A longitudinal assessment of heat exposure and biomarkers of kidney function on heat shock protein 70 and antibodies among agricultural workers.

BACKGROUND: Exposure to extreme heat impacts millions of people worldwide and outdoor workers are among the populations most affected by hot temperatures. Heat stress induces several biological responses in humans, including the production of heat shock proteins (HSP) and antibodies against HSP (anti-HSP) which may play a central role in the body's cellular response to a hot environment. OBJECTIVE: This longitudinal study investigated the impact of elevated temperatures and humidity on the presence of HSP70 and anti-HSP70 and examined relationships with markers of kidney function in an at-risk workforce under conditions of extreme heat and exertion in Guatemala. METHODS: We collected ambient temperature and relative humidity data as well as biomarkers and clinical data from 40 sugarcane workers at the start and the end of a 6-month harvest. We used generalized mixed-effects models to estimate temperature effects on HSP70 and anti-HSP70 levels. In addition, we examined trends between HSP70 and anti-HSP70 levels and markers of kidney function across the harvest. RESULTS: At the end of the harvest, temperatures were higher, and workers had, on average, higher levels of HSP70 and anti-HSP70 compared to the beginning of the season. We observed significant increasing trends with temperature indices, heat index, and HSP70 levels. Maximum temperature was associated with HSP70 increments after controlling for age, systolic and diastolic blood pressure (ß: 0.21, 95% Confidence Interval: 0.09, 0.33). Kidney function decline across the harvest was associated with both higher levels of anti-HSP70 levels at the end of the harvest as well as greater increases in anti-HSP70 levels across the harvest. CONCLUSIONS: These results suggest that workplace heat exposure may increase the production of HSP70 and anti-HSP70 levels and that there may be a relationship between increasing anti-HSP70 antibodies and the development of renal injury. HSP70 holds promise as a biomarker of heat stress in exposed populations.

Postmenopausal women treated for breast cancer with insulin resistance: clinical, analytical, cross-sectional.

This study aims to investigate the potential association between serum levels of cytokines, HSP60, HSP70 and IR (HOMA-IR) in postmenopausal women. We conducted a cross-sectional study involving 381 postmenopausal women, including 94 with a breast cancer diagnosis and 278 without. We analyzed anthropometric and laboratory measurements. Immunoassays were used to measure cytokines (TNF-α, IL-10, and IL-6) as well as heat shock proteins (HSP) 60 and 70 in the serum using the ELISA technique. Women diagnosed with breast cancer showed higher levels of HOMA-IR, IL-6, TNF, and HSP60, and lower levels of IL-10 and HSP70 compared to women without cancer. An association was found between HSP70 and HOMA-IR only in women with breast cancer (ß = 0.22, p = .030; without cancer: ß = 0.04, p = .404), regardless of age, waist circumference, smoking, and physical activity. No associations were observed between cytokines, HSP60, and HOMA-IR in both groups of women. HSP70 is positively associated with IR in women diagnosed with breast cancer.

[Occupational chronic psychological stress and transaminase, HSP70 gene family and its proteins association of the interaction with metabolic syndrome].

