Therapeutic and vaccinomic potential of moonlighting proteins for the discovery and design of drugs and vaccines against schistosomiasis.

Despite significant and coordinated efforts to combat schistosomiasis, such as providing clean water, sanitation, hygiene, and snail control, these strategies still fall short, as regions previously thought to be disease-free have shown active schistosomiasis transmission. Therefore, it is necessary to implement integrated control methods, emphasizing vaccine development for sustainable control of schistosomiasis. Vaccination has significantly contributed to global healthcare and has been the most economically friendly method for avoiding pathogenic infections. Over the years, different vaccine candidates for schistosomiasis have been investigated with varying degrees of success in clinical trials with many not proceeding past the early clinical phase. Recently, proteins have been mentioned as targets for drug discovery and vaccine development, especially those with multiple functions in schistosomes. Moonlighting proteins are a class of proteins that can perform several functions besides their known functions. This multifunctional property is believed to have been expressed through evolution, where the polypeptide chain gained the ability to perform other tasks without undergoing any structural changes. Since proteins have gained more traction as drug targets, multifunctional proteins have thus become attractive for discovering and developing novel drugs since the drug can target more than one function. Moonlighting proteins are promising drug and vaccine candidates for diseases such as schistosomiasis, since they aid in disease promotion in the human host. This manuscript elucidates vital moonlighting proteins used by schistosomes to drive their life cycle and to ensure their survival in the human host, which can be used to develop anti-schistosomal therapeutics and vaccinomics.

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

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

Heat shock proteins (HSPs) in non-alcoholic fatty liver disease (NAFLD): from molecular mechanisms to therapeutic avenues.

Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver conditions characterized by fat accumulation without excessive alcohol consumption, represents a significant global health burden. The intricate molecular landscape underlying NAFLD pathogenesis involves lipid handling, inflammation, oxidative stress, and mitochondrial dysfunction, with endoplasmic reticulum (ER) stress emerging as a key contributor. ER stress triggers the unfolded protein response (UPR), impacting hepatic steatosis in NAFLD and contributing to inflammation, fibrosis, and progression to NASH and eventually hepatocellular carcinoma (HCC). Heat shock proteins (HSPs), including small HSPs such as HSP20 and HSP27, HSP60, HSP70, GRP78, and HSP90, are integral to cellular stress responses. They aid in protein folding, prevent aggregation, and facilitate degradation, thus mitigating cellular damage under stress conditions. In NAFLD, aberrant HSP expression and function contribute to disease pathogenesis. Understanding the specific roles of HSP subtypes in NAFLD offers insights into potential therapeutic interventions. This review discusses the involvement of HSPs in NAFLD pathophysiology and highlights their therapeutic potential. By elucidating the molecular mechanisms underlying HSP-mediated protection in NAFLD, this article aims to pave the way for the development of targeted therapies for this prevalent liver disorder.

Magical role of iron nanoparticles for enhancement of thermal efficiency and gene regulation of fish in response to multiple stresses.

The present study addresses the challenges of uncontrolled temperature and pollution in aquatic environments, with a focus on fish ability to tolerate high temperature. The investigation aimed to determine the role of iron nanoparticles (Fe-NPs) in enhancing the thermal tolerance of Pangasianodon hypophthalmus exposed to high-temperature stress, arsenic (As), and ammonia (NH3) toxicity. Fe-NPs were synthesized using green approaches, specifically from fish gill. The dietary Fe-NPs were formulated and supplemented at 10, 15, and 20 mg kg⁻1 of feed. Notably, Fe-NPs at 15 mg kg⁻1 diet significantly reduced the critical thermal minimum (CTmin) (14.44 ± 0.21 °C) and the lethal thermal minimum (LTmin) (13.46 ± 0.15 °C), compared to the control and other treatment groups. Conversely, when Fe-NPs at 15 mg kg⁻1 were supplemented with or without exposure to stressors (As + NH3+T), the critical thermal maximum (CTmax) increased to 47.59 ± 0.16 °C, and the lethal thermal maximum (LTmax) increased to 48.60 ± 0.37 °C, both significantly higher than the control and other groups. A strong correlation was observed between LTmin and CTmin (R2 = 0.90) and between CTmax and LTmax (R2 = 0.98). Furthermore, dietary Fe-NPs at 15 mg kg⁻1 significantly upregulated the expression of stress-related genes, including HSP70, iNOS, Caspase-3a, CYP450, MT, cat, sod, gpx, TNFα, IL, TLR, and Ig. The enhanced thermal tolerance (LTmin and LTmax) can be attributed to these gene regulations, suggesting the mechanistic involvement of Fe-NPs in improving thermal resilience. Overall, the findings demonstrate that dietary supplementation with Fe-NPs, particularly at 15 mg kg⁻1, improves thermal tolerance and stress response in P. hypophthalmus by enhancing gene expression and overall thermal efficiency under stressor conditions.

