PCSK9 inhibition interrupts the cross-talk between keratinocytes and macrophages and prevents UVB-induced skin damage.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that promotes the degradation of low-density lipoprotein receptors. It is involved in hyperlipidemia as well as other diseases, such as cancer and skin inflammation. However, the detailed mechanism for PCSK9 on ultraviolet B (UVB)-induced skin lesions was not clear. Thus, the role and possible action mechanism of PCSK9 in UVB-induced skin damage in mice were studied here using siRNA and a small molecule inhibitor (SBC110736) against PCSK9. Immunohistochemical staining revealed a significant increase in PCSK9 expression after UVB exposure, indicating the possible role of PCSK9 in UVB damage. Skin damage, increase in epidermal thickness, and keratinocyte hyperproliferation were significantly alleviated after treatment with SBC110736 or siRNA duplexes, compared with that in the UVB model group. Notably, UVB exposure triggered DNA damage in keratinocytes, whereas substantial interferon regulatory factor 3 (IRF3) activation was observed in macrophages. Pharmacologic inhibition of STING or cGAS knockout significantly reduced UVB-induced damage. In the co-culture system, supernatant from UVB-treated keratinocyte induced IRF3 activation in macrophages. This activation was inhibited with SBC110736 and by PCSK9 knockdown. Collectively, our findings reveal that PCSK9 plays a critical role in the crosstalk between damaged keratinocytes and STING activation in macrophages. The interruption of this crosstalk by PCSK9 inhibition may be a potential therapeutic strategy for UVB-induced skin damage.

Histone deacetylase 9 plays a role in sevoflurane-induced neuronal differentiation inhibition by inactivating cAMP-response element binding protein transcription and inhibiting the expression of neurotrophin-3.

Postoperative cognitive decline (POCD) is a common and serious complication following anesthesia and surgery; however, the precise mechanisms of POCD remain unclear. Our previous research showed that sevoflurane impairs adult hippocampal neurogenesis (AHN) and thus cognitive function in the aged brain by affecting neurotrophin-3 (NT-3) expression; however, the signaling mechanism involved remains unexplored. In this study, we found a dramatic decrease in the proportion of differentiated neurons with increasing concentrations of sevoflurane, and the inhibition of neural stem cell differentiation was partially reversed after the administration of exogenous NT-3. Understanding the molecular underpinnings by which sevoflurane affects NT-3 is key to counteracting cognitive dysfunction. Here, we report that sevoflurane administration for 2 days resulted in upregulation of histone deacetylase 9 (HDAC9) expression, which led to transcriptional inactivation of cAMP-response element binding protein (CREB). Due to the colocalization of HDAC9 and CREB within cells, this may be related to the interaction between HDAC9 and CREB. Anyway, this ultimately led to reduced NT-3 expression and inhibition of neural stem cell differentiation. Furthermore, knockdown of HDAC9 rescued the transcriptional activation of CREB after sevoflurane exposure, while reversing the downregulation of NT-3 expression and inhibition of neural stem cell differentiation. In summary, this study identifies a unique mechanism by which sevoflurane can inhibit CREB transcription through HDAC9, and this process reduces NT-3 levels and ultimately inhibits neuronal differentiation. This finding may reveal a new strategy to prevent sevoflurane-induced neuronal dysfunction.

Strontium Uptake and Effect in Lettuce and Radish Cultivated Under Hydroponic Conditions.

