption of organismal physiology and behavior by nanoplastics (NPs) has been extensively reported. Heat shock proteins (Hsps) are important for redundant protein breakdown, environmental changes, and intracellular protein transport. An exhaustive identification of Hsp70 genes and an experiment where different concentrations of NPs were stressed were performed to study how Hsp70 genes respond to NPs stress in Monodonta labio. Our results identified 15 members of Hsp70 within the genome of M. labio and provided insights into their responses to different concentrations of acute NP stress. Phylogenetic analyses revealed extensive amplification of the Hsp70 genes from the Hsc70 subfamily, with gene duplication events. As a result of NP stress, five of fifteen genes showed significant upregulation or downregulation. Three Hsp70 genes were highly expressed at an NP concentration of 0.1 mg/L, and no genes were downregulated. At 10 mg/L, they showed significant upregulation of two genes and significant downregulation of two genes. At 1 mg/L treatment, three genes were significantly downregulated, and no genes were significantly upregulated. Moreover, a purifying selection was revealed using a selection test conducted on duplicate gene pairs, indicating functional redundancy. This work is the first thorough examination of the Hsp70s in Archaeogastropoda. The findings improve knowledge of Hsp70s in molluscan adaptation to NP stress and intertidal living and offer essential data for the biological study of M. labio. [ABSTRACT FROM AUTHOR]

Context: The interface of Hsp70-Bim protein–protein interaction (PPI) has been identified as a specific target for Chronic Myeloid Leukemia (CML) therapy and the specific inhibitors were developed to exhibit in vivo anti-leukemia activities. Herein, we explored the binding mechanism of a Hsp70-Bim inhibitor, 6-(cyclohexylthio)-3-((2-morpholinoethyl) amino)-1-oxo-1H-phenalene-2-carbonitrile (S1g-6), to Hsp70 at the atomic level by MD simulation. TYR-149, THR-222, ALA-223, and GLY-224 on Hsp70 were identified as four key residues that contribute to Hsp70/S1g-6 complex. Moreover, the site mutation validation demonstrated the TYR-149 of Hsp70 is a "hot-spot" in the Hsp70-Bim PPI interface. These results could benefit the design of further inhibitors to occupy the Bim binding site on the Hsp70 surface. Methods: The binding mechanism of S1g-6 and Hsp70 was predicted through the molecular dynamics (MD) method by Gromacs-2021.3. The MD simulation was performed with 100-ps NVT and 100-ps NPT ensemble, and the force field was chosen as the Charmm36 force field. The temperature was set as 300 K, the time step was 2 fs and the total MD simulation time was 500 ns. [ABSTRACT FROM AUTHOR]

Gastric ulcer is one of the most frequent gastrointestinal ailments worldwide. Indomethacin, one of the most potent NSAIDs, suffers undesirable ulcerogenic activity. Caffeic acid phenethyl ester (CAPE) has known health benefits. The current study examined the potential of CAPE to combat indomethacin-induced gastric ulcers in rats. Animals were randomized into 5 groups: control, Indomethacin (50 mg/kg) mg/kg), Indomethacin + CAPE (5 mg/kg/day), Indomethacin + CAPE (10 mg/kg), and Indomethacin + Omeprazole (30 mg/kg). CAPE prevented the rise in ulcer index, attenuated histopathological changes and preserved gastric mucin concentration. CAPE efficiently significantly prevented accumulation of malondialdehude (MDA) and prevented exhaustion of the enzymatic activities of catalase (CAT) and superoxide dismutase (SOD). Further, CAPE prevented the rise in the expression of tumor necrosis factor-α (TNF-α), cyclo-oxygenase-2 (COX-2) and nuclear factor kapp-B (NFκB). This was associated with down-regulation of Bax and up-regulation of Bcl-2 mRNA. Finally, CAPE prevented induced indomethacin-induced decrease in heat shock protein 70 (HSP70) in gastric tissues. In conclusion, CAPE possesses the ability to prevent indomethacin-induced gastric ulcer in rats. This involves, at least partially, antioxidation, anti-inflammation, anti-apoptosis and enhancement of HSP70 expression. [ABSTRACT FROM AUTHOR]

IntroductionPrion diseases are deadly neurodegenerative disorders in both animals and humans, causing the destruction of neural tissue and inducing behavioral manifestations. Heat shock proteins (Hsps), act as molecular chaperones by supporting the appropriate folding of proteins and eliminating the misfolded proteins as well as playing a vital role in cell signaling transduction, cell cycle, and apoptosis control. SW02 is a potent activator of Hsp 70 kDa (Hsp70).MethodsIn the current study, the protective effects of SW02 against prion protein 106-126 (PrP106-126)-induced neurotoxicity in human neuroblastoma cells (SH-SY5Y) were investigated. In addition, the therapeutic effects of SW02 in ME7 scrapie-infected mice were evaluated.ResultsThe results showed that SW02 treatment significantly increased Hsp70 mRNA expression levels and Hsp70 ATPase activity (p < 0.01). SW02 also significantly inhibited cytotoxicity and apoptosis induced by PrP106-126 (p < 0.01) and promoted neurite extension. In vivo, intraperitoneal administration of SW02 did not show a statistically significant difference in survival time (p = 0.16); however, the SW02-treated group exhibited a longer survival time of 223.6 ± 6.0 days compared with the untreated control group survival time of 217.6 ± 5.4 days. In addition, SW02 reduced the PrPSc accumulation in ME7 scrapie-infected mice at 5 months post-injection (p < 0.05). A significant difference was not observed in GFAP expression, an astrocyte marker, between the treated and untreated groups.ConclusionIn conclusion, the potential therapeutic role of the Hsp70 activator SW02 was determined in the present study and may be a novel and effective drug to mitigate the pathologies of prion diseases and other neurodegenerative diseases. Further studies using a combination of two pharmacological activators of Hsp70 are required to maximize the effectiveness of each intervention.