OBJECTIVE: To explore the association of Occupational chronic psychological stress with transaminase, heat shock protein70(HSP70)gene family and their protein interaction with metabolic syndrome(MS). METHODS: A case-control study was used. According to the inclusion and exclusion criteria, from March 2015 to March 2016, 583 unrelated MS patients were selected as the case group and 585 unrelated healthy people as the control group among hospitalized and physical examination subjects aged 20-60 in Wuzhong People's Hospital and General Hospital of Ningxia Medical University. Questionnaire survey, physical examination, clinical and biochemical indicators, serum HSP70 level and five-locus polymorphism detection of HSP70 gene were carried out. GMDR 0.7 software was used to analyze the relationship between psychological stress, transaminase, HSP70 gene and its protein interaction and MS. RESULTS: After adjusting for age and sex, the rs1008438, rs1061581, rs539689 and rs222795 locus of HSP70 gene in the Co-dominant model and Dominant model and the rs222795 loci in the Over-dominant model carry wild homozygous genotype and heterozygous genotype were all related to the reduction of MS risk(OR<1, P<0.05). GMDR result: the 2-factor interaction model composed of psychological stress and serum HSP70, the 2-3 factor interaction model composed of transaminase activity, and the 2-6 factor interaction model composed of five locus of HSP70 gene, the 2-9 factor interaction model consisting of psychological stress and transaminase activity, HSP70 gene and its protein were all significantly associated with MS(P<0.01, P<0.05), all each factor interaction models were the best, and the 9-factor optimal interaction model had the highest risk of MS(OR=46.51, 95%CI 27.65-78.26), and the risk of MS in high-risk type was 45.23 times higher than that in low-risk type(95%CI 31.29-65.38, P<0.01). CONCLUSION: HSP70 gene family carrying wild-type alleles is a protective factor for MS. The interaction among Occupational chronic psychological stress interacts with transaminases, HSP70 gene and its serum proteins may be associated with MS. With the increase of involvement interaction factors, the risk of MS increased significantly. The interaction of multiple factors can greatly increase its risk.

Onset of Adverse Abdominal Events Due to Intestinal Ischemia-Reperfusion Injury after Aortic Cross-Clamping Is Associated with Elevated HSP70 Serum Levels in the Early Postoperative Phase.

Tissue injury of the viscera during open thoracoabdominal aortic (TAA) reconstructions has been reported as the aftermath of the ischemia-reperfusion mechanism following supracoeliac aortic cross-clamping. Abdominal complications after open aortic reconstructions, although rare through the intraoperative implementation of selective visceral artery blood perfusion, are associated with high rates of reinterventions and a poor prognosis. Recent animal experiments demonstrated that provoking mesenteric ischemia in rats induces the leukocyte-mediated transcription of heat-shock protein 70 (HSP70), a chaperone belonging to the danger-associated molecular pattern proteins (DAMPs). Translating these findings clinically, we investigated the serum levels of HSP70 in patients undergoing open aortic reconstructions with supracoeliac clamping. We postoperatively observed a relevant induction of HSP70, which remained significantly elevated in cases of postoperative abdominal complications (paralytic ileus, abdominal compartment syndrome, and visceral malperfusion). The receiver-operator curve analysis revealed the reliable prognostic accuracy of HSP70 as a biomarker for these complications as soon as 12 h post-operation (AUC 0.908, sensitivity 88.9%, specificity 83.3%). In conclusion, measuring HSP70 serum levels in the early postoperative phase may serve as a further adjutant in the diagnostic decision making for both the vascular surgeon and intensivist for the timely detection and management of abdominal complications following open TAA surgery.

Exogenous Hsp70 attenuates nitroglycerin-induced migraine-like symptoms in mice.

Although the connection between heat shock protein 70 (HSP70) and vestibular migraine is not clear, HSP70 is neuroprotective in other scenarios. This study aimed to investigate the potential of exogenous HSP70 for treating migraine-like symptoms in a mouse model of nitroglycerin (NTG)-induced migraine. HSP70 levels were assessed in patients with vestibular migraine and healthy individuals by ELISA. Migraine was induced in mice by NTG, and HSP70 expression was examined in the trigeminal nucleus caudalis (TNC) tissue of mice treated with NTG and NTG together with exogenous HSP70. The effects of exogenous HSP70 on migraine-like symptoms were assessed through behavioral assays. Finally, the impact of HSP70 on oxidative stress and NF-κB signaling in mice with migraine was investigated. Serum HSP70 in patients with vestibular migraine was significantly lower than that of healthy individuals. NTG administration significantly suppressed HSP70 expression in mouse TNC tissue, which was reversed by exogenous HSP70. HSP70 alleviated NTG-induced mechanical hypersensitivity, light aversion, and anxiety-like behavior. Finally, exogenous HSP70 suppressed NTG-induced oxidative stress and NF-κB signaling. Our study suggests that exogenous HSP70 may be a potential therapy for alleviating migraine symptoms and our promising finding warrants further investigation of HSP70 for clinical application.NEW & NOTEWORTHY The study suggests that exogenous HSP70 may be a potential therapy for alleviating migraine symptoms and our promising finding warrants further investigation of HSP70 for clinical application.

