Multi-omics analysis reveals that linoleic acid metabolism is associated with variations of trained immunity induced by distinct BCG strains.

Trained immunity is one of the mechanisms by which BCG vaccination confers persistent nonspecific protection against diverse diseases. Genomic differences between the different BCG vaccine strains that are in global use could result in variable protection against tuberculosis and therapeutic effects on bladder cancer. In this study, we found that four representative BCG strains (BCG-Russia, BCG-Sweden, BCG-China, and BCG-Pasteur) covering all four genetic clusters differed in their ability to induce trained immunity and nonspecific protection. The trained immunity induced by BCG was associated with the Akt-mTOR-HIF1α axis, glycolysis, and NOD-like receptor signaling pathway. Multi-omics analysis (epigenomics, transcriptomics, and metabolomics) showed that linoleic acid metabolism was correlated with the trained immunity-inducing capacity of different BCG strains. Linoleic acid participated in the induction of trained immunity and could act as adjuvants to enhance BCG-induced trained immunity, revealing a trained immunity-inducing signaling pathway that could be used in the adjuvant development.

Integrated manganese (III)-doped nanosystem for optimizing photothermal ablation: Amplifying hyperthermia-induced STING pathway and enhancing antitumor immunity.

Despite the great promise initially demonstrated by photothermal ablation (PTA) therapy, its inability to completely ablate large tumors is problematic, because this has been found to result in residual tumors at ablation margins and bring a relative high rate of subsequent recurrences and metastases. To address this issue, we herein report a smart photothermal nanosystem (PBM) based on FDA-approved Prussian blue (PB) nanoparticles, doped with Mn (III) to suppress the tumor debris left by incomplete ablation. Notably, our study demonstrated that PTA-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway by generating damaged cytosolic DNA. This PBM nanosystem, which consumes glutathione and continuously releases Mn(II), further amplifies the PTA-induced cGAS-STING pathway in CT26 colon and 4T1 breast tumor models. Moreover, treatment with PBM following PTA boosted the robust immune response in situ and extended to the whole body with a remarkable suppression effect on both local residual and distant tumors. This work, which improves the antitumor efficacy of nonablated areas utilizing hyperthermia-enhanced immune therapy, may therefore provide a promising adjuvant antitumor strategy for the issue of incomplete ablation. STATEMENT OF SIGNIFICANCE: This work discovered, for the first time, that photothermal ablation-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway. Taking advantage of this finding, we developed a smart photothermal material (PBM) tailored for incomplete tumor ablation. This integrated Mn(III)-doped nanosystem (PBM) demonstrated superior therapeutic benefits due to the thermal ablation process and immune enhancement. As the photothermal ablation-induced cGAS-STING pathway was triggered, the released Mn(III) consumes GSH while continuously transferred to Mn(II), which further amplified STING activation and facilitated a more robust antitumor immunity, thereby remarkably inhibiting both local residual and distant tumors in virtue of the biological changes under thermal ablation.

Effect of Electroacupuncture on Visceral and Hepatic Fat in Women with Abdominal Obesity: A Randomized Controlled Study Based on Magnetic Resonance Imaging.

OBJECTIVE: Visceral adipose tissue (VAT) and hepatic fat deposition are the most important risk factors for women's health. Acupuncture, including electroacupuncture (EA), is used to treat obesity throughout the world. The effect of EA is evaluated mainly by body mass index (BMI) and waist circumference (WC). Few studies have assessed its effect in reducing VAT volume and hepatic fat fraction (HFF) based on an exact measurement method such as magnetic resonance imaging (MRI). This study aimed to resolve this issue. METHODS: Thirty subjects were randomly divided into two groups. The control group (n = 15) did not receive any intervention and maintained a normal diet and their usual exercise habits. The treatment group (n = 15) received EA three times a week for 3 months. BMI and WC were measured using different devices. VAT and HFF were measured by MRI and calculated by related software before and after the intervention. RESULTS: A marked difference was evident in group that received EA treatment in the following tests. The differences in BMI (U = 21.00, p < 0.001), WC (U = 40.50, p = 0.002), VAT volume (U = 13.00, p < 0.001), and mean HFF (U = 0.00, p < 0.001) before and after the intervention in the treatment group were distinct and significant compared with those of the control group. Three months later, the treatment group showed a lower BMI (W = 91.00, p = 0.001), WC (t = 4.755, p < 0.001), VAT volume (t = 5.164, p < 0.001), and mean HFF (W = 120.00, p = 0.001) compared with pretreatment levels. Compared with the control group, the treatment group showed a lower VAT volume (t = 60.00, p = 0.029) after 3 months of treatment. After 3 months, the control group showed higher mean HFF (t = -2.900, p = 0.012) and VAT volume (W = 11.50, p = 0.006) compared with their initial levels. CONCLUSION: Based on MRI evaluation, this randomized controlled study proved that EA treatment reduces BMI and WC as well as VAT volume and HFF in women with abdominal obesity.