[Objective] The purpose of the study was to clone heat shock protein Hsp70 gene from Apocheima cinerarius, analyze its physicochemical properties and expression, and explore the role of this gene in coping with the adverse environment of A. cinerarius. [Method] In the study, Hsp70 was cloned and named as AcinHsp70 (GenBank entry number: OP750249) based on the transcriptome data (under different low temperature stress of A. cinerarius larvae). The physical and chemical properties of Hsp70 gene were analyzed by using bioinformation analysis software. qPCR was used to detect the expression profiles of AcinHsp70 under different temperature stresses (10,5, 0, 5 and 25 °C) and under different time treatments at 4 °C. [Result] The total length of CDS of AcinHsp70 sequence was 1899 bp, encoding 633 amino acids, the molecular weight of protein was 69.91 kDa, and the isoelectric point was 5.51. The N-terminus of the protein lacked a signal peptide and transmembrane region. Phosphorylation sites were identified at serine, threonine and tyrosine residues (24, 26, and 8 sites respectively). No glycosylation sites were observed. The average hydrophilicity of the protein was 0.507, with a predicted instability coefficient of 33. 19, indicating its stability as a hydrophilic protein. Subcellular localization analysis revealed predominant cytoplasmic distribution. The results of sequence comparison and phylogenetic analysis showed that the A. cinerarius was closely related to Melitaea cinxia, and the sequence identity reached 92.91%. Gene expression results showed that AcinHsp70 expression was not significantly different under different temperature (except for 10 °C) stress, and the expression was significantly up-regulated after recovery. The expression level of the AcinHsp70 exhibited an initial increase followed by a subsequent decrease, with maximum expression after 1 hour treatment at 4 °C. [Conclusion] AcinHsp70 is closely related to the response of A. cinerarius to low temperature stress, and the results help to reveal the molecular function of Acinhsp70 under low temperature stress. [ABSTRACT FROM AUTHOR]

Heat shock proteins are natural biomarker that plays a vital role in genetic variability and adaptive survival in organisms under environmental stress. We assessed the effect of the stressor using Heat shock protein 70 in Hemibarbus labeo and Lepomis macrochirus at three geological points of Juam and Yedang lake. The study focused on the stress-relieving effect of heat shock protein 70 expressed in fish associated with physicochemical factors in the lake ecosystem. We recorded significant upregulation (p < 0.05) of the heat shock protein 70 gene in L. macrochirus in Juam (0.99-fold) and Yedang (1.44-fold). The upregulation in H. labeo indicated 0.83-fold in Juam and 1.21-fold in Yedang. The water quality index determined using physicochemical factors was low in the middle regions of both lakes. However, the maximum gene expression distribution was found in Yedang. The two-way clustering analysis revealed ammonia, total phosphorus, and suspended solids with maximum stress threshold. Dissolved oxygen, pH, nitrate, and organic carbon were the stress factors with minimal concentrations induced expression. The key observations are (i) the vital influence of molecular markers regulated tolerance at initial stress levels, (ii) the synergistic effect of the stressors and Heat shock protein 70 induction impacted adaptive strategy in fishes to regain tolerance (iii) fish population (L. macrochirus) with elevated response exhibited maximum distribution, correlating with the practical scenario. Heat shock protein 70 expressions through metabolic compensation strategy thus influenced the size of inhabited fish population retarding biodiversity of the lake ecosystem. [ABSTRACT FROM AUTHOR]

Tegumentary leishmaniasis (TL) is endemic but neglected in southern Europe. Therefore, this study aimed to analyze the Leishmania strains causing TL cases in northeastern Italy, where an upsurge of TL cases has been observed in the last decade. Sections from 109 formalin-fixed and paraffin-embedded (FFPE) biopsies of skin and mucosal tissues were collected from TL cases in the selected area. Two DNA targets were amplified and sequenced: the ribosomal internal transcribed spacer 1 (ITS1) and the heat-shock protein 70 gene (hsp70). An in silico analysis was also performed on 149 genomes belonging to the Leishmania donovani complex. A total of 88 out of 109 (80.7%) samples from 83 TL cases were successfully typed by ITS1 and/or hsp70. ITS1 analysis identified L. infantum in 67 cases (91.8%), while L. major (n = 4, 5.5%) and L. tropica (n = 2, 2.7%) were detected in the remaining cases that were categorized as imported. Further, the hsp70 typing of 75 autochthonous cases showed the presence of eight distinct sequence variants belonging to the Leishmania donovani complex, with high genetic variability when compared to known L. infantum populations. In conclusion, our findings show that peculiar L. infantum variants are emerging in the novel focus on TL in northeastern Italy. [ABSTRACT FROM AUTHOR]

