Search

Background: The JAK2-STAT signaling pathway plays a critical role in myeloproliferative neoplasms (MPN). An activating mutation in JAK2 (V617F) is present in ~ 95% of polycythemia vera, essential thrombocythemia, and primary myelofibrosis cases. This study aims to explore the selective JAK2V617F inhibitor, evaluate the efficacy and possible mechanism of ZT55 on MPN. Methods: HTRF assays were conducted to evaluate the selective inhibition of ZT55 for JAKs. Cell apoptosis, proliferation, and cycle arrest assays were performed to examine the effect of ZT55 on HEL cell line with JAK2V617F mutation in vitro. Western analysis was used to monitor the expression and activity of proteins on JAK2/STAT pathway. A mice xenograft model was established to evaluate the antitumor efficacy of ZT55 in vivo. Peripheral blood samples from patients with the JAK2V617F mutation were collected to estimate the effect of ZT55 on erythroid colony formation by colony-forming assay. Results: We found that ZT55 showed a selective inhibition of a 0.031 μM IC50 value against JAK2. It exhibited potent effects on the cellular JAK-STAT pathway, inhibiting tyrosine phosphorylation in JAK2V617F and downstream STAT3/5 transcription factors. ZT55 inhibited the proliferation of the JAK2V617F-expressing HEL cell line, leading to cell cycle arrest at the G2/M phase and induction of caspase-dependent apoptosis. Notably, ZT55 also significantly suppressed the growth of HEL xenograft tumors in vivo. Further evaluation indicated that ZT55 blocked erythroid colony formation of peripheral blood hematopoietic progenitors from patients carrying the JAK2V617F mutation. Conclusion: These results suggest that ZT55 is a highly-selective JAK2 inhibitor that can induce apoptosis of human erythroleukemia cells by inhibiting the JAK2-STAT signaling. [ABSTRACT FROM AUTHOR]

Photodynamic immunotherapy (PDI) is an innovative approach to cancer treatment that utilizes photodynamic therapy (PDT) and photosensitizers (PSs) to induce immunogenic cell death (ICD). However, currently most commonly used PSs have restricted capabilities to generate reactive oxygen species (ROS) via a type-II mechanism under hypoxic environments, which limits their effectiveness in PDI. To overcome this, we propose a novel approach for constructing oxygen independent PSs based on stable organic free-radical molecules. By fine-tuning the characteristics of tris(2,4,6-trichlorophenyl)-methyl (TTM) radicals through the incorporation of electron-donating moieties, we successfully found that TTMIndoOMe could produce substantial amounts of ROS even in hypoxic environments. In vitro experiments showed that TTMIndoOMe could effectively produce O 2 ˙ - , kill tumor cells and trigger ICD. Moreover, in vivo experiments also demonstrated that TTMIndoOMe could further trigger anti-tumor immune response and exhibit a superior therapeutic effect compared with PDT alone. Our study offers a promising approach towards the development of next-generation PSs functioning efficiently even under hypoxic conditions and also paves the way for the creation of more effective PSs for PDI., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Xuelian, as a traditional Chinese ethnodrug, plays an important role in anti-inflammation, immunoregulation, promoting blood circulation, and other physiological functions. It has been prepared into different traditional Chinese medicine preparations for clinical use, with xuelian koufuye (XL) being widely used to treat rheumatoid arthritis. However, whether XL can relieve inflammatory pain and its analgesic molecular mechanism are still unknown. The present study explored the palliative effect of XL on inflammatory pain and its analgesic molecular mechanism. In complete Freund's adjuvant (CFA)-induced inflammatory joint pain, oral XL dose-dependently improved the mechanical withdrawal threshold of inflammatory pain from an average value of 17.8 g to 26.6 g ( P < 0.05) and high doses of XL significantly reduced inflammation-induced ankle swelling from an average value of 3.1 cm to 2.3 cm compared to the model group ( P < 0.05). In addition, in carrageenan-induced inflammatory muscle pain rat models, oral XL dose-dependently improved the mechanical withdrawal threshold of inflammatory pain from an average value of 34.3 g to 40.8 g ( P < 0.05). The phosphorylated p65 was inhibited in LPS-induced BV-2 microglia and spinal cord of mice in CFA-induced inflammatory joint pain within a value of 75% ( P < 0.001) and 52% reduction ( P < 0.05) on average, respectively. In addition, the results showed that XL could effectively inhibit the expression and secretion of IL-6 from an average value of 2.5 ng/ml to 0.5 ng/ml ( P < 0.001) and TNF- α from 3.6 mg/ml to 1.8 ng/ml with IC 50 value of 20.15  μ g/mL and 112  μ g/mL respectively, by activating the NF- κ B signaling pathway in BV-2 microglia ( P < 0.001). The above-given results provide a clear understanding of the analgesic activity and mechanism of action not found in XL. Considering the significant effects of XL, it can be evaluated as a novel drug candidate for inflammatory pain, which establishes a new experimental basis for expanding the indications of XL in clinical treatment and suggests a feasible strategy to develop natural analgesic drugs., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Shuai Shao et al.)