Design, Synthesis, Anti-TMV Activity, and Structure-Activity Relationships of Seco-pregnane C21 Steroids and Their Derivatives.

seco-pregnane C21 steroids exhibit high antiviral activity against the tobacco mosaic virus (TMV). However, the structural modification of seco-pregnane C21 steroids and the structure-activity relationship (SAR) of the modified compounds remain unevaluated. Hence, the present study investigated how variations in the original skeletons of natural seco-pregnane C21 steroids affect their antiviral activity. A series of glaucogenin C and A derivatives were designed and synthesized for the first time, and their anti-TMV activity was evaluated. Bioassay results showed that most of the newly designed derivatives exhibited good to excellent antiviral activity; among these derivatives, 5g, 5j, and 5l with higher antiviral activity than that of ningnanmycin emerged as new antiviral candidates. Reverse transcription-polymerase chain reaction and Western blotting assay revealed reduced levels of TMV coat protein (TMV-CP) gene transcription and TMV-CP protein expression, which confirmed the antiviral activity of these derivatives. These compounds also downregulated the expression of NtHsp70-1 and NtHsp70-061. Computational simulations indicated that 5l displayed strong van der Waals energy and electrostatic with the TMV coat protein, affording a lower binding energy (ΔGbind = -56.2 kcal/mol) compared with Ribavirin (ΔGbind = -47.6 kcal/mol). The SAR of these compounds was also evaluated, which demonstrated for the first time that substitutions at C-3 and double bonds of C-5/C-6 and C-13/C-18 are crucial for maintaining high anti-TMV activity.

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

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

Assessing the toxicity of green Agaricus bisporus-based Cadmium Sulfide nanoparticles on Musca domestica as a biological model.

The common housefly, Musca domestica, known for transmitting over 100 infections, was studied using green-synthesized Cadmium Sulfide nanoparticles (CdS NPs) from Agaricus bisporus. These CdS NPs were tested on third-instar larvae under laboratory conditions using dipping and feeding methods with concentrations (75, 100, 125, 150, 175, and 200 µg/mL). The toxicity, measured by LC50, was found to be 138 µg/mL for dipping treatment and 123 µg/mL for feeding treatment. Analysis with an energy-dispersive X-ray microanalyzer confirmed Cd accumulation in the larval midgut, indicating penetration of CdS NPs into the organism, which may potentially increase their toxicity. CdS NPs caused disruptions in Heat Shock Protein 70, cell apoptosis, and various biochemical components. Scanning electron microscopy revealed morphological abnormalities in larvae, pupae, and adults exposed to CdS NPs. Ultrastructural examination showed significant midgut tissue abnormalities in larvae treated with 123 µg/mL of CdS NPs. Our study demonstrated that green-synthesized CdS NPs from A. bisporus can effectively control the development of M. domestica larvae.

Imidacloprid unique and repeated treatment produces cholinergic transmission disruption and apoptotic cell death in SN56 cells.

Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), ß-amyloid-precursor-protein (ßAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3ß), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 µM-800 µM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aß and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aß and Tau accumulation through BACE1, GSK3ß, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.