Repeated hot water immersion (HWI) can improve glycemic control in healthy individuals but data are limited for individuals with type 2 diabetes mellitus (T2DM). The present study investigated whether repeated HWI improves insulin sensitivity and inflammatory status and reduces plasma ([extracellular heat shock protein 70]) [eHSP70] and resting metabolic rate (RMR). Fourteen individuals with T2DM participated in this pre- versus postintervention study, with outcome measures assessed in fasted (≥12 h) and postprandial (2-h post-75 g glucose ingestion) states. HWI consisted of 1 h in 40°C water (target rectal temperature 38.5°C-39°C) repeated 8-10 times within a 14-day period. Outcome measures included insulin sensitivity, plasma [glucose], [insulin], [eHSP70], inflammatory markers, RMR, and substrate utilization. The HWI intervention increased fasted insulin sensitivity (QUICKI; P = 0.03) and lowered fasted plasma [insulin] (P = 0.04), but fasting plasma [glucose] (P = 0.83), [eHSP70] (P = 0.08), [IL-6] (P = 0.55), [IL-10] (P = 0.59), postprandial insulin sensitivity (P = 0.19), plasma [glucose] (P = 0.40), and [insulin] (P = 0.47) were not different. RMR was reduced by 6.63% (P < 0.05), although carbohydrate (P = 0.43) and fat oxidation (P = 0.99) rates were unchanged. This study shows that 8-10 HWIs within a 14-day period improved fasting insulin sensitivity and plasma [insulin] in individuals with T2DM, but not when glucose tolerance is challenged. HWI also improves metabolic efficiency (i.e., reduced RMR). Together these results could be clinically important and have implications for metabolic health outcomes and well-being in individuals with T2DM. NEW & NOTEWORTHY This is the first study to investigate repeated HWI to raise deep body temperature on insulin sensitivity, inflammation, eHSP70, and substrate utilization in individuals with T2DM. The principal novel findings were improvements in fasting insulin sensitivity and fasting plasma [insulin] but no change in fasting plasma [glucose], postprandial insulin sensitivity, plasma [insulin], or [glucose]. There was also no change in eHSP70, inflammatory status, or substrate utilization but there were reductions in RMR and oxygen consumption. [ABSTRACT FROM AUTHOR]

Melatonin is a hormone secreted from the pineal gland. Hypothermic effect of melatonin has been reported in working donkeys. It may, thus, exert positive effects on the responses of donkeys exposed to strenuous physical activity. The study was aimed at evaluating the effects of melatonin administration on changes in tumour necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), heat shock protein 70 (HSP70), and sestrin-2 (Sesn2) concentrations in donkeys subjected to packing (load-carrying) during the hot-dry season. Ten male pack donkeys (2–3 years old; 93 ± 2.7 kg) were divided into two groups (group 1, packing + melatonin (P + M), and group 2, packing − melatonin (P − M)) randomly served as the subjects. Melatonin administration was done for 7 consecutive days to P + M donkeys while P − M donkeys served as controls. They were all packed three times within the week, one day apart. During the experiment, meteorological parameters were recorded. Blood sample was collected before and after packing for the evaluation of concentrations of TNF-α, IL-10, HSP70, and Sesn2. The temperature-humidity index was 80.33 after packing. There was significant (P ˂ 0.05) increase in the concentrations of IL-10 in both P + M and P − M donkeys. Concentration of HSP70 increased significantly (P ˂ 0.05) in P − M donkeys only. The result shows that packing during hot-dry conditions was stressful to the donkeys as evidenced by increase in concentrations of HSP70. Administration of melatonin pre-packing prevented increase in the concentrations of HSP70 in P + M donkeys. The donkeys were exposed to heat stress, the oral administration of melatonin alleviated the heat stress impacts and stress due to packing and may improve their health status and work output during the hot-dry season. [ABSTRACT FROM AUTHOR]

Objective To research the expression level of heat shock protein 70 (HSP70) and S100 calcium-binding protein A9 (S100A9) in glioma tissue and their differential diagnostic value in low-level brain glioma and dysembryoplastic neuroepithelial tumor (DNT) .Methods All pathological specimens were taken from 160 newly diagnosed patients with gliomas in Guangdong Clifford Hospital and Chinese People′s Liberation Army Southern Theater Command Gneral Hospital from January 2015 to December 2020,including 40 patients with World Health Organization (WHO) grade Ⅰ,Ⅱ,Ⅲ and Ⅳ gliomas.Immunohistochemical method was used to detect the expression levels of HSP70 and S100A9 in 160 cases of glioma and normal brain tissue adjacent to tumor, and 20 cases of DNT.Results The detectable rates of HSP70 and S100A9 were 85.0% (136/160) and 7.5% (12/160),respectively.The expression of HSP70 in gliomas with differences WHO grades was statistically significant (P＜0.05),and the expression level increased with the improvement of who grade of gliomas, which could also be used for the differential diagnosis of low-grade gliomas and DNT.S100A9 had no statistical difference in different WHO grades (P＞0.05),and it could not be used for the differential diagnosis of DNT and low-grade glioma.There was no correlation between HSP70 and S100A9 expression in glioma tissues.Conclusion HSP70 can be used in the diagnosis of brain glioma.The expression level increases with the improvement of WHO grade of glioma, and can be used in the differential diagnosis of low-level glioma and DNT.S100A9 has no such value. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease that affects millions of elderly people worldwide and is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The precise mechanisms underlying the pathogenesis of PD are still not fully understood, but it is well accepted that the misfolding, aggregation, and abnormal degradation of proteins are the key causative factors of PD. Heat shock protein 70 (Hsp70) is a molecular chaperone that participates in the degradation of misfolded and aggregated proteins in living cells and organisms. Parkin, an E3 ubiquitin ligase, participates in the degradation of proteins via the proteasome pathway. Recent studies have indicated that both Hsp70 and Parkin play pivotal roles in PD pathogenesis. In this review, we focus on discussing how dysregulation of Hsp70 and Parkin leads to PD pathogenesis, the interaction between Hsp70 and Parkin in the context of PD and their therapeutic applications in PD. [ABSTRACT FROM AUTHOR]