Heat Shock Protein 70 Is Associated With Cardioversion Outcome and Recurrence of Symptomatic Recent Onset Atrial Fibrillation in Hypertensive Patients.

ABSTRACT: Accumulating evidence indicates that heat shock proteins (HSPs) may represent a suitable biomarker to predict atrial fibrillation (AF). We investigated the relation of circulating serum HSP70 (sHSP70) with inflammatory cytokines and recurrence of symptomatic recent onset AF (ROAF). We enrolled 90 patients with ROAF (the duration from onset of symptoms ≤24 hours) and 30 controls. Patients received amiodarone for cardioversion and rhythm control. The association of serum HSP70, serum interleukin-2 (sIL-2), and serum interleukin-4 (sIL-4) with the presence of cardioversion and AF recurrence within a year was investigated. Toll-like receptor 4 (TLR4) signaling dependence for IL-2 and IL-4 induction in response to stimulation with HSP70 was tested in rat aortic vascular smooth muscle cell cultures. Patients had higher sHSP70 and sIL-2 and lower sIL-4 compared with controls. Serum HSP70 was independently associated with ROAF (P = 0.005) and correlated with sIL-2 (r = 0.494, P < 0.001) and sIL-4 (r = -0.550, P < 0.001). By 48 hours, 71 of the 90 patients were cardioverted, with noncardioverted patients having higher sHSP70 and sIL-2 and lower sIL-4, which were the only independent factors associated with cardioversion. AF recurred in 38 of the 71 cardioverted patients in 1 year. A cutoff value of sHSP70 ≥0.65 ng/mL and sIL-2 ≥0.21 pg/mL was the only independent factor associated with AF recurrence (hazard ratio: 3.311, 95% confidence interval: 1.503-7.293, P = 0.003 and hazard ratio: 3.144, 95% confidence interval: 1.341-7.374, P = 0.008, respectively). The exposure of smooth muscle cell to HSP70 in vitro increased the expression of IL-2 (5×) and IL-4 (1.5×) through TLR4-dependent and receptor-independent mechanisms. In conclusion, sHSP70 and sIL-2 might constitute a prognostic tool for determining the cardioversion and recurrence likelihood in ROAF.

Reaction Kinetics Modeling of eHsp70 Induced by Norepinephrine in Response to Exercise Stress.

Exercise elicits a systemic adaptation reaction, involving both neuroendocrine and cellular/paracrine stress responses, exemplified by the sympathoadrenergic activity and the release of cellular Hsp70 into the circulation. Regular sports training is known to result in increased fitness. In this study, we characterized the plasma norepinephrine and Hsp70 levels and modeled their relationship in response to exercise stress by bicycle ergometer in 12 trained judoka athletes and in 10 healthy controls. Resting norepinephrine was similar in both groups, whereas Hsp70 was significantly higher in controls compared to athletes. Intense exercise load induced both norepinephrine and Hsp70 elevation. However, both norepinephrine and Hsp70 were significantly lower in athletes compared to the control group. A reaction kinetic model was developed that provided a quantitative description of norepinephrine-facilitated extracellular Hsp70 release, congruent with the experimental data. Our study indicates that exercise-induced norepinephrine and extracellular Hsp70 may be coordinated responses to physiological stress, which are robustly affected by regular sports activity.

Analysis of HSPA1B (+1267A>G) Genetic Polymorphism in Patients with Vibration Disease in Combination with Metabolic Syndrome.

In 167 men with vibration syndrome (VS), allele and genotype frequencies of HSPA1B (+1267A>G) genetic polymorphism (rs1061581) were studied depending on the type of vibration exposure and on the presence or absence of metabolic syndrome (MetS). The examined subjects were divided into two groups: VS patients (n=80) and VS+MetS patients (n=87). The differences in the lipid profiles between groups were revealed against the background of the lack of distinctions in the age of patients for A/G and G/G genotypes carriers. An increase in A/A (p=0.03) and a decrease in A/G (p=0.04) genotype frequencies in VS patients caused by hand-transmitted vibration in comparison with those in whom the disease was caused by a combination of hand-transmitted and whole-body vibration were found. The shifts in the frequencies of the above genotypes (p=0.01) were similar in patients with both types of vibration exposure in the VS+MetS group in comparison with VS group; the carriage of genotypes with the G allele in VS group exceeded that in VS+MetS group (p=0.01).