Chaperoning system: Intriguing target to modulate the expression of CFTR in cystic fibrosis.

The correction of protein folding is fundamental for cellular functionality and its failure can lead to severe diseases. In this context, molecular chaperones are crucial players involved in the tricky process of assisting in protein folding, stabilization, and degradation. Chaperones, such as heat shock proteins (HSP) 90, 70, and 60, operate within complex systems, interacting with co-chaperones both to prevent protein misfolding and direct to the correct folding. Chaperone targeting drugs could represent a challenging approach for the treatment of cystic fibrosis (CF), an autosomal recessive genetic disease caused by mutations in the CFTR gene, encoding for the CFTR chloride channel. In this review, we discuss the potential role of molecular chaperones as proteostasis modulators affecting CFTR biogenesis. In particular, we focused on HSP90 and HSP70, for their key role in CFTR folding and trafficking, as well as on HSP60 for its involvement in the inflammation process.

Detection of autoantibodies to heat shock protein 70 in the saliva and urine of normal individuals.

Cells exposed to stressors of various origin activate protective mechanisms that include the expression of heat shock proteins (Hsps)/molecular chaperones belonging to several families. Well-characterized inducible Hsp70 is present in all human cell-types and biological fluids, including blood, urine, and saliva. The presence of anti-Hsp70 autoantibodies in the serum of healthy individuals has already been confirmed, and their elevated titers positively correlated with the severity of several pathological conditions, including coeliac disease and dermatitis herpetiformis - a cutaneous manifestation of coeliac disease. Here, using an indirect enzyme-linked immunosorbent assay, we demonstrate, for the first time, that anti-Hsp70 autoantibodies are present in the saliva and urine of healthy individuals. Although the occurrence of anti-Hsp70 autoantibodies in the biological fluids of healthy individuals is intriguing, their physiological role is currently unknown. It is believed that antibodies reacting with self-molecules present in the serum of healthy individuals are part of natural autoantibody pool with multiple regulatory functions. On the other hand, some autoantibodies (e.g., typical of autoimmune bullous skin diseases or systemic lupus erythematosus) may be present before the onset of the disease and serve as specific predictive biomarkers. Therefore, we would like to initiate a discussion or future research direction on the use of anti-Hsp70 autoantibodies as a potential "biomarker" in the diagnosis or prediction of autoimmune diseases. Our findings can be considered in biomedical research to develop noninvasive, inexpensive and easy-to-use tests. Nevertheless, large-scale comparative studies should be initiated, involving the collection and analysis of biological samples such as saliva or urine from patients suffering from autoimmune diseases or other inflammatory or neoplastic diseases, to determine whether the levels of anti-Hsp70 autoantibodies are indeed elevated and whether they correlate with the clinical picture of any disease or established biomarkers.

Hsp70 Negatively Regulates Autophagy via Governing AMPK Activation, and Dual Hsp70-Autophagy Inhibition Induces Synergetic Cell Death in NSCLC Cells.