To explore the function and evolutionary relationships of inducible heat shock protein 70 (Hsp70) in Daphnia magna, cDNAs of four Hsp70 family members (DmaHsp70, DmaHsp70-2, DmaHsp70-12, DmaHsp70-14) were cloned. While all DmaHsp70s possess three function domains, it is noteworthy that only DmaHsp70 ends with a “EEVD” motif. Phylogenetic analysis indicates that the Hsp70-12 lineage is distanced from the rest, and therefore it is an uncharacterized lineage of Hsp70. The differences in isoelectric point and 3-dimensional (3D) conformation of the N-terminal nucleotide binding domain (NBD) of DmaHsp70s further support the theory. DmaHsp70s exhibit varied motif distribution patterns and the logo sequences of motifs have diverse signature characteristics, indicating that different mechanisms are involved in the regulation of ATP binding and hydrolysis for the DmaHsp70s. Protein-protein network together with the predicted subcellular locations of DmaHsp70s suggest that they likely fulfill distinct roles in cells. The transcription of four DmaHsp70s were changed during the recovery stage after thermal stress or oxidative stress. But the expression pattern of them were dissimilar. Collectively, these results collectively elucidated the identification of a previously uncharacterizedHsp70 lineage in animal and extended our understanding of the Hsp70 family.

Abstract Natural killer (NK) cells are central components of the innate immunity system against cancers. Since tumor cells have evolved a series of mechanisms to escape from NK cells, developing methods for increasing the NK cell antitumor activity is of utmost importance. It is previously shown that an ex vivo stimulation of patient‐derived NK cells with interleukin (IL)‐2 and Hsp70‐derived peptide TKD (TKDNNLLGRFELSG, aa450‐461) results in a significant upregulation of activating receptors including CD94 and CD69 which triggers exhausted NK cells to target and kill malignant solid tumors expressing membrane Hsp70 (mHsp70). Considering that TKD binding to an activating receptor is the initial step in the cytolytic signaling cascade of NK cells, herein this interaction is studied by molecular docking and molecular dynamics simulation computational modeling. The in silico results showed a crucial role of the heterodimeric receptor CD94/NKG2A and CD94/NKG2C in the TKD interaction with NK cells. Antibody blocking and CRISPR/Cas9–mediated knockout studies verified the key function of CD94 in the TKD stimulation and activation of NK cells which is characterized by an increased cytotoxic capacity against mHsp70 positive tumor cells via enhanced production and release of lytic granules and pro‐inflammatory cytokines.

Abstract Background Oral cancer is a common cause of death worldwide. The search for novel biomarkers for oral cancer is an ongoing struggle. Prognostic biomarkers are of great importance in diagnosis, and prediction of the cancer outcome. There are several disagreements in oral cancer studies over the role of heat shock proteins as prognostic markers. The current study investigated HSP70 expression in diverse tissues ranging from normal oral mucosa to dysplastic oral epithelium and oral squamous cell carcinoma to determine its role in oral carcinogenesis. Moreover, HSP70 was evaluated concerning different prognostic parameters to determine its capability in predicting cancer progression. Recurrence of tumor was recorded, and patients` disease-free survival was calculated and analyzed considering HSP70 expression to determine the potential utility of HSP70 immuno-expression in predicting recurrence. Methods A retrospective study was accomplished on 50 cases of OSCC. Biopsies from the cancerous tissue, the free surgical margin, and the normal oral mucosa were used. The grading of dysplastic epithelium and OSCCs followed the criteria of WHO classification (2017). The clinicopathological and follow-up records for each patient were retrieved. Pearson’s Chi-square test, one-way ANOVA, and post hoc tests were used to analyze the variance of HSP70 immuno-expression concerning different parameters. The Kaplan–Meier method was used to compute and visualize disease-free survival, and the log-rank test was used to analyze the data. With Cox regression, univariate and multivariate survival analyses were run. A P-value of 0.05 or less was regarded as statistically significant. Results A significant increased expression of HSP70 was observed as the tissue progressed from normal to dysplastic epithelium, and carcinoma (P = 0.000). HSP70 revealed a significant increased expression by progression from mild to severe dysplasia (P = 0.023), and also from well to moderately and poorly differentiated carcinoma (P = 0.000). High HSP70 immuno-expression was significantly associated with progression of OSCC; large-sized tumors (P = 0.002), advanced TNM clinical stages (P = 0.001), positive nodal involvement (P = 0.001), presence of recurrence (P = .008), and reduced DFS (P = 0.014). Conclusion HSP70 has a crucial contribution to oral carcinogenesis, and its immune-expression could potentially be used as predictor of progression and recurrence of OSCC patients. Trial registration: Retrospectively registered.

Abstract Background Photothermal therapy (PTT) is taken as a promising strategy for cancer therapy, however, its applicability is hampered by cellular thermoresistance of heat shock response and insufficient accumulation of photothermal transduction agents in the tumor region. In consideration of those limitations, a multifunctional “Golden Cicada” nanoplatform (MGCN) with efficient gene delivery ability and excellent photothermal effects is constructed, overcoming the thermoresistance of tumor cells and improving the accumulation of indocyanine green (ICG). Results Down-regulation of heat shock protein 70 (HSP70) makes tumor cells more susceptible to PTT, and a better therapeutic effect is achieved through such cascade augmented synergistic effects. MGCN has attractive features with prolonged circulation in blood, dual-targeting capability of CD44 and sialic acid (SA) receptors, and agile responsiveness of enzyme achieving size and charge double-variable transformation. It proves that, on the one hand, MGCN performs excellent capability for HSP70-shRNA delivery, resulting in breaking the cellular thermoresistance mechanism, on the other hand, ICG enriches in tumor site specifically and possesses a great thermal property to promoted PTT. Conclusions In short, MGCN breaks the protective mechanism of cellular heat stress response by downregulating the expression of HSP70 proteins and significantly augments synergistic effects of photothermal/gene therapy via cascade augmented synergistic effects.