The effect of whole-body cryostimulation on body composition and leukocyte expression of HSPA1A, HSPB1, and CRP in obese men.

In recent years, the prevalence of obesity has increased dramatically and has become a 21st century epidemic. Obesity is associated with the development of many diseases, and therefore treatments that can reduce body mass are actively sought. The aim of this study was to examine the effect of 20 cryostimulation sessions on body composition in obese/high body mass (HBM, n = 12) males and normal body mass (NBM, n = 9) controls. The HBM group had a mean age = 29.08 ± 4.19 years, body fat percentage = 32.08 ± 6.16%, body mass index = 36.23 ± 8.13 kg/m2) and NBM group had a mean age = 22.00 ± 2.45 years, body fat percentage = 12.14 ± 4.93%, body mass index = 23.58 ± 2.00 kg/m2. Kilocalorie intake was similar for both groups. All participants received 20 sessions of systemic cryostimulation at -120°C for 2-3 min in a cryochamber. Blood samples were collected before the first session, 1 h after the 10th session, and 1 h after the 20th cryostimulation session. C-reactive protein (CRP) plasma concentrations, and expression of the heat shock protein genes (HSPA1A, HSPB1) and CRP mRNA in leukocytes were evaluated after 10 and 20 cryostimulation sessions. In both groups, 20 sessions were associated with a significant decrease in body mass, fat mass and the percentage of body fat. CRP concentrations were significantly higher in obese people before the first session and after 10 treatments, but not at the end of study. Expression of HSPA1A and HSPB1 mRNA gradually decreased with the number of cryostimulation sessions. A significant difference in HSPA1A expression was found after 20 sessions (NBM > HBM) and for HSPB1 at baseline and after 20 sessions (HBM > NBM). Our results show that cryostimulation influences body composition and that cryostimulation-induced HSP genes expression depends on the number of cryosessions and baseline body mass, and is differentially altered in HBM individuals. Further research on the interaction between body mass and cold adaptation is warranted.

Serum HSP70 level in patients with endometrial cancer with and without diabetes.

Diabetes mellitus (DM) is associated with an increased risk of endometrial carcinoma (EC). Heat shock proteins have a role in the modulation of both diseases. The aim of this study was to investigate extracellular HSP70 (eHSP70) level alternations in patients with two different types of EC (endometrioid and non-endometrioid) with and without type 2 diabetes. In a case-control study, 88 participants were enrolled in four groups including: 18 EC patients with DM, 19 EC patients without DM, 29 patients with DM, and 22 healthy individuals. Blood samples were taken before surgery in cancer patients. Estradiol, eHSP70, sex hormone-binding globulin (SHBG), FBS, and HbA1c were assessed. Serum HSP70 level was higher in patients with diabetes (52.24 ± 14.2 ng/ml) compared to healthy controls (39.04 ± 6.96) (p < .05). It was lower in EC (26.05 ± 12.28) compared to healthy controls (39.04 ± 6.96) (p < .05). eHSP70 was also lower in endometrioid-type carcinoma (22.57 ± 11) compared to non-endometrioid type (31.55 ± 12.38) (p < .05). Further analysis showed increased levels of eHSP70 in patients having both endometrioid-type carcinoma and diabetes (27.23 ± 11.41) compared to the same patients without DM (17.08 ± 7.78) (p < .05). Presence of diabetes in patients with endometrioid type carcinoma resulted in an increase in eHSP70 approaching the level of eHSP70 in patients with non-endometrioid histology.

A study on stress response and fertility parameters in phenotypically thermotolerant and thermosensitive dairy cows during summer heat stress.