Proteostasis mechanisms, such as proteotoxic-stress response and autophagy, are increasingly recognized for their roles in influencing various cancer hallmarks such as tumorigenesis, drug resistance, and recurrence. However, the precise mechanisms underlying their coordination remain not fully elucidated. The aim of this study is to investigate the molecular interplay between Hsp70 and autophagy in lung adenocarcinoma cells and elucidate its impact on the outcomes of anticancer therapies in vitro. For this purpose, we utilized the human lung adenocarcinoma A549 cell line and genetically modified it by knockdown of Hsp70 or HSF1, and the H1299 cell line with knockdown or overexpression of Hsp70. In addition, several treatments were employed, including treatment with Hsp70 inhibitors (VER-155008 and JG-98), HSF1 activator ML-346, or autophagy modulators (SAR405 and Rapamycin). Using immunoblotting, we found that Hsp70 negatively regulates autophagy by directly influencing AMPK activation, uncovering a novel regulatory mechanism of autophagy by Hsp70. Genetic or chemical Hsp70 overexpression was associated with the suppression of AMPK and autophagy. Conversely, the inhibition of Hsp70, genetically or chemically, resulted in the upregulation of AMPK-mediated autophagy. We further investigated whether Hsp70 suppression-mediated autophagy exhibits pro-survival- or pro-death-inducing effects via MTT test, colony formation, CellTiter-Glo 3D-Spheroid viability assay, and Annexin/PI apoptosis assay. Our results show that combined inhibition of Hsp70 and autophagy, along with cisplatin treatment, synergistically reduces tumor cell metabolic activity, growth, and viability in 2D and 3D tumor cell models. These cytotoxic effects were exerted by substantially potentiating apoptosis, while activating autophagy via rapamycin slightly rescued tumor cells from apoptosis. Therefore, our findings demonstrate that the combined inhibition of Hsp70 and autophagy represents a novel and promising therapeutic approach that may disrupt the capacity of refractory tumor cells to withstand conventional therapies in NSCLC.

The immunomodulatory effects of cannabidiol on Hsp70-activated NK cells and tumor target cells.

BACKGROUND: Cannabidiol (CBD), the major non-psychoactive component of cannabis, exhibits anti-inflammatory properties, but less is known about the immunomodulatory potential of CBD on activated natural killer (NK) cells and/or their targets. Many tumor cells present heat shock protein 70 (Hsp70) on their cell surface in a tumor-specific manner and although a membrane Hsp70 (mHsp70) positive phenotype serves as a target for Hsp70-activated NK cells, a high mHsp70 expression is associated with tumor aggressiveness. This study investigated the immuno-modulatory potential of CBD on NK cells stimulated with TKD Hsp70 peptide and IL-2 (TKD+IL-2) and also on HCT116 p53wt and HCT116 p53-/- colorectal cancer cells exhibiting high and low basal levels of mHsp70 expression. RESULTS: Apart from an increase in the density of NTB-A and a reduced expression of LAMP-1, the expression of all other activatory NK cell receptors including NKp30, NKG2D and CD69 which are significantly up-regulated after stimulation with TKD+IL-2 remained unaffected after a co-treatment with CBD. However, the release of major pro-inflammatory cytokines by NK cells such as interferon-γ (IFN-γ) and the effector molecule granzyme B (GrzB) was significantly reduced upon CBD treatment. With respect to the tumor target cells, CBD significantly reduced the elevated expression of mHsp70 but had no effect on the low basal mHsp70 expression. Expression of other NK cell ligands such as MICA and MICB remained unaffected, and the NK cell ligands ULBP and B7-H6 were not expressed on these target cells. Consistent with the reduced mHsp70 expression, treatment of both effector and target cells with CBD reduced the killing of high mHsp70 expressing tumor cells by TKD+IL-2+CBD pre-treated NK cells but had no effect on the killing of low mHsp70 expressing tumor cells. Concomitantly, CBD treatment reduced the TKD+IL-2 induced increased release of IFN-γ, IL-4, TNF-α and GrzB, but CBD had no effect on the release of IFN-α when NK cells were co-incubated with tumor target cells. CONCLUSION: Cannabidiol (CBD) may potentially diminish the anti-tumor effectiveness of TKD+IL-2 activated natural killer (NK) cells.

Disclosing the Novel Protective Mechanisms of Ocrelizumab in Multiple Sclerosis: The Role of PKC Beta and Its Down-Stream Targets.