Cancer is one of the world's major causes of death. The aim of this study is to examine the acute effects of resveratrol on testicular toxicity, oxidative stress, and apoptosis caused by MTX, which is widely used in the treatment of many diseases, especially cancer, histochemically, immunohistochemically, and biochemical methods using different parameters. A total of 32 Wistar albino male rats were randomly divided into 4 groups: control, resveratrol (RES), MTX, and MTX + RES, with 8 animals in each group. At the end of the experiment, tissue and blood samples were taken, and histochemical, immunohistochemical, and biochemical parameters were examined. In this study, where parameters were compared for the first time, total thiol (TT) and native thiol (NT) are the highest in the RES group, disulfide (DS), and ischemia-modified albumin (IMA) are the highest in the MTX group. Total oxidant status (TOS) and oxidative stress index (OSI) are the highest in the MTX group, and total antioxidant status (TAS) is the highest in the RES group. Separation and deterioration in the tunica albuginea, congestion and edema in the interstitial region, vacuolization in the seminiferous epithelium, and spermatogenic serial cells spilling into the lumen without completing their maturation were observed. When examined in terms of histochemical, immunohistochemical, and biochemical examinations, our study revealed that resveratrol has positive effects on methotrexate-induced acute testicular damage, oxidative stress, and apoptosis. [ABSTRACT FROM AUTHOR]

Background: Oral cancer is a common cause of death worldwide. The search for novel biomarkers for oral cancer is an ongoing struggle. Prognostic biomarkers are of great importance in diagnosis, and prediction of the cancer outcome. There are several disagreements in oral cancer studies over the role of heat shock proteins as prognostic markers. The current study investigated HSP70 expression in diverse tissues ranging from normal oral mucosa to dysplastic oral epithelium and oral squamous cell carcinoma to determine its role in oral carcinogenesis. Moreover, HSP70 was evaluated concerning different prognostic parameters to determine its capability in predicting cancer progression. Recurrence of tumor was recorded, and patients' disease-free survival was calculated and analyzed considering HSP70 expression to determine the potential utility of HSP70 immuno-expression in predicting recurrence. Methods: A retrospective study was accomplished on 50 cases of OSCC. Biopsies from the cancerous tissue, the free surgical margin, and the normal oral mucosa were used. The grading of dysplastic epithelium and OSCCs followed the criteria of WHO classification (2017). The clinicopathological and follow-up records for each patient were retrieved. Pearson's Chi-square test, one-way ANOVA, and post hoc tests were used to analyze the variance of HSP70 immuno-expression concerning different parameters. The Kaplan–Meier method was used to compute and visualize disease-free survival, and the log-rank test was used to analyze the data. With Cox regression, univariate and multivariate survival analyses were run. A P-value of 0.05 or less was regarded as statistically significant. Results: A significant increased expression of HSP70 was observed as the tissue progressed from normal to dysplastic epithelium, and carcinoma (P = 0.000). HSP70 revealed a significant increased expression by progression from mild to severe dysplasia (P = 0.023), and also from well to moderately and poorly differentiated carcinoma (P = 0.000). High HSP70 immuno-expression was significantly associated with progression of OSCC; large-sized tumors (P = 0.002), advanced TNM clinical stages (P = 0.001), positive nodal involvement (P = 0.001), presence of recurrence (P =.008), and reduced DFS (P = 0.014). Conclusion: HSP70 has a crucial contribution to oral carcinogenesis, and its immune-expression could potentially be used as predictor of progression and recurrence of OSCC patients. Trial registration: Retrospectively registered. [ABSTRACT FROM AUTHOR]

Small‐scale spatial variation in temperature plays a key role in limiting the distribution of organisms in thermally heterogeneous environments. In the rocky intertidal zone, intra‐day temperature variation at small scales (cm–m) can easily exceed 30°C.To experimentally test the impact of this small‐scale temperature heterogeneity on the distribution of an ecologically important limpet species (Cellana denticulata), boulders on an intertidal rocky reef in New Zealand were rotated and small‐scale temperature variability and food availability were measured throughout 1 year. Small‐scale variability in thermal tolerance, heart rate and heat shock protein expression was also measured to relate in situ limpet distributions with environmental conditions. Temperature variability was measured using limpet bio‐mimics and HOBO pendant temperature loggers, while food availability (chlorophyll a concentration) was measured on in situ concrete fibreboard tiles.To measure limpet distributions, every tagged limpet on each of 18 boulders was followed from June 2021 to 2022. During each sampling, the location of each limpet, compass direction and slope of the surface that each limpet inhabited was measured. To test for physiological differences among limpets from each microhabitat, thermal tolerance and heat shock protein expression were measured in collected limpets; in situ heart rates and body temperatures were also measured sporadically on hot days.Maximum predicted body temperatures (36–39°C), heart rates and actual body temperatures were greatest on equatorial surfaces (i.e. surfaces facing the equator) whereas food availability was greatest on poleward‐facing surfaces. During summer, limpets moved towards surfaces that minimised their body temperatures and maximised food availability, namely vertical and poleward‐facing surfaces and undersides of boulders.Thermal tolerance, measured using Arrhenius breakpoint temperatures (mean ± SE: 34.7–35.8 ± 0.4–0.7°C) and flat line temperatures (36.2–37.4 ± 0.3–0.4°C), was similar among limpets facing different directions. Surprisingly, heat shock protein expression was relatively consistent throughout the year and among directions.Overall, limpet populations are resilient to thermal stress because they effectively use behavioural thermoregulation to exploit cooler microhabitats that also have greater food availability during summer. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