The accumulation of strontium (Sr) in lettuce and radish under 0 (control), 0.5, 1, 2.5, 5, and 10 mM Sr treatments in hydroponic solution at 16, 23 and 30 days and the effects of Sr stress on six nutrient elements in plants were investigated. The results showed that Sr concentrations in plant aerial and underground parts increased in low-Sr treatments (0.5, 1 and 2.5 mM) and fluctuated in high-Sr treatments (5 and 10 mM) throughout the three sampling periods. Sr concentrations were higher in roots than in leaves, reaching 108.8 ± 14.7 and 134.1 ± 1.2 mg/g in lettuce and radish roots, respectively, after 10 mM Sr treatment. Translocation factor (TF) values (ratio of the Sr concentrations in aerial parts to that in roots) were inversely related to the Sr content in the hydroponic solution, and reached 1.45 ± 0.17 to 0.15 ± 0.03 and 1.06 ± 0.20 to 0.12 ± 0.004 for lettuce and radish. The variation in chlorophyll content was consistent with that in plant biomass.

Salvianolic acid A prevents UV-induced skin damage by inhibiting the cGAS-STING pathway.

DNA damage resulting from UV irradiation on the skin has been extensively documented in numerous studies. In our prior investigations, we demonstrated that UVB-induced DNA breakage from keratinocytes can activate the cGAS-STING pathway in macrophages. The cGAS-STING signaling pathway serves as the principal effector for detecting and responding to abnormal double-stranded DNA in the cytoplasm. Expanding on our previous findings, we have further validated that STING knockout significantly diminishes UVB-induced skin damage, emphasizing the critical role of cGAS-STING activation in this context. Salvianolic acid A, a principal active constituent of Salvia miltiorrhiza Burge, has been extensively studied for its therapeutic effects in conditions such as coronary heart disease, angina pectoris, and diabetic peripheral neuropathy. However, its effect on cGAS-STING pathway and its ability to alleviate skin damage have not been previously reported. In a co-culture system, supernatant from UVB-treated keratinocytes induced IRF3 activation in macrophages, and this activation was inhibited by salvianolic acid A. Our investigation, employing photodamage and photoaging models, establishes that salvianolic acid A effectively mitigates UV-induced epidermal thickening and collagen degeneration. Treatment with salvianolic acid A significantly reduced skin damage, epidermal thickness increase, and keratinocyte hyperproliferation compared to the untreated photo-damage and photoaging model groups. In summary, salvianolic acid A emerges as a promising candidate for preventing UV-induced skin damage by inhibiting cGAS-STING activation. This research enhances our understanding of the intricate mechanisms underlying skin photodamage and provides a potential avenue for the development of therapeutic interventions.

White-Cell Derived Inflammatory Biomarkers in Prediction of Postoperative Delirium in Elderly Patients Undergoing Surgery for Lower Limb Fracture Under Non-General Anaesthesia.

Purpose: The aim of this study was to investigate whether white-cell derived biomarkers could serve as potential markers in prediction of postoperative delirium (POD) after lower limb fracture. Patients and Methods: Elderly patients with surgery for lower limb fracture under non-general anaesthesia were included. Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and platelet-to-white cell ratio (PWR), which were most recently measured preceding surgery and measured within 24h after surgery, were calculated. Delirium was measured with Confusion Assessment Method (CAM) once daily from preoperative day 1 to postoperative day 3 or hospital discharge. Results: The incidence of POD was 32.6% (60/184). Between patients with and those without POD, there were significant differences in preoperative hematological biomarkers (neutrophil count, lymphocyte count, NLR and PWR) and postoperative hematological biomarkers (white cell count, neutrophil count, lymphocyte count, NLR, PLR and PWR). More obvious changes before and after operation for NLR, PLR and C-reactive protein (CRP) were found in patients with POD. Multivariate logistic regression showed that benzodiazepines (OR, 7.912; 95% CI, 1.884-33.230; p = 0.005), change of CRP (OR, 1.017; 95% CI, 1.007-1.027; p = 0.001) and postoperative NLR (OR, 1.358; 95% CI, 1.012-1.823; p = 0.041) were associated with POD. When the changes of NLR, PLR and PWR entered multivariate logistic regression, older age (OR, 1.073; 95% CI, 1.001-1.149; p = 0.046), benzodiazepines (OR, 6.811; 95% CI, 1.652-28.081; p = 0.008), greater change of CRP (OR, 1.015; 95% CI, 1.006-1.023; p = 0.001) and greater change of NLR (OR, 1.266; 95% CI, 1.035-1.549; p = 0.022) were associated with increased risk of POD. Postoperative NLR had high accuracy to predict POD with area under curve (AUC) of 0.790 (95% CI 0.708 to 0.872). Conclusion: Age, benzodiazepines, postoperative NLR, change of NLR and change of CRP were independent predictable markers for POD in elderly patients undergoing surgery for lower limb fracture under non-general anaesthesia. Early postoperative NLR may help to recognize POD as soon as possible.