It is well documented that heat stress (HS) causes subfertility in dairy cows. However, during the last ten years we have been observing that, under high temperature-humidity index (THI ≥ 75), despite the overall reduced fertility, some cows conceive at the first artificial insemination (AI). Here, we examined distinctive features of cows with conserved fertility under severe HS. From the databases of three herds, 167 lactating Holstein cows were selected; group TT cows (n = 57) conceived in the previous summer (THI ≥ 75) at the 1st AI, and group TS (n = 110) failed to conceive at the same period after at least 2 consecutive AIs. The animals calved in spring, and in August, blood samples were collected during a hot day (THI ≥ 81) for the determination of cortisol and HSP70 concentrations. In one farm, the validity of fertility data of the previous year was re-examined. In 28 cows from group TT and in 39 cows from group TS, the conception rate was examined during July and August. In 6 cows from each group (TT and TS) the oestrous cycles were synchronized, ovulation was induced with GnRH (THI = 80), and the concentration of the pre-ovulatory LH surge was determined in 9 blood samples. The progesterone concentration in the ensuing cycle was determined in blood samples collected every other day. Overall, cortisol and HSP70 were significantly lower in TT group compared to TS. More (p < .05) animals from group TT conceived at the first AI compared with those from group TS. The induced pre-ovulatory LH surge peaked at higher level (p < .002) in group TT than in group TS, while no difference was recorded among groups either in mean progesterone concentrations or in the duration of the ensuing oestrous cycle. These results are highly suggestive that thermotolerance in some dairy cows is an inherent characteristic, warranting further genetic investigation.

Tinnitus, hearing loss and inflammatory processes in an older Portuguese population.

Objective: Tinnitus is associated with various conditions such as presbycusis, infectious, autoimmune and many other diseases. Our study aims to identify an association between inflammatory markers and the presence of tinnitus or hearing loss (HL).Design: Exploratory study including a structured interview, complete ENT observation, audiological and inflammatory markers evaluation.Study Sample: Sixty women and 54 men (55 to 75 years) from the Portuguese population, with or without sensory presbycusis and/or tinnitus.Results: IL10 levels were significantly lower in participants with tinnitus than in those without tinnitus. Moreover, TGF-ß was lower in older participants (p = 0.034), IL1α was higher in participants with tonal tinnitus (p = 0.033), and IL2 was lower in participants who reported partial or complete residual inhibition (p = 0.019). Additionally, we observed a negative correlation between tinnitus duration and IL10 levels (r= -.281), and between HSP70 levels and tinnitus loudness (r= -.377). TNF-α and HSP70 levels appears to be sensitive to the time when samples were collected (morning or afternoon).Conclusions: The results of our study showing fluctuations in inflammatory markers along the hearing loss process, reinforce the idea that inflammatory mechanisms are involved in hearing loss pathogenesis but also in tinnitus. IL10 levels appear significantly altered in tinnitus but not in hearing loss.

Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in a patient with NSCLC stage IIIb inducing long-term tumor control: a case study.

BACKGROUND: Membrane heat shock protein 70 (mHsp70) is indicative of high-risk tumors and serves as a tumor-specific target for natural killer (NK) cells stimulated with Hsp70 peptide (TKD) and Interleukin(IL)-2. Radiochemotherapy (RCT), mHsp70-targeting NK cells, and programmed death(PD)-1 inhibition were combined to improve the efficacy of tumor-specific immune cells in a non-small cell lung carcinoma (NSCLC) patient. PATIENT: Following simultaneous RCT (64.8 Gy), a patient with inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated with 4 cycles of autologous ex vivo TKD/IL-2-activated NK cells and the PD-1 antibody nivolumab as a second-line therapy. Blood samples were taken for immunophenotyping during the course of therapy. RESULTS: Adoptive transfer of ex vivo TKD/IL-2-activated NK cells after RCT combined with PD-1 blockade is well tolerated and results in superior overall survival (OS). No viable tumor cells but a massive immune cell infiltration in fibrotic tissue was detected after therapy. Neither tumor progression nor distant metastases were detectable by CT scanning 33 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell and CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. CONCLUSION: A combined therapy consisting of RCT, mHsp70-targeting NK cells, and PD-1 antibody inhibition is well tolerated, induces anti-tumor immunity, and results in long-term tumor control in one patient with advanced NSCLC. Further, randomized studies are necessary to confirm the efficacy of this combination therapy.

