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Myeloproliferative neoplasms (MPN) are a group of clonal disorders that affect hematopoietic stem/progenitor cells. These disorders are often caused by oncogenic driver mutations associated with persistent Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling. While JAK inhibitors, such as ruxolitinib, reduce MPN-related symptoms in myelofibrosis, they do not influence the underlying cause of the disease and are not curative. Due to these limitations, there is a need for alternative therapeutic strategies and targets. Heat shock proteins (HSPs) are cytoprotective stress-response chaperones involved in protein homeostasis and in many critical pathways, including inflammation. Over the last decade, several research teams have unraveled the mechanistic connection between STAT signaling and several HSPs, showing that HSPs are potential therapeutic targets for MPN. These HSPs include HSP70, HSP90 (chaperoning JAK2) and both HSP110 and HSP27, which are key factors modulating STAT3 phosphorylation status. Like the HSPs, the PD-1/PD-L1 signaling pathway has been widely studied in cancer, but the importance of PD-L1-mediated immune escape in MPN was only recently reported. In this review, we summarize the role of HSPs and PD-1/PD-L1 signaling, the modalities of their experimental blockade, and the effect in MPN. Finally, we discuss the potential of these emerging targeted approaches in MPN therapy.
Emerging evidence has supported that intensive exercise induces weakened performance and immune and metabolic disorders. We systematically evaluated the effects of quercetin against hepatic inflammatory damage caused by repeated intensive exercise and explored the potential mechanism.

Male BALB/c mice were administered quercetin (100 mg/kg BW) for four weeks, and performed a treadmill running protocol of 28 m/min, 5° slope, 90 min/day concurrently for the last seven days.

Quercetin administration reduced the leakage of aspartic acid and alanine aminotransferase and improved ultrastructural abnormalities such as swelling, and degeneration caused by high-intensity running in mice. Quercetin significantly decreased the hepatic and plasmatic levels of inflammatory cytokines IL-1β, IL-6, TNF-α, inducible nitric oxide synthase, cyclooxygenase-2 and intercellular adhesion molecule-1-provoked by over-exercise. Furthermore, diminished activation and nuclear translocation of NF-κB were found after quercetin treatment through inhibiting IKKα and Iκbα phosphorylation of intensive running mice.

Quercetin offers protection for mouse livers against intensive sports-induced inflammatory injury, and the suppression of the NF-κB signal transduction pathway may play a role in its anti-inflammatory effects. Our findings broaden our understanding of natural phytochemicals as a promising strategy to prevent excessive exercise damage.
Quercetin offers protection for mouse livers against intensive sports-induced inflammatory injury, and the suppression of the NF-κB signal transduction pathway may play a role in its anti-inflammatory effects. Our findings broaden our understanding of natural phytochemicals as a promising strategy to prevent excessive exercise damage.Acrylamide (AA) is a neo-formed toxic compound that develops in foods during cooking at temperatures above 120 °C. AA shows in vivo neurotoxic and carcinogenic effects, and it is potentially carcinogenic for humans. Its occurrence is common in baked food, such as bread and similar products. This study set out to analyze bread and sweets from the Italian market to evaluate the effects of the benchmark thresholds set by EU Regulation 2017/2158 and to ascertain the exposure of the Italian population to AA, across three age groups, through the consumption of baked products, according to the margin of exposure (MOE) approach. Two hundred samples were tested, and the content of AA ranged from 31 to 454 µg/kg for bread and products thereof and from 204 to 400 µg/kg for the sweets category. The exposure data did not show any neurotoxic health concern, whereas the MOE related to the carcinogenic endpoint is well below the minimum safety value of 10,000.Background and Objectives Telomere regulation have an association with colorectal cancer. Previous studies demonstrated its implication in colorectal carcinogenesis. This study aimed to identify the role of telomerase reverse transcriptase (TERT) in colorectal carcinogenesis and determine TERT expression and their associated genes in precancerous lesions. Materials and Methods TERT expression in 93 colorectal precursor lesions was analyzed. This included 61 tubular adenomas (TAs) and 32 serrated polyps (SPs). Furthermore, KRAS and BRAF gene mutations and microsatellite instability were analyzed. Statistical tests were performed to analyze the relationship between variables. Results TERT expression in TAs, when compared with those observed in paired adjacent nontumor tissues, was 0.92 ± 0.78. TERT expression levels were significantly lower in SPs (0.38 ± 0.14, p less then 0.001). KRAS and BRAF mutations were mutually exclusive in TAs and SPs (p less then 0.001). TERT expression tended to be associated with KRAS mutations (46.7% vs. 22.0%, p = 0.098) and low-grade tumors (35.0% vs. 16.0%, p = 0.096), but this difference was insignificant. Conclusions TERT expression has a pivotal role in progression to TAs in colorectal tissue. Considering the association between TERT expression and KRAS mutation, therapeutic drugs targeting this pathway can be developed for cancer prevention.Impaired cargo trafficking and the aggregation of intracellular macromolecules are key features of neurodegeneration, and a hallmark of aged as well as diseased retinal pigment epithelial (RPE) cells in the eye. Here, photoreceptor outer segments (POS), which are internalized daily by RPE cells, were modified by UV-irradiation to create oxidatively modified POS (OxPOS). Oxidative modification was quantified by a protein carbonyl content assay. DMX-5084 Human ARPE-19 cells were synchronously pulsed with POS or OxPOS to study whether oxidatively modified cargos can recapitulate features of RPE pathology associated with blinding diseases. Confocal immunofluorescence microscopy analysis showed that OxPOS was trafficked to LAMP1, LAMP2 lysosomes and to LC3b autophagy vacuoles. Whilst POS were eventually degraded, OxPOS cargos were sequestered in late compartments. Co-localization of OxPOS was also associated with swollen autolysosomes. Ultrastructural analysis revealed the presence of electron-dense OxPOS aggregates in RPE cells, which appeared to be largely resistant to degradation.
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