Electroacupuncture prevents the development or establishment of chronic pain via IL-33/ST2 signaling in hyperalgesic priming model rats.

BACKGROUND: Chronic pain is acomplexhealth issue. Compared to acute pain, which has a protective value, chronic pain is defined as persistent pain after tissue injury. Few clinical advances have been made to prevent the transition from acute to chronic pain. Electroacupuncture (EA), the most common form of acupuncture, is widely used in clinical practice to relieve pain. METHODS: The hyperalgesic priming model, established via a carrageenan injection followed by a prostaglandin E2 injection, was used to investigate the development or establishment of chronic pain. We observed the hyperalgesic effect of EA on rats and investigated the expression p38 mitogen-activated protein kinase, interleukin-33 (IL-33), and its receptor ST2 in astrocytes in the L4-L6 spinal cord dorsal horns (SDHs) after EA. The IL-33/ST2 signaling pathway in SDH is associated with the development of chronic pain. RESULTS: EA can reverse the pain threshold in hyperalgesic priming model rats and regulates the expression of phosphorylated p38, IL-33, and ST2 in astrocytes in the L4-L6 SDHs. We discovered that EA raises the pain threshold. This suggests that EA can prevent the development or establishment of chronic pain by inhibiting IL-33/ST2 signaling in the lower central nervous system. CONCLUSIONS: EA can alleviate the development or establishment of chronic pain by modulating IL-33/ST2 signaling in SDHs. Our findings will help clinicians understand the mechanisms of EA analgesia.

Identification of Flavonoids from Scutellaria barbata D. Don as Inhibitors of HIV-1 and Cathepsin L Proteases and Their Structure-Activity Relationships.

Scutellaria barbata D. Don (SB, Chinese: Ban Zhi Lian), a well-known medicinal plant used in traditional Chinese medicine, is rich in flavonoids. It possesses antitumor, anti-inflammatory, and antiviral activities. In this study, we evaluated the inhibitory activities of SB extracts and its active components against HIV-1 protease (HIV-1 PR) and SARS-CoV2 viral cathepsin L protease (Cat L PR). UPLC/HRMS was used to identify and quantify the major active flavonoids in different SB extracts, and fluorescence resonance energy transfer (FRET) assays were used to determine HIV-1 PR and Cat L PR inhibitions and identify structure-activity relationships. Molecular docking was also performed, to explore the diversification in bonding patterns of the active flavonoids upon binding to the two PRs. Three SB extracts (SBW, SB30, and SB60) and nine flavonoids inhibited HIV-1 PR with an IC50 range from 0.006 to 0.83 mg/mL. Six of the flavonoids showed 10~37.6% inhibition of Cat L PR at a concentration of 0.1 mg/mL. The results showed that the introduction of the 4'-hydroxyl and 6-hydroxyl/methoxy groups was essential in the 5,6,7-trihydroxyl and 5,7,4'-trihydroxyl flavones, respectively, to enhance their dual anti-PR activities. Hence, the 5,6,7,4'-tetrahydroxyl flavone scutellarein (HIV-1 PR, IC50 = 0.068 mg/mL; Cat L PR, IC50 = 0.43 mg/mL) may serve as a lead compound to develop more effective dual protease inhibitors. The 5,7,3',4'-tetrahydroxyl flavone luteolin also showed a potent and selective inhibition of HIV-1 PR (IC50 = 0.039 mg/mL).

Design, synthesis, and in vitro cytotoxicity evaluation of novel dihydroartemisinin-isatin hybrids tethered via different length of esters as potential anti-breast cancer agents.

In the present work, we reported the design, synthesis, and in vitro cytotoxicity evaluation of novel dihydroartemisinin-isatin hybrids tethered via different length of esters against MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines. The preliminary results showed that the majority of the hybrids exhibited good anti-breast cancer cell activity. In particular, hybrids 7 g and 7n not only were more potent than ART, DHA and ADR against the four tested breast cancer cell lines, but also were non-toxic towards normal MCF-10A breast cells. The selectivity index values of hybrids 7 g and 7n were > 12.83 and > 25.97 respectively, revealing their excellent safety and selectivity profiles. The drug-resistant index values of hybrids 7 g and 7n were in a range of 0.33 to 1.12, implying that these hybrids had the potential to overcome drug resistance. Accordingly, hybrids 7 g and 7n could be considered as potential lead molecules for the development of novel anti-breast cancer agents with minimal untoward events to normal human cells. The structure-activity relationships indicated that the length of ester likner between DHA and isatin as well as substituents at C-3 and C-5 positions of isatin moiety had great impact on the activity.