The increased expression of the inducible Hsp70 (HSP70A1A) in serum of patients with heart failure and its protective effect against the cardiotoxic agent doxorubicin.

The aim of this study was to examine the potential association between the expression of Hsp70 protein and heart failure and to investigate the possible protective effect of Hsp70 against the doxorubicin-induced toxicity. Initially, at clinical level, the expression levels of the inducible Hsp70 were quantified in serum from patients with heart failure. Our results showed that in heart failure, Hsp70 concentration appeared to be increased in blood sera of patients compared to that of healthy individuals. The enhanced expression of Hsp70 in serum of patients with heart failure seemed to be associated with various features, such as gender, age and the type of heart failure, but not with its etiology. Next, in our study at cellular level, we used primary cell cultures isolated from embryos of Hsp70-transgenic mice (Tg/Tg) overexpressing human HSP70 and wild-type mice (F1/F1). After exposure to a wide range of doxorubicin concentrations and incubation times, the dose- and time-dependent toxicity of the drug, which appeared to be reduced in Tg/Tg cells, was demonstrated. In addition, doxorubicin administration appeared to result in a dose- and time-dependent decrease in the activity of two of the major endogenous antioxidant enzymes (SOD and GPx). The increased activity of these enzymes in Tg/Tg cells compared to the control F1/F1 cells was obvious, suggesting that the presence of Hsp70 confers enhanced tolerance against DOX-induced oxidative stress. Overall, it has been indicated that Hsp70 protein exerts a very important protective action and renders cells more resistant to the harmful effects of doxorubicin.

Heat Shock Protein 70 Messenger RNA in Rat Leukocytes Elevates After Severe Intestinal Ischemia-Reperfusion.

BACKGROUND: Heat shock protein 70 (HSP70) confers protection against heat shock, oxidative stress, infection, and inflammation in many cell types. A recent study reported that the induction of HSP70 was associated with morphologic protection against ischemia-reperfusion injury (IRI) in the rat small intestine. This study investigated the dynamics of HSP70 in leukocytes during intestinal IRI in a rat model. MATERIALS AND METHODS: Serial blood samples were collected at 60-minute intervals up to 240 min from male Wistar rats (n = 15). The rats were divided into three groups of five each: the control group, the nonlethal IRI group, and the lethal IRI group. Rats belonging to the control group underwent a sham operation, and laparotomy was performed on rats in the lethal and nonlethal IRI groups. The nonlethal group experienced a 30-minute clamping of the superior mesenteric artery, and the lethal group experienced a 75-minute clamping of the superior mesenteric artery. The expression of HSP70 messenger RNA (mRNA) in leukocytes was measured by real-time quantitative polymerase chain reaction. Mixed-effects modeling of repeated measures was used to carry out the statistical analysis. The Bonferroni correction was applied to multiple comparisons. A P value < 0.0167 was considered to indicate statistical significance. RESULTS: The expression of HSP70 mRNA in leukocytes increased 60 min after reperfusion in both IRI groups, and it was 12.8 times higher in the lethal group and 3.6 times higher in the nonlethal group compared with the control group. The expression of mRNA in the lethal group was significantly increased compared with the nonlethal group and the control group at 120 and 180 min after reperfusion. At 120 min after reperfusion, the expression of HSP70 mRNA was 6.1 times higher in the lethal group than in the nonlethal group (P = 0.0075) and 17.7 times higher than in the control group (P = 0.0011). At 180 min after reperfusion, the expression of HSP70 mRNA was 6.8 times higher in the lethal group than in the nonlethal group (P = 0.0007) and 4.3 times higher than in the control group (P = 0.0032). Although the expression of HSP70 mRNA in the nonlethal group was elevated in the early stages of reperfusion, there was no difference between the nonlethal group and the control group (P = 0.0212 at 60 min). CONCLUSIONS: The expression of HSP70 mRNA in leukocytes may be a clinically useful indicator for evaluating pathologic conditions in intestinal IRI.