[Evaluate the Efficacy of Electroacupuncture Therapy on Abdominal Fat in Obese Women by Using Magnetic Resonance Imaging].

OBJECTIVE: To evaluate the efficacy of electroacupuncture (EA) therapy on abdominal fat in obese women by using magnetic resonance imaging(MRI). METHODS: Thirty abdominal obesity women patients were randomly divided into control group (n=15) and EA group (n=15). The obesity patients of the control group did not receive any treatment for weight reduction, and those of the EA group were treated by EA stimulation of bilateral Neiting (ST 44), Fenglong (ST 40), Zusanli (ST 36), Huaroumen (ST 24), Tianshu (ST 25), Wailing (ST 26), Shuidao (ST 28), Fujie (SP 14), Daheng (SP 13), etc. for 25 min, once every other day, 3 times per week for 3 months. The patient's body weight, height, waist circumference (WC) were mea-sured with different devices, and the body mass index (BMI) was calculated, and the subcutaneous adipose tissue thickness at the inferior edges of L4, L5 and S3 and the superior edge of the pubic symphysis and the total abdominal fat volume between the L4 and S3 levels were detected using MRI systems before and after the treatment. RESULTS: The effects of the EA group were significantly superior to those of the control group in lowering difference values (between pre- and post-treatment) of BMI, WC and subcutaneous adipose tissue thickness at the levels of the inferior edges of L4, L5, S3 and the superior edge of the pubic symphysis(all P<0.01)and in reducing total abdominal fat volume between L4 and S3 (all P<0.01). After the treatment, the subcutaneous adipose tissue thickness at the superior edge of the pubic symphysis (P<0.01) and the total abdominal fat volume between L4 and S3 (P<0.05) were significantly decreased in the EA group compared to pre-treatment. There were no significant differences between post- and pre-treatment in BMI, WC, subcutaneous adipose tissue thickness at the levels of the L4, L5 and S3 in both EA and control groups and in the subcutaneous adipose tissue thickness at the level of the superior edge of the pubic symphysis and the total abdominal fat volume between L4 and S3 in the control group (P>0.05). CONCLUSIONS: EA intervention can effectively reduce abdominal fat in obese women based on the evaluation of MRI.

Effect of Bushen Yiqi Huoxue recipe on placental vasculature in pregnant rats with fetal growth restriction induced by passive smoking.

