Astragalus mongholicus Bunge and Curcuma aromatica Salisb. modulate gut microbiome and bile acid metabolism to inhibit colon cancer progression

IntroductionAlterations in the gut microbiome and bile acid metabolism are known to play a role in the development and progression of colon cancer. Medicinal plants like Astragalus mongholicus Bunge and Curcuma aromatica Salisb. (AC) have shown preferable therapeutic effect on cancer therapy, especially digestive tract tumors like colon cancer. However, the precise mechanisms of AC inhibiting colon cancer, particularly in relation to the gut microbiome and bile acid dynamics, are not fully understood.MethodsOur research aimed to investigate the anti-tumor properties of AC in mice with CT26 colon cancer and further investigate its underlying mechanism via intestinal microbiota. The size and pathological changes of solid tumors in colon cancer are used to evaluate the inhibitory effect of AC on colon cancer. Metagenomics and 16s rRNA gene sequencing were employed to clarify the dysbiosis in the gut microbiome of colon cancer and its impact on colon cancer. The levels of bile acids (BAs) in the feces of mice from each group were measured using UPLC-Qtrap-MS/MS.ResultsAC effectively suppressed the growth of colon cancer and reduced histological damage. Notably, AC treatment led to changes in the gut microbiome composition, with a decrease in pathogenic species like Citrobacter and Candidatus_Arthromitus, and an increase in beneficial microbial populations including Adlercreutzia, Lachnospiraceae_UCG-001, and Parvibacter. Additionally, AC altered bile acid profiles, resulting in a significant decrease in pro-carcinogenic bile acids such as deoxycholic acid (DCA) and lithocholic acid (LCA), while increasing the concentration of the cancer-inhibitory bile acid, ursodeoxycholic acid (UDCA). Tracking and analyzing the data, AC may mainly upregulate FabG and baiA genes by increasing the relative abundance of Adlercreutzia and Parvibacter bacteria, which promoting the metabolism of pro-carcinogenic LCA.DiscussionThese findings provide strong evidence supporting the role of AC in regulating gut microbiome-mediated bile acid metabolism, which is crucial in impeding the progression of colon cancer

Regulation of microglia related neuroinflammation contributes to the protective effect of Gelsevirine on ischemic stroke

Stroke, especially ischemic stroke, is an important cause of neurological morbidity and mortality worldwide. Growing evidence suggests that the immune system plays an intricate function in the pathophysiology of stroke. Gelsevirine (Gs), an alkaloid from Gelsemium elegans, has been proven to decrease inflammation and neuralgia in osteoarthritis previously, but its role in stroke is unknown. In this study, the middle cerebral artery occlusion (MCAO) mice model was used to evaluate the protective effect of Gs on stroke, and the administration of Gs significantly improved infarct volume, Bederson score, neurobiological function, apoptosis of neurons, and inflammation state in vivo. According to the data in vivo and the conditioned medium (CM) stimulated model in vitro, the beneficial effect of Gs came from the downregulation of the over-activity of microglia, such as the generation of inflammatory factors, dysfunction of mitochondria, production of ROS and so on. By RNA-seq analysis and Western-blot analysis, the JAK-STAT signal pathway plays a critical role in the anti-inflammatory effect of Gs. According to the results of molecular docking, inhibition assay, and thermal shift assay, the binding of Gs on JAK2 inhibited the activity of JAK2 which inhibited the over-activity of JAK2 and downregulated the phosphorylation of STAT3. Over-expression of a gain-of-function STAT3 mutation (K392R) abolished the beneficial effects of Gs. So, the downregulation of JAK2-STAT3 signaling pathway by Gs contributed to its anti-inflammatory effect on microglia in stroke. Our study revealed that Gs was benefit to stroke treatment by decreasing neuroinflammation in stroke as a potential drug candidate regulating the JAK2-STAT3 signal pathway

Estrogen-immuno-neuromodulation disorders in menopausal depression

Abstract A significant decrease in estrogen levels puts menopausal women at high risk for major depression, which remains difficult to cure despite its relatively clear etiology. With the discovery of abnormally elevated inflammation in menopausal depressed women, immune imbalance has become a novel focus in the study of menopausal depression. In this paper, we examined the characteristics and possible mechanisms of immune imbalance caused by decreased estrogen levels during menopause and found that estrogen deficiency disrupted immune homeostasis, especially the levels of inflammatory cytokines through the ERα/ERβ/GPER-associated NLRP3/NF-κB signaling pathways. We also analyzed the destruction of the blood-brain barrier, dysfunction of neurotransmitters, blockade of BDNF synthesis, and attenuation of neuroplasticity caused by inflammatory cytokine activity, and investigated estrogen-immuno-neuromodulation disorders in menopausal depression. Current research suggests that drugs targeting inflammatory cytokines and NLRP3/NF-κB signaling molecules are promising for restoring homeostasis of the estrogen-immuno-neuromodulation system and may play a positive role in the intervention and treatment of menopausal depression