The 150-kDa oxygen-regulated protein (ORP150) regulates proteinuria in diabetic nephropathy via mediating VEGF.

The 150-kDa oxygen-regulated protein (ORP150) belongs to a family of the heat shock protein implicated in the cellular response to environmental stress. Previous data demonstrated that ORP150 regulates the secretion of vascular endothelial growth factor (VEGF) to drive progression of angiogenesis associated with proliferative diabetic retinopathy. However, the expression and biological functions of serum ORP150 levels in diabetic nephropathy (DN) remain unclear. In this study, we reported for the first time that ORP150 was up-regulated in serum of patients with DN. Moreover, we observed the dramatic increase in serum ORP150 accompanied with the elevated levels of proteinuria and serum VEGF levels in DN, indicating the possible involvement of ORP150 in regulation of albuminuria via mediating VEGF in DN. Employing the streptozotocin (STZ) to construct the DN model, we confirmed the positive correlation of ORP150 with VEGF in vivo. Monoclonal anti-ORP150 antibodies treatment significantly decreased the secretion of VEGF and albuminuria in STZ-induced DN models. Consequently, our data suggested that ORP150 levels were positively correlated with proteinuria burden via mediating VEGF in DN. It may be considered as a novel diagnostic and therapeutic target.

Determination of neuroinflammatory biomarkers in autistic and neurotypical Saudi children.

To identify neuroinflammatory biomarkers in patients with various severity of autism spectrum disorder (ASD) increases the insight about the pathogenesis and pathophysiology of this neurodevelopmental disorder. The aim of the present study was to analyze the levels in plasma of TGFß2, Heat shock protein 70 (HSP70), and hematopoietic prostaglandin D2 synthase (H-PGDS) in Saudi ASD children and healthy age-matched neurotypical controls. Also, it was in the present study examined the correlation among these neuroinflammatory biomarkers and the sensory deficit exhibited by the ASD children. Blood samples from 38 Saudi children with ASD and 32 age-matched neurotypical controls were withdrawn after an overnight fast. For the blood taking 3 mL EDTA containing blood collection tubes was used. The samples were centrifuged for 20 min (4 °C; 3000×g) directly after the blood sampling. The harvested plasma was used for in vitro quantification of TGF-ß2, HSP70, and H-PGDS by using the sandwich enzyme immunoassay. Receiver operating characteristic (ROC) analysis and predictiveness curves showed that each of TGF-ß2, HSP70 or H-PGDS alone could not be used as a predictive neuroinflammatory biomarker for ASD. However, when TGF-ß2 and HSP70 were combined in one ROC curve, the AUC was increased to an appreciable value that makes them together robust predictors of variation between the ASD and neurotypical control groups. Overall, it was in the present study found significant differences for TGF-ß2 and HSP70 when the ASD and neurotypical control groups were compared, independently of the sensory deficit level. In conclusion, the present study highlights the usefulness of TGF-ß2, HSP70, and H-PGDS as diagnostic tools to differentiate between ASD and neurotypical control children, but not among subgroups of ASD children exhibiting different severity levels of sensory dysfunction. The presented data also suggest the effectiveness of ROC as a powerful statistical tool, which precisely can measure a combined effect of neuroinflammatory biomarkers intended for diagnostic purposes.

First detection of heat shock protein 60 and 70 in the serum of early pregnant bitches.