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for both Relapsing and Primary Progressive forms of Multiple Sclerosis (MS) treatment. OCR is postulated to act via rapid B cell depletion; however, by analogy with other anti-CD20 agents, additional effects can be envisaged, such as on Protein Kinase C (PKC). Hence, this work aims to explore novel potential mechanisms of action of OCR in peripheral blood mononuclear cells from MS patients before and after 12 months of OCR treatment. We first assessed, up-stream, PKCßII and subsequently explored two down-stream pathways: hypoxia-inducible factor 1 alpha (HIF-1α)/vascular endothelial growth factor (VEGF), and human antigen R (HuR)/manganese-dependent superoxide dismutase (MnSOD) and heat shock proteins 70 (HSP70). At baseline, higher levels of PKCßII, HIF-1α, and VEGF were found in MS patients compared to healthy controls (HC); interestingly, the overexpression of this inflammatory cascade was counteracted by OCR treatment. Conversely, at baseline, the content of HuR, MnSOD, and HSP70 was significantly lower in MS patients compared to HC, while OCR administration induced the up-regulation of these neuroprotective pathways. These results enable us to disclose the dual positive action of OCR: anti-inflammatory and neuroprotective. Therefore, in addition to B cell depletion, the effect of OCR on these molecular cascades can contribute to counteracting disease progression.

IL-28A/IL-10Rß axis promotes angiogenesis via eNOS/AKT signaling and AP-1/NF-κB/MMP-2 network by regulating HSP70-1 expression.

INTRODUCTION: Angiogenesis plays a significant role in the development of tumor progression and inflammatory diseases. The role of IL-28A in angiogenesis and its precise regulatory mechanisms remain rarely elucidated. OBJECTIVES: We report the novel regulatory role of IL-28A in physiological angiogenesis. The study aimed to elucidate the regulatory mechanisms involved in IL-28A-mediated angiogenesis and identify key genes associated with IL-28A-induced angiogenic responses. METHODS: To know the effect of IL-28A on angiogenesis, HUVECs were applied to perform proliferation, migration, invasion, tube formation, immunoblot, and EMSA. Gene expression changes in HUVECs following IL-28A treatment were analyzed by NGS. The functional role of HSP70-1 and IL-10Rß in IL-28A-induced angiogenic responses was evaluated using PCR and siRNA knockdown. Animal studies were conducted by aortic ring ex vivo assays, Matrigel plug in vivo assays, and immunochemistry using HSP70-1 knockout and transgenic mice models. The efficacy of IL-28A in angiogenesis was confirmed in a hind-limb ischemia model. RESULTS: Autocrine/paracrine actions in HUVECs regulated IL-28A protein expression. Exogenous IL-28A increased the proliferation of HUVECs via eNOS/AKT and ERK1/2 signaling. IL-28A treatment promoted migration, invasion, and capillary tube formation of HUVECs through induction of the AP-1/NF-κB/MMP-2 network, which was associated with eNOS/AKT and ERK1/2 signaling. The efficacy of IL-28A-induced angiogenic potential was confirmed by aortic ring and Matrigel plug assay. HSP70-1 was identified as an IL-28A-mediated angiogenic effector gene using bioinformatics. Knockdown of HSP70-1 abolished angiogenic responses and eNOS/AKT signaling in IL-28A-treated HUVECs. IL-28A-induced microvessel sprouting formation was testified in HSP70-1-deficient and HSP70-1 transgenic mice. Flow recovery in hind-limb ischemia mice was accelerated by IL-28A injection. Finally, ablation of the IL-10Rß gene impeded the angiogenic responses and eNOS/AKT signaling stimulated by IL-28A in HUVECs. CONCLUSION: HSP70-1 drives the progression of angiogenesis by the IL-28A/IL-10Rß axis via eNOS/AKT signaling and the AP-1/NF-κB/MMP-2 network.

Analysis of Co-expression of HSP 70 and BCL 2 in Oral Precancer and Cancer Patients Using Immunohistochemistry.