Prion protein (PrP) adopts either a helical conformation (PrPC) or an alternative, beta sheet-rich, misfolded conformation (PrPSc). The PrPSc form has the ability to "infect" PrPC and force it into the misfolded state. Accumulation of PrPSc is associated with a number of lethal neurodegenerative disorders, including Creutzfeldt-Jacob disease (CJD). Knockout of PrPC protects cells and animals from PrPSc infection; thus, there is interest in identifying factors that regulate PrPC stability, with the therapeutic goal of reducing PrPC levels and limiting infection by PrPSc. Here, we assembled a short-hairpin RNA (shRNA) library composed of 25+ shRNA sequences for each of 133 protein homeostasis (aka proteostasis) factors, such as molecular chaperones and co-chaperones. This Proteostasis shRNA Library was used to identify regulators of PrPC stability in HEK293 Hu129M cells. Strikingly, the screen identified a number of Hsp70 family members and their co-chaperones as putative targets. Indeed, a chemical pan-inhibitor of Hsp70s reduced PrPC levels and limited conversion to PrPSc in N2a cells. These results implicate specific proteostasis sub-networks, especially the Hsp70 system, as potential new targets for the treatment of CJD. More broadly, the Proteostasis shRNA Library might be a useful tool for asking which proteostasis factors are important for a given protein.

Bovine respiratory disease (BRD) is the most significant health problem associated with newly received cattle in the beef industry. Serum concentrations of extracellular histones increase in a variety of diseases and histones are known to be cytotoxic to mammalian cells. Work in our lab indicated that failure to protect against cytotoxic effects of extracellular histones may be a component of severe cases of respiratory disease in cattle. The mechanisms or proteins that neutralize cytotoxic effects of extracellular histones are not fully elucidated, but C-reactive protein and complement activity have been associated with a reduced cytotoxic effect of extracellular histones. Work in the literature suggests that heat shock protein 70 (HSP70) concentrations in the serum is increased in disease and may directly activate complement. Unpublished observations in our lab indicated that HSP70 potentially interacts with histones to exacerbate cytotoxicity leading to our hypothesis that increased concentrations of HSP70 will decrease the protective capacity against histone cytotoxicity. Therefore, the objectives of the current study were to evaluate serum concentrations of HSP70 in weaned bulls entering the feedlot and the effects of increasing HSP70 concentrations on histone cytotoxicity in vitro. Weaned seedstock bulls (n = 130) composed of various breeds were fed using the GrowSafe System at the Tucumcari Bull Test for 122 d. At receiving, blood samples were obtained via coccygeal venipuncture, centrifuged, and serum immediately frozen on dry ice. Serum was analyzed for complement activity (CH50 assay) and protective capacity against extracellular histones using our novel histone toxicity assay. The ratio value of histone toxicity to CH50 was used to separate a subset of bulls as protective (n = 10) and non-protective (n = 10). Concentrations of HSP70 were quantified utilizing a commercially available ELISA kit. Data were analyzed using the GLM procedure of SAS. Serum concentrations of HSP70 were similar (P > 0.10) for protective and non-protective bulls. To test the responses to increased concentrations of HSP70 to mimic disease, protective and nonprotective serum was tested against histones alone and in combination with 0.5 or 40 ng/mL recombinant bovine HSP70. Complement activity from protective and non-protective bulls was not influenced (P > 0.10) in the presence and absence of recombinant bovine HSP70. Exogenous HSP70 at 0.5 or 40 ng/mL did not influence protective capacity in non-protective animals (P = 0.95). However, HSP70 at 0.5 ng/mL did not (P = 0.18) reduce protective capacity and reduced protective capacity (P < 0.01) at 40 ng/mL in serum from bulls that were assigned to the protective group. Results indicate that weaned bulls entering the feedlot display varied capacity to protect against histone toxicity and increased concentrations of HSP70 can reduce the protective capacity indicating that circulating HSP70 may play a role in bovine respiratory disease pathogenesis. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) exposure is a risk factor for endothelial dysfunction and cardiovascular disease. Ferroptosis is a type of cell death that relies on lipid peroxidation. Whether ferroptosis acts in Cd-induced vascular endothelial damage and the underlying mechanisms remain unclear. Herein, we found that Cd resulted in ferroptosis of vascular endothelial cells (ECs) in vivo and in vitro. In the visualized zebrafish embryos, Cd accumulated in vascular ECs, ROS and lipid peroxidation levels were increased, and the oxidoreductase system was disturbed after exposure. Moreover, Cd decreased Gpx4 in ECs and caused smaller mitochondria with increased membrane density. Accompanied by ferroptosis, the number of ECs and the area of the caudal venous plexus in zebrafish embryos were reduced, and the survival rate of HUVECs decreased. These effects were partially reversed by ferrostatin-1 and aggravated by erastin. Mechanistically, an excessive increase in Heat Shock Protein 70 (Hsp70) was identified by transcriptomics after Cd exposure. Inhibition of Hsp70 by VER-155008 or siRNA ameliorated Cd-induced ferroptosis, thereby alleviating endothelial injury. Furthermore, Hsp70 regulated Cd-induced ferroptosis by targeting multiple targets, including Gpx4, Fth1, Nrf2 and Acsl4. Our findings provide a new approach to investigating the endothelial damage of Cd and indicate that regulation of Hsp70 is an important target for alleviating this process.