Heat shock proteins (HSPs) belong to a group of cellular stress proteins. Heat shock protein 10 immunoregulates and promotes growth during early gestation in humans, while HSP70 is considered to regulate autophagy and apoptosis during pregnancy and parturition. Both HSPs are detectable in the serum and placentas of early pregnant women and considered to contribute to the establishment of pregnancy. Within this pilot study we aimed (1) to assess whether HSPs 10, 60 and 70 are measurable in the serum of healthy early pregnant and non-pregnant bitches, and (2) to explore whether measurable differences between groups indicate pregnancy. Blood was collected from 31 bitches on days 7, 14 and 21 after mating. At 21 days post mating, all bitches were examined for pregnancy by ultrasonography; 23 were pregnant, and the eight non-pregnant bitches served as controls. Pregnant bitches had normal parturitions and gave birth to healthy puppies. The serum concentrations of HSPs 10, 60 and 70 were measured by electrophoresis and western blot. Serum HSP10 was not detectable. Average serum HSP70 concentration was significantly (d7, P = 0.030; d14, P = 0.023; d21, P = 0.030) lower in pregnant animals at all days investigated, while serum HSP60 was significantly lower at day 21 of gestation (P = 0.024) when compared to the controls. HSP 60 and HSP70 concentrations correlated positively (d7, r = +0.386, P = 0.021; d14, r = 0.450, P = 0.008; d21, r = +0.472, P = 0.006). We conclude that in pregnant bitches, serum concentrations of HSP60 and HSP70 are significantly decreased between days 7 and 21 of gestation, in comparison to non-pregnant bitches in early dioestrus, raising the question about intrauterine functions during the peri-implantation period.

Secretion of heat shock -60, -70 kD protein, IL-1ß and TNFα levels in serum of a term normal pregnancy and patients with pre-eclampsia development.

The extracellular heat shock proteins (eHsp) family act as molecular chaperones regulating folding, transporting protein and are associated with immune modulation in different physiological and pathological processes. They have been localized in different gestational tissues and their concentration in amniotic fluid and serum has been determined. In the present study, we proposed to determine the concentration of eHsp-60, -70, IL-1ß and TNFα in the serum of pregnant patients with 34 weeks of gestation with and without clinical evidences of preeclampsia (PE). Our results indicate significant increase of these markers in patients with PE with respect to healthy pregnant patients without active labor. Finally, the concentration of eHsp-60 and -70 correlated positively with the hepatic dysfunction markers uric acid, lactate dehydrogenase (LDH), glutamic oxaloacetic transaminase (GOT) glutamic pyruvic transaminase (GPT), and inflammatory IL-1ß and TNFα response. In conclusion, our results demonstrate a strong associated between Hsp and marker of hepatic dysfunction.

HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer.

BACKGROUND/AIMS: HSP70/HSP90-organizing protein (HOP) is an adaptor protein that mediates heat shock protein 70 (HSP70) and HSP90 folding. HOP can be secreted by cancer cells and promote malignant cell growth in an autocrine manner. Here, we studied its role in gastric cancer (GC). METHODS: HOP mRNA and protein levels were detected by quantitative real-time PCR and western blotting, respectively, and enzyme-linked immunosorbent assay was used to determine the serum levels. Immunohistochemistry was performed to analyze HOP expression in 117 GC tissues and 32 adjacent normal tissues. The Cell Counting Kit-8 cell viability assay, flow cytometry, and western blotting were used to analyze the effects of HOP on cell proliferation and apoptosis, and the potential underlying mechanisms. RESULTS: HOP mRNA and protein levels were significantly higher in GC tissues than in normal tissues in our medical center (P< 0.001) and in The Cancer Genome Atlas database (P< 0.001). GC patients had higher serum levels of HOP than age-matched healthy controls (P< 0.001); however, once tumors were removed, serum levels significantly decreased (P< 0.01). In human GC tissues, increased HOP expression was associated with tumor progression and poor survival. Notably, autocrine HOP promoted cell proliferation through the phospholipase Cγ1-extracellular signal-regulated kinase 1/2-dependent pathway, and inhibited cell apoptosis by regulating the activities of caspase 9, caspase 3, and B-cell lymphoma 2. Blocking extracellular HOP with neutralizing antibody reduced proliferation and enhanced fluorouracil-induced apoptosis of GC cells. CONCLUSIONS: Our findings demonstrate that HOP is an important molecular marker and prognostic factor for GC, and functionally contributes to tumor cell growth and survival. These results provide a rationale for considering HOP as a potential therapeutic target and chemosensitizer in GC.