Effect of strontium on nutrient uptake, physiological parameters, and strontium localization in lettuce.

Human activities increase the risk of stable and radioactive strontium (Sr) isotopes entering the environment and food chain. In this study, the effects of Sr on the nutrient uptake and physiological responses of lettuce under different "Sr treatment" concentrations (0, control, 1, 2, 3, 4, and 5 mM) and "times" (7, 14, and 21 day) were studied in a hydroponic system. In addition, the distribution of Sr on the surfaces and cross-sections of lettuce leaves was revealed by scanning electron microscopy with energy-dispersive X-ray (SEM-EDX) analysis. A two-way analysis of variance (ANOVA) method was used to analyze the significance of "Sr treatment," "time," and their "interaction." The results showed that an increase in Sr uptake in lettuce could significantly reduce the uptake of calcium (Ca). The contents of sulfur (S), potassium (K), and iron (Fe) in lettuce leaves showed significant differences with the sampling day. Similarly, the fresh weight of lettuce leaves and roots as well as the photosynthetic pigment contents of lettuce leaves was also significantly different with the sampling day. The activities of antioxidant enzymes (superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD)) showed significant differences with the sampling day. The activities of SOD and CAT decreased significantly with the sampling day, while POD increased significantly. The MDA content increased significantly with increasing hydroponic Sr concentration on the 21st day. SEM-EDX analysis showed that the weight percentage of Sr in the vascular bundle sheath in the cross-section of lettuce leaves was relatively higher than that in the mesophyll. This study aids our understanding of the distribution of Sr in lettuce leaf tissues and the effect of Sr on lettuce physiology.

Combination of apatinib with apo-IDO1 inhibitor for the treatment of colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in the world. Recently, many clinical studies have demonstrated the therapeutic potential of immune checkpoint therapy combined with inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) in colon cancer. Compound B37, identified in our previous experiment, is an apo-form indoleamine-2,3-dioxygenase 1 inhibitor (apo-IDO1 inhibitor), which has been shown to significantly suppress tumor growth combined with an anti-PD1 antibody. We speculated whether this apo-IDO inhibitor (B37) combined with a VEGFR2 inhibitor (apatinib) would further improve its anti-tumor activity. Therefore, a syngeneic mouse colon cancer model (mouse colon cancer cell line CT26) was established to investigate the anti-tumor activity of B37 combined with apatinib. As expected, the combination of B37 and apatinib (VEGFR2 inhibitor) improved the therapeutic effect compared with apo-IDO1 inhibitor and apatinib monotherapy, as shown by the reduced growth of transplanted tumors, weakened proliferation, and increased apoptosis of cancer cells. Specifically, there was a 24.8% reduction in tumor volume using apatinib and 31.3% reduction using B37. The combination-treated group showed remarkable inhibition of tumor growth (52.2%). For tumor weight, there was a 29.2% reduction in the apatinib-treated group and 35.0% reduction in the B37-treated group. The combination-treated group showed a 56.3% reduction. Moreover, the combination therapy reprogrammed the immune microenvironment by increasing infiltration of CD4+ and CD8+ T cells, decreasing the ratio of regulatory T cells, and promoting the killing ability of T cells manifested by elevated expression of IFN-γ and granzyme B in the combination-treated group. Our study indicates that the combination of apo-IDO1 inhibitor and apatinib is a promising strategy for CRC therapy.