The objective: to investigate the relationship between HSP70 concentrations in maternal serum and preeclampsia and assess the prospects of using HSP70 as a preeclampsia predictor. Materials and methods. The original publications, which study HSP70 in maternal serum of preeclamptic women, were searched and analyzed. Papers were identified with Scopus, PubMed Central, Virtual Health Library databases, published before January 2023, the keywords were «HSP70», «preeclampsia», «heat shock protein 70», «pregnant». Statistical analysis was performed via software EZR 1.55. Results. 16 case-control studies were included, making a total of 751 pregnant women with preeclampsia and 719 healthy pregnant women. The analysis found the statistically significant difference between HSP70 concentrations in maternal serum of preeclamptic and healthy pregnant patients. Cochrane Q-test showed high heterogeneity among studies (p<0.01), the value of the І² statistic was 97%. Dividing the studies into groups made it possible to reduce or remove heterogeneity completely. This high level of heterogeneity for publications together, but low within most groups, suggests that there are certain factors that significantly influence some studies. Conclusions. The conducted systematic review and meta-analysis confidently indicate an increased average serum concentration of HSP70 in pregnant women with preeclampsia compared to healthy pregnant women at the corresponding gestational age. No statistically significant relationship was found between increased HSP70 concentration in preeclampsia and pregnant women’s age, gestational age, systolic and diastolic blood pressure. Quantitative assessment of HSP70 levels is complicated by the lack of a single standard for laboratory diagnostics. The case-control design of the presented studies limits their significance. The use of HSP70 as a predictor of preeclampsia is promising, but requires further study and prospective cohort studies. [ABSTRACT FROM AUTHOR]

Heat shock protein 70 (HSP70) regulates the ligand binding of the glucocorticoid receptor (GR). In asthma patients, heat treatment increased both the GR expression and secretion of extracellular HSP70 (eHSP70) by bronchial epithelial cells (EC). The objective of this study was to assess the effects of eHSP70 on GR expression and the GR-dependent regulation of immune response in human bronchial ECs. Cells were treated with either eHSP70 or transfected with an expression vector for intracellular HSP70 (iHSP70). Ribonucleic acid (RNA) and protein levels were detected by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunofluorescence. Interleukin (IL-6 and IL-8) secretion was determined by enzyme linked immunosorbent assay (ELISA). The overexpression of iHSP70 decreased, while eHSP70 increased GR expression. In addition, eHSP70 increased the expression of the GR target dual-specificity phosphatase 1 (DUSP-1). In doing so, eHSP70 reduced the tumor growth factor (TGF)-β1-dependent activation of extracellular signal-regulated kinase (Erk)-1/2 and cyclic AMP response element binding protein (CREB) and the secretion of IL-6 and IL-8. Blocking the GR or Toll-like receptor 4 (TLR4) counteracted all eHSP70-induced effects. This study demonstrates a novel anti-inflammatory effect of eHSP70 by the signaling cascade of TLR4-GR-DUSP1, which inhibits TGF-β1-activated pro-inflammatory ERK1/2-CREB signaling and cytokine secretion. The findings suggest that eHSP70 might present a novel non-steroidal therapeutic strategy to control airway inflammation in asthma. [ABSTRACT FROM AUTHOR]

A heat shock protein 70 (Hsp70) was identified from Procambarus clarkii (named as PcHsp70). The open reading frame of the PcHsp70 cDNA was 1917 bp, encoding a 638 aa protein with signature sequences of the Hsp70 family. Tissue distribution results showed that PcHsp70 has relatively high expression in immune-related tissues such as hepatopancreas, gill, and hemocytes. The expressions of PcHsp70 in hepatopancreas and gill were significantly induced by Gram-positive bacterium, Gram-negative bacterium, and white spot syndrome virus stimulation, indicating that PcHsp70 may be involved in the immune response to pathogen invasion. The research will provide a foundation for understanding the resistance and stress mechanism of Hsp70 in P. clarkii. [ABSTRACT FROM AUTHOR]

Lacking a precise targeting strategy, castration-resistant prostate cancer (CRPC) is still hard to be treat effectively. Exploring treatment options that can accurately target CPRC is an important issue with urgent need. In this study, a novel nanotechnology-based strategy had been developed for the precise target treatment of CRPC. By combining microwaves and photothermal therapy (PTT), this nanoplatform, cmHSP70-PL-AuNC-DOX, targets tumor tissues with outstanding precision and achieves better anti-tumor activity by simultaneously eliciting photothermal and chemotherapeutic effects. From nanotechnology, cmHSP70-modified and thermo-sensitive liposome-coated AuNC-DOX were prepared and used for CRPC-targeted photothermal ablation and chemotherapy. Doxorubicin (DOX) was selected as the chemotherapeutic agent for cytotoxicity. In terms of the curative scheme, prostate tissues were firstly pre-treated with microwaves to induce the expression of heat shock protein 70 (HSP70) and its migration to the cell membrane, which was then targeted by HSP70 antibody (cmHSP70) coated on the nanoparticles to achieve accurate drug delivery. The nanoplatform then achieved precise ablation and controlled release of DOX under external near-infrared (NIR) irradiation. Through the implementation, the targeting, cell killing, and safety of this therapeutical strategy had been verified in vivo and in vitro. This work establishes an accurate, controllable, efficient, non-invasive, and safe treatment platform for targeting CRPC, provides a rational design for CRPC's PTT, and offers new prospects for nanomedicines with great precision. [ABSTRACT FROM AUTHOR]