Introduction: Understanding of molecular model of oral carcinogenesis has carried cancer chemotherapy far forward from conventional drug therapies. Small molecule inhibitors have gained acceptance as it has fewer adverse effects and also provide targeted drug therapy. The association of HSP 70 (Heat Shock Protein 70) and BCL 2 (B-cell lymphoma 2) proteins with oral precancer and cancer is already established. However, the complex interaction between these two proteins and how they affect each other's expression is still not understood completely. In our study, we aimed to correlate the expression of HSP 70 and BCL 2 with different histopathological grades of oral precancer and cancer tissue samples using tissue immunohistochemistry. Materials and Methods: Tissue samples were taken from a total of 250 patients (100 OPMDs and 150 OSCCs) and subjected to immunohistochemistry using anti-human mouse monoclonal antibodies to HSP70 and BCL2. Immunostaining was done, and the immunostaining intensity distribution (IID) index was calculated. Results and Discussion: Immunoreactivity scores for both HSP 70 and BCL 2 correlated with different grades of dysplasia. However, only HSP 70 had a statistically significant association (p = 0.066). We also found that HSP 70 showed an inverse correlation, with higher expression majorly seen in well-differentiated OSCCs. Conclusion: Our study unveiled the HSP 70-BCL 2 interaction and provides insights about how this might affect drug designing and help overcome therapeutic lags. However, further studies are needed to provide a comprehensive review of such interactions among various small molecules.

[The effect of electromagnetic fields on tendinopathies : Study on the effect analysis of a singular application of high-energy pulsed electromagnetic fields]. / Die Wirkung von elektromagnetischen Feldern auf Tendinopathien : Studie zur Effektanalyse einer singulären Anwendung von hochenergetischen gepulsten elektromagnetischen Feldern.

OBJECTIVE: Tendinopathies are diseases that often entail long-term treatment consisting of analgesics, physiotherapy, orthotics, and sparing. The aim of this study was to investigate the effect of a single application of a high-energy PEMF (pulsed electromagnetic field) on pain perception and blood born inflammation parameters. METHODS: 34 patients were randomly assigned to a verum group (10 min PEMF, 0,78 T) or a placebo group (10 min sham condition). Prior to and up to one week after the patient blinded treatment (t1-t5), local pain state was assessed by means of algometry as pain pressure threshold (PPT). Accordingly, heat-shock protein 70 (HSP70) levels were analysed. Statistical analyses included 2­way ANOVA (2â€¯× 5). The clinical trial was registered (DRKS00031321). RESULTS: After randomization and drop-out (verum n = 17, placebo n = 13) baseline-analyses did not reveal significant between-group differences for PPT (p = 0,096), for HSP70 (p = 0,524), or any other sample characteristics (p > 0,05). Pain reduction during one week of observation showed to be significantly higher (p = 0,045, η2 = 0,013) for the PEMF group (PPT: +83 bis +139%) compared to the placebo group (PPT: +10 bis +36%). There were no HSP70 associated effects. CONCLUSIONS: A single bout of high energy PEMF led to an immediate pain relief in tendinopathy patients lasting at least for one week, but the hypothesized underlying HSP70 associated inflammatory pathway could not be confirmed.

Clinical, Pathological, and Immunohistochemical Predictors of Cause-Specific Mortality in Papillary Thyroid Cancer: Multivariate Analysis.

The association of clinical, pathological, and immunohistochemical characteristics of papillary thyroid cancer with cause-specific mortality was analyzed in a case-control study within a cohort of patients from the Altai Regional Oncology Center. According to multivariate analysis, the independent predictors of fatal outcome within 10 years after surgery in patients living in Altai region are nuclear pattern of Hsp70 expression, thyroid capsular invasion, Ki-67 expression index >7%, and patient's age >45 years for men and >50 years for women. The prognostic model based on these features contributes to a significant improvement in the individual prognostic performance for papillary thyroid cancer in the modeling sample. The model has high statistical significance (χ2=64.73; p<0.001) and discriminative power (AUC=0.950, prediction accuracy 88.5%).

Targeting host inducible-heat shock protein 70 with PES-Cl is a promising antiviral strategy against SARS-CoV-2 infection and pathogenesis.