Improvement of magnesium isoglycyrrhizinate on DSS-induced acute and chronic colitis.

Inflammatory bowel disease (IBD) is a worldwide prototypical complex disease, owing to its multifactorial causes, relapsing and remitting condition and high incidence. Thus, effective therapeutic approaches need to be developed for patients with IBD. Currently, we reported the improving effect of magnesium isoglycyrrhizinate on colitis induced by dextran sulfate sodium (DSS). We found that magnesium isoglycyrrhizinate treatment significantly alleviated DSS-induced acute and chronic colitis by inhibiting the inflammatory response characterized by reduce of the infiltrations of immune cell and the level of pro-inflammatory cytokines. Besides, magnesium isoglycyrrhizinate treatment significantly inhibited the level of ROS and decreased the gut barrier destruction after DSS treatment. Furthermore, the results also showed that administration of magnesium isoglycyrrhizinate significantly reduced the colonic fibrosis. Taken together, these results revealed the potency of magnesium isoglycyrrhizinate on the intestinal inflammation, by which points to the possible use of magnesium isoglycyrrhizinate for IBD therapy in clinical applications.

Effects of particles on potential denitrification in the coastal waters of the Beibu Gulf in China.

Although the influence of suspended particulate matter (SPM) on denitrifying activity has been identified in river waters recently through metabolic incubations and community gene analysis, the regulations of SPM to denitrification in marine systems are still poorly understood. In the present study, the effects of suspended particle properties (including concentration, composition and size) on potential denitrification were explored in the coastal Beibu Gulf water columns based on a series of 15N-labeled incubations under artificial anaerobic condition. A gradient of oxygen (O2) concentrations was also manipulated in the incubated seawaters to test the sensitivity of denitrification to O2 exposure. According to our experiments, potential denitrification was the dominant pathway for N2 production with major contribution (>60%) recovered from the particle-associated (PA) fraction. The Highest rate occurred in the benthic nepheloid layer, where high particle content induced by sediment resuspension were observed, suggesting that resuspended particles may act as a hot spot for marine nitrogen (N) loss. Both content and lability of particulate organic carbon (POC) were tightly related to the denitrification rates, with denitrification enhanced by autochthonous POC fractions more significantly. The PA denitrification was higher on small particles (1.2-10µm) compared to the large ones (>10µm), probably due to larger specific surface area and higher specific POC content in small particles. O2 suppressed denitrifying activity for both bulk water samples and PA fractions. Although in situ denitrifying activity should be minor or neglected because of high-O2 inhibition, the novel findings of particle effects on anaerobic denitrification can still be applied to hypoxic marine environments. Our research also implies that resuspended particles from sediment may act as a hot spot for N loss, and therefore to be a first step toward future studies in high particle loaded marine regimes.

[Development and inheritance of ZHENG's acupuncture school].

ZHENG's acupuncture school in Gansu,represented by ZHENG Yulin and ZHENG Kuishan,is of great influence in China. ZHENG's acupuncture school originated from Huangdi Neijing(Inner Canon of Yellow Emperor) and Nanjing(Classic of Questioning),and shaped around Yuan Dynasty and Ming Dynasty. Professor ZHENG Kuishan has formed a unique "ZHENG's acupuncture" diagnosis and treatment system by inheritance and innovation. He clinically paid attention to basic training,obtaining qi and keeping spirit,as well as syndrome differentiation,reinforcing and reducing. Also,he took the priority the pressing hand with bilaterally needle manipulation. Besides,he thought important simplicity,innovation and acupoints selecting according to time. We inherited ZHENG's acupuncture from his family,teachers'techniques,international communication,college and university education and scientific research. In this article we prescribe the development,the inheritance and the protection measures of ZHENG's acupuncture school in terms of its origination,academic thought,and inheritance research,etc.,so as to provide references for further study and inheritance.