Isotopic variations in surface waters and groundwaters of an extremely arid basin and their responses to climate change

<jats:p>Abstract. Climate change accelerates the global water cycle. However, the relationships between climate change and hydrological processes in the alpine arid regions remain elusive. We sampled surface water and groundwater at high spatial and temporal resolutions to investigate these relationships in the Qaidam Basin, an extremely arid area in the northeastern Tibetan Plateau. Stable H–O isotopes and radioactive 3H isotopes were combined with atmospheric simulations to examine hydrological processes and their response mechanisms to climate change. Contemporary climate processes and change dominate the spatial and temporal variations of surface water isotopes, specifically the westerlies moisture transport and the local temperature and precipitation regimes. The H–O isotopic compositions in the eastern Kunlun Mountains showed a gradually depleted eastward pattern, while a reverse pattern occurred in the Qilian Mountains water system. Precipitation contributed significantly more to river discharge in the eastern basin (approximately 45 %) than in the middle and western basins (10 %–15 %). Moreover, increasing precipitation and a shrinking cryosphere caused by current climate change have accelerated basin groundwater circulation. In the eastern and southwestern Qaidam Basin, precipitation and meltwater infiltrate along preferential flow paths, such as faults, volcanic channels, and fissures, permitting rapid seasonal groundwater recharge and enhanced terrestrial water storage. However, compensating for water loss due to long-term ice and snow melt will be a challenge under projected increasing precipitation in the southwestern Qaidam Basin, and the total water storage may show a trend of increasing before decreasing. Great uncertainty about water is a potential climate change risk facing the arid Qaidam Basin. </jats:p&gt

Emodin reverses leukemia multidrug resistance by competitive inhibition and downregulation of P-glycoprotein.

Development of multidrug resistance (MDR) is a continuous clinical challenge partially due to the overexpression of P-glycoprotein (P-gp) for chronic myelogenous leukemia (CML) patients. Herein, we evaluated the inhibitory potency of emodin, a natural anthraquinone derivative isolated from Rheum palmatum L, on P-gp in P-gp positive K562/ADM cells. Competition experiments combined with molecular docking analysis were utilized to investigate the binding modes between emodin and binding sites of P-gp. Emodin reversed adriamycin resistance in K562/ADM cells accompanied with the decrease of P-gp protein expression, further increasing the uptake of rhodamine123 in both K562/ADM and Caco-2 cells, indicating the inhibition of P-gp efflux function. Moreover, when incubated with emodin under different conditions where P-gp was inhibited, K562/ADM cells displayed increasing intracellular uptake of emodin, suggesting that emodin may be the potential substrate of P-gp. Importantly, rhodamine 123 could increase the Kintrinsic (Ki) value of emodin linearly, whereas, verapamil could not, implying that emodin competitively bound to the R site of P-gp and noncompetition existed between emodin and verapamil at the M site, in a good accordance with the results of molecular docking that emodin bound to the R site of P-gp with higher affinity. Based on our results, we suggest that emodin might be used to modulate P-gp function and expression

Effect of emodin combined with various amount of rhodamine 123 or verapamil on inhibition of P-gp.

<p>K562/ADM cells were incubated with emodin (0.25–20 μM), together with 1, 3, 10 μM of rhodamine 123, respectively (A); The <i>K</i>_<i>i</i> of emodin was calculated and plotted against the concentrations of rhodamine 123 (B). K562/ADM cells were incubated with emodin (0.25–20 μM) with 0.5, 1, 2 μM of verapamil and 1 μM of rhodamine 123 (C). The calculated values of <i>K</i>_<i>i</i> for emodin were plotted against the concentrations of verapamil (D). Data were represented as the mean ± S.D of three independent experiments.</p

Effect of emodin on expression of P-gp protein in K562/ADM cells.

<p>The cells were incubated in absence or presence of adriamycin or emodin for 48 h. The protein expression was determined by western blot analysis (A) and the relative expression of P-gp was calculated (B). *<i>p</i>< 0.05; **<i>p</i>< 0.01.</p