Synthesis and biological evaluation of panaxatriol derivatives against myocardial ischemia/reperfusion injury in the rat.

Panaxatriol (PT) is a natural product derived from ginseng that possesses cardioprotective effects in isolated rat hearts. To develop more potent therapeutic agents against myocardial ischemia/reperfusion (MI/R) injury from natural products, a novel series of heterocycle ring-fused panaxatriol derivatives were designed and synthesized. In vitro results showed that approximately half of them exhibited increased cytoprotective activity compared with PT in a cardiomyocyte model of oxygen-glucose deprivation and reperfusion (OGD/R) injury. Furthermore, the in vitro activity of the representative derivative, compound 18, was also confirmed in a rat model of MI/R injury. In vivo results showed that 18 can markedly reduce myocardial infarction size, decrease circulating cardiac troponin I (cTnI) leakage, and alleviate cardiac tissue damage in the rats. Therefore, these findings provide the basis for further development of novel anti-MI/R injury agents.

Synthesis and evaluation of panaxatriol derivatives as Na+, K+-ATPase inhibitors.

Panaxatriol, a triterpene bearing a steroid-like structure similar to cardiac glycosides, was presumed to share the same bioactivity with cardiac glycosides, and may be a potential Na+, K+-ATPase inhibitor. In this paper, a series of panaxatriol derivatives were synthesized and evaluated for Na+, K+-ATPase inhibitory activities. The results of biological tests showed that more than half of the synthesized derivatives presented increased inhibitory activities compared with panaxatriol. Of these compounds, 13a with a 3, 4-seco skeleton showed the most potent inhibitory activity, which was equal to that of the standard drug digoxin. To understand the binding mode of the most active compound, molecular docking study of 13a with Na+, K+-ATPase was conducted. Therefore, 13a may serve as a new lead compound for the development of novel Na+, K+-ATPase inhibitors.

ent-Strobane and ent-Pimarane Diterpenoids from Siegesbeckia pubescens.

Two strobane diterpenoids, strobols A (1) and B (2), 15 new pimarane diterpenoids (3-6 and 8-18), and the known compounds kirenol (19), darutigenol (20), and ent-2ß,15,16,19-tetrahydroxypimar-8(14)-ene (7) were isolated from the aerial parts of Siegesbeckia pubescens Makino. The structures of the new compounds were established based on the interpretation of HRESIMS and NMR analysis. The configurations of 1, 6, and 17 were confirmed by X-ray crystallographic data. Compounds 3, 5, and 11 inhibited the migration of MB-MDA-231 breast cancer cells induced by the chemokine epithelial growth factor, with IC50 values of 4.26, 3.45, and 9.70 µM, respectively.

Persistent sulfate formation from London Fog to Chinese haze.

Sulfate aerosols exert profound impacts on human and ecosystem health, weather, and climate, but their formation mechanism remains uncertain. Atmospheric models consistently underpredict sulfate levels under diverse environmental conditions. From atmospheric measurements in two Chinese megacities and complementary laboratory experiments, we show that the aqueous oxidation of SO2 by NO2 is key to efficient sulfate formation but is only feasible under two atmospheric conditions: on fine aerosols with high relative humidity and NH3 neutralization or under cloud conditions. Under polluted environments, this SO2 oxidation process leads to large sulfate production rates and promotes formation of nitrate and organic matter on aqueous particles, exacerbating severe haze development. Effective haze mitigation is achievable by intervening in the sulfate formation process with enforced NH3 and NO2 control measures. In addition to explaining the polluted episodes currently occurring in China and during the 1952 London Fog, this sulfate production mechanism is widespread, and our results suggest a way to tackle this growing problem in China and much of the developing world.