Interactions of vascular endothelial growth factor (VEGF) with receptors VEGFR1/Flt1 and VEGFR2/Flk1, and those of angiopoietins (Ang-1, Ang-2) with receptor Tie2 play important roles in placental angiogenesis. This study investigated vascular morphology and expression of these angiogenic factors in rat placenta on the day 15, 18, 21 of gestation (D15, D18 and D21). The rats were randomly assigned into 3 groups: normal group, model group [fetal growth restriction (FGR) model], and Bushen Yiqi Huoxue (BYHR) recipe treatment group (BYHR group, the pregnant rats with FGR were treated with BYHR recipe). Morphological analysis indicated that during initial villous formation, fetal nucleated erythrocytes (FNEs) appeared in maternal blood sinus (MBS). Subsequently, FNEs were surrounded by endothelial cells to form fetal capillary (FC) and then by trophoblast cells to form villi. As pregnancy proceeded, FC density increased progressively with increasing endothelial identification staining (EIS) in normal and BYHR groups. Whereas, villous formation was suppressed, normal increase in FC density was impaired and EIS was weakened in model group. Quantitative PCR analysis showed that VEGF and Flk1 mRNA increased over gestation in all groups, indicating that VEGF might play a pivotal role in FC growth during late gestation. VEGF mRNA was increased on D15, while decreased on D21 in model group as compared with normal group and BYHR group. Immunohistochemically, Ang-2 protein was highly expressed in FNEs, gradually disappeared as villi matured, and decreased over gestation in all groups, indicating that Ang-2 might play a pivotal role in villous formation, which was further supported by decreased Ang-2 mRNA and protein expression in model group on D15. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio increased from D15 to D18 in all groups as placenta matured. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio were decreased on D18 in model group as compared with normal and BYHR groups, indicating delayed maturity of FGR placenta. Alterations in angiogenic factors may result in altered placental vasculature and cause placental insufficiency. BYHR recipe could balance the angiogenic factors to promote the formation and maturation of FGR placental vasculature.

Effects of Acupuncture on CCL2 and CXCL8 Expression and the Subset of uNK Cells in Rats with Embryo Implantation Failure.

The present study was designed to investigate the efficacy and mechanism of acupuncture treatment on embryo implantation failure in rats. The pregnant rats were randomized into normal group (N), implantation failure group (M), acupuncture treatment group (A), and progestin treatment group (W). The embryo implantation failure model was established by mifepristone. Efficacy of acupuncture treatment was evaluated by the number of implanted embryos. The expression of CCL2 and CXCL8 and the subset of uterine natural killer cells in the endometrium were detected. We demonstrated that the number of implanted embryos was dramatically reduced after mifepristone (M group) treatment, while the acupuncture (A group) and progestin (W group) treatments significantly rescued impaired embryo implantation. The protein and mRNA expressions of CCL2 and CXCL8 were significantly reduced by mifepristone treatment, but the attenuated expression of CCL2 and CXCL8 was markedly reversed by acupuncture or progestin treatment. More importantly, acupuncture and progestin could markedly increase the subset of uNK cells in rats with embryo implantation failure. These evidences suggest that acupuncture is able to modulate the endometrial immune microenvironment and thus improve embryo implantation in pregnant rats, which provides solid experimental evidence for the curative effect of acupuncture treatment on infertility.

[Effect of Bushen Yiqi Huoxue Recipe on placental trophoblast apoptosis in fetal growth restricted pregnant rat].

OBJECTIVE: To observe the effect of Bushen Yiqi Huoxue Recipe (BYHR, a Chinese medical prescription for reinforcing Shen, replenishing qi and promoting blood circulation) on placental trophoblast apoptosis in fetal growth restricted (FGR) pregnant rat for the sake of explore its mechanism of action in treating FGR. METHODS: FGR animal model was established by passive smoking, 32 pregnant rats were divided into four groups at random: the normal group, the model group, the Chinese medicine (CM) group (model rats treated by BYHR) and the Western medicine (WM) group (model rats treated by arginine). The histological change of placenta was examined with HE stain, the trophoblast apoptosis was detected by TUNEL and RT-PCR, and the expressions of Bcl-2 and Bax in the placenta were detected by immunohistochemical method. RESULTS: Blood stasis and villous ischemia were seen in placenta of FGR model rats. Placental microcirculation was significantly improved in the CM group, but in the WM group only partially improved. The median apoptotic index of syncytial trophoblast cells in the four groups, in normal, model, CM, and WM order, was 45%, 75%, 57% and 70%, as compared with the model group, it was much lower in the normal group and the CM group (P < 0.01), but a similar level was shown in the WM group. No significant difference in mRNA and protein expressions of Bcl-2 and Bax was found among the four groups. CONCLUSION: BYHR can improve the placental microcirculation in FGR rats to prevent excessive apoptosis through a mechanism other than the classical Bax/Bcl-2 apoptotic pathway, which needs further exploring.