Two sulfonated C 20 -diterpenoid alkaloid iminiums with a novel skeleton, named aconicatisulfonines A ( 1 ) and B ( 2 ), respectively, were isolated from a water extract of the Aconitum carmichaelii lateral roots. Structures of 1 and 2 were determined by spectroscopic data and quantum calculations as well as X-ray crystallographic analysis. Biosynthetic pathways via semipinacol rearrangements of atisane derivatives are proposed for 1 and 2 . Compounds 1 and 2 exhibited remarkable analgesic activities against acetic acid-induced mice writhing.

Eight new C 19 -diterpenoid alkaloid arabinosides, named aconicarmichosides E-L ( 1 - 8 ), were isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii (Fu Zi). Their structures were determined by spectroscopic and chemical methods including 2D NMR experiments and acid hydrolysis. Compounds 1 - 8 , together with the previously reported four neoline 14- O -arabinosides from the same plant, represent the only examples of glycosidic diterpenoid alkaloids so far. At a dose of 1.0 mg/kg (i.p.), as compared with the black control, compounds 1 , 2 , and 4 - 6 exhibited analgesic effects with >65.6% inhibitions against acetic acid-induced writhing of mice. Structure-activity relationship was also discussed.

A novel sulfonated C 20 -diterpenoid alkaloid with an unprecedented carbon skeleton and significant analgesic activity (46.7% inhibition at 0.1 mg/kg, i.p.), named aconicarmisulfonine A (1), was isolated from an aqueous extract of the lateral roots of Aconitum carmichaelii. Its structure was determined by comprehensive analysis of spectroscopic data, especially by 2D NMR spectroscopic data combined with ECD calculation and single-crystal X-ray diffraction. The plausible biosynthetic pathways of compound 1 are also discussed.

Apigenin, one of the most common flavonoids, has demonstrated anti-inflammatory, anticarcinogenic, and free radical-scavenging activities. Recent studies revealed its protective effects against amyloid-β (Aβ)-induced neurotoxicity, but the mechanism was unclear. In the present study, we aimed to explore the anti-amnesic and protective effects of apigenin against Aβ₂₅₋₃₅-induced toxicity and the underlying mechanisms in the cerebral cortex in mice. The learning and memory impairments, changes in morphology of major components of neurovascular unit, ultrastructural changes and oxidative stress of cerebral cortex, cerebrovascular dysfunction, and neuronal changes were detected after oral administration of apigenin continuously for 8 days. Our results demonstrate that oral administration of apigenin for Aβ₂₅₋₃₅-induced amnesic mice conferred robust neurovascular coupling protection, involving improvement of the learning and memory capabilities, maintenance of neurovascular unit integrity, modulation of microvascular function, reduction of neurovascular oxidative damage, increase of regional cerebral blood flow, improvement of cholinergic system involving the inhibition of AChE activity and elevation of ACh level, and modification of BNDF, TrkB, and phospho-CREB levels.