One of the fundamental mechanisms developed by the host to contain the highly infectious and rapidly proliferating SARS-coronavirus is elevation of body temperature, a natural fallout of which is heat shock proteins over-expression. Here, for the first time, we demonstrate that the SARS-CoV-2 exploits the host Heat shock protein 70 (Hsp70) chaperone for its entry and propagation, and blocking it can combat the infection. SARS-CoV-2 infection as well as febrile temperature enhanced Hsp70 expression in host Vero E6 cells. Furthermore, heat shock or viral infection elevated the host cell autophagic response which is a prerequisite for viral propagation. In addition, Hsp70 protein demonstrated strong interaction with host Angiotensin-converting enzyme 2 (ACE2) as well as the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein, indicating that interaction of Hsp70 with ACE2 and Spike protein may serve to protect them during febrile conditions. Suppressive and prophylactic treatment of Vero E6 cells with Hsp70 inhibitor PES, 2-(3-chlorophenyl) ethynesulfonamide (PES-Cl), abrogated viral infection more potently than the currently used drug Remdesivir. In conclusion, our study not only provides a fundamental insight into the role of host Hsp70 in SARS-CoV-2 pathogenesis, it paves the way for development of potent and irresistible anti-viral therapeutics.

The Role of Heat Shock Protein 70 (HSP70) in the Pathogenesis of Ocular Diseases-Current Literature Review.

Heat shock proteins (HSPs) have been attracting the attention of researchers for many years. HSPs are a family of ubiquitous, well-characterised proteins that are generally regarded as protective multifunctional molecules that are expressed in response to different types of cell stress. Their activity in many organs has been reported, including the heart, brain, and retina. By acting as chaperone proteins, HSPs help to refold denatured proteins. Moreover, HSPs elicit inhibitory activity in apoptotic pathways and inflammation. Heat shock proteins were originally classified into several subfamilies, including the HSP70 family. The aim of this paper is to systematise information from the available literature about the presence of HSP70 in the human eye and its role in the pathogenesis of ocular diseases. HSP70 has been identified in the cornea, lens, and retina of a normal eye. The increased expression and synthesis of HSP70 induced by cell stress has also been demonstrated in eyes with pathologies such as glaucoma, eye cancers, cataracts, scarring of the cornea, ocular toxpoplasmosis, PEX, AMD, RPE, and diabetic retinopathy. Most of the studies cited in this paper confirm the protective role of HSP70. However, little is known about these molecules in the human eye and their role in the pathogenesis of eye diseases. Therefore, understanding the role of HSP70 in the pathophysiology of injuries to the cornea, lens, and retina is essential for the development of new therapies aimed at limiting and/or reversing the processes that cause damage to the eye.

Immunoexpression Pattern of Autophagy-Related Proteins in Human Congenital Anomalies of the Kidney and Urinary Tract.

The purpose of this study was to evaluate the spatiotemporal immunoexpression pattern of microtubule-associated protein 1 light chain 3 beta (LC3B), glucose-regulated protein 78 (GRP78), heat shock protein 70 (HSP70), and lysosomal-associated membrane protein 2A (LAMP2A) in normal human fetal kidney development (CTRL) and kidneys affected with congenital anomalies of the kidney and urinary tract (CAKUT). Human fetal kidneys (control, horseshoe, dysplastic, duplex, and hypoplastic) from the 18th to the 38th developmental week underwent epifluorescence microscopy analysis after being stained with antibodies. Immunoreactivity was quantified in various kidney structures, and expression dynamics were examined using linear and nonlinear regression modeling. The punctate expression of LC3B was observed mainly in tubules and glomerular cells, with dysplastic kidneys displaying distinct staining patterns. In the control group's glomeruli, LAMP2A showed a sporadic, punctate signal; in contrast to other phenotypes, duplex kidneys showed significantly stronger expression in convoluted tubules. GRP78 had a weaker expression in CAKUT kidneys, especially hypoplastic ones, while normal kidneys exhibited punctate staining of convoluted tubules and glomeruli. HSP70 staining varied among phenotypes, with dysplastic and hypoplastic kidneys exhibiting stronger staining compared to controls. Expression dynamics varied among observed autophagy markers and phenotypes, indicating their potential roles in normal and dysfunctional kidney development.