Context: Heat shock protein 70 (HSP70) and glutathione peroxidase 5 (GPX5) are biomarkers of oxidative stress and stress in temperate, tropical environments, which are crucial for male reproduction. Their expression and distribution patterns in the testis and epididymis of Bactrian camels are still unknown. Aims: This study aims to investigate the HSP70 and GPX5 expression and localisation in 3- and 6-year-old Bactrian camel testis and epididymis. Methods: Reverse transcription quantitative polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry were used to detect HSP70 in the testis and epididymis (caput, corpus and cauda) and GPX5 in the epididymis at two developmental stages (3-year-old puberty group and 6-year-old adult group). Key results: HSP70 was upregulated in the testis. Immunohistochemistry results indicated the HSP70 protein was mainly detected in spermatids and Leydig cells of testicular tissue. In the epididymis, HSP70 was located at the luminal spermatozoa, the epithelium lining the epididymal and the epididymal interstitium. GPX5 expression was significantly higher in the caput epididymis than in the corpus and cauda epididymis. GPX5 protein was observed in the epithelium lining the epididymal, interstitium and luminal spermatozoa in the epididymis by immunohistochemistry. Conclusions: Bactrian camel HSP70 and GPX5 exhibited spatiotemporal expression specificity. Implications: HSP70 and GPX5 may be essential for germ cell development and reproductive success after sexual maturation in Sonid Bactrian camels. Bactrian camels have adapted to desert and semi-desert areas, and provide milk, meat and wool. Until now, our understanding of the expression patterns of the genes in the camel reproductive organs has been extremely limited. HSP70 and GPX5 are genes involved with anti-freezing and antioxidant activity. Our findings indicate that these two genes show spatiotemporal expression specificity in Bactrian camel testis and epididymis. This provides a good starting point for discussion and further research in the camel testis and epididymis. [ABSTRACT FROM AUTHOR]

The current study was undertaken to understand the underlying molecular mechanism(s) by which HIV Transactivator of transcription (Tat) alters oligodendrocyte maturation through the generation of reactive oxygen species (ROS), impairment of lysosomal functioning, and dysregulation of autophagy. We exposed primary rat immature oligodendrocytes to HIV Tat and utilized various experimental techniques to assess its effects on oligodendrocytes maturation. We measured ROS levels, assessed lysosomal membrane potential, determined cathepsin D activity, and analyzed the expression of autophagy-related markers. Furthermore, we investigated the potential of ROS scavengers and lysosomal protectants to mitigate the damaging effects of HIV Tat on oligodendrocytes maturation. Exposure of primary rat immature oligodendrocytes to HIV Tat significantly increased ROS levels, indicating the induction of oxidative stress. This oxidative stress impaired lysosomal functioning, as evidenced by a substantial increase in lysosomal membrane potential and a decrease in cathepsin D activity. Compromised lysosomal function resulted in dysregulated autophagy, which was confirmed by increased expression of SQSTM1. However, the administration of ROS scavengers and lysosomal protectants effectively attenuated the detrimental effects of HIV Tat on oligodendrocytes maturation. Our findings demonstrate that HIV Tat exposure induces oxidative stress, impairs lysosomal functioning, and dysregulates autophagy in oligodendrocytes. These molecular changes likely contribute to the altered maturation of oligodendrocytes observed in HIV-infected individuals. Understanding these underlying mechanisms provides valuable insights into the pathogenesis of HIV-associated neurocognitive disorders and highlights the potential of therapeutic strategies targeting ROS scavenging and lysosomal protection as adjunctive approaches for managing such complications in HIV +ve individuals. [ABSTRACT FROM AUTHOR]

Heat shock protein 70 (HSP70) is an evolutionarily conserved protein chaperone in prokaryotic and eukaryotic organisms. This family is involved in the maintenance of physiological homeostasis by ensuring the proper folding and refolding of proteins. The HSP70 family in terrestrial plants can be divided into cytoplasm, endoplasmic reticulum (ER)-, mitochondrion (MT)-, and chloroplast (CP)-localized HSP70 subfamilies. In the marine red alga Neopyropia yezoensis, the heat-inducible expression of two cytoplasmic HSP70 genes has been characterized; however, little is known about the presence of other HSP70 subfamilies and their expression profiles under heat stress conditions. Here, we identified genes encoding one MT and two ER HSP70 proteins and confirmed their heat-inducible expression at 25 °C. In addition, we determined that membrane fluidization directs gene expression for the ER-, MT-, and CP-localized HSP70 proteins as with cytoplasmic HSP70s. The gene for the CP-localized HSP70 is carried by the chloroplast genome; thus, our results indicate that membrane fluidization is a trigger for the coordinated heat-driven induction of HSP70 genes harbored by the nuclear and plastid genomes in N. yezoensis. We propose this mechanism as a unique regulatory system common in the Bangiales, in which the CP-localized HSP70 is usually encoded in the chloroplast genome. [ABSTRACT FROM AUTHOR]

Heat shock proteins (HSPs) are chaperones that catalyze the refolding of denatured proteins. In addition to their ability to prevent protein denaturation and aggregation, the HSPs have also been shown to modulate many signaling pathways. Among HSPs, the inducible 70 kDa HSP (HSP70) has especially been shown to improve neurological outcome in experimental models of brain ischemia and injury. HSP70 can modulate various aspects of the programmed cell death pathways and inflammation. This review will focus on potential mechanisms of the neuroprotective effects of HSP70 in stroke and brain trauma models. We also comment on potential ways in which HSP70 could be translated into clinical therapies.