Sex hormone-binding globulin exerts sex-related causal effects on lower extremity varicose veins: evidence from gender-stratified Mendelian randomization.

Background: The association between serum sex hormones and lower extremity varicose veins has been reported in observational studies. However, it is unclear whether the association reflects a causal relationship. Besides, serum sex hormone-binding globulin (SHBG) has been rarely studied in lower extremity varicose veins. Here, we aim to investigate the association between serum levels of SHBG, testosterone, and estradiol and the risk of lower extremity varicose veins using Mendelian randomization (MR). Methods: We obtained genome-wide association study summary statistics for serum SHBG levels with 369,002 European participants, serum testosterone levels with 424,907 European participants, serum estradiol levels with 361,194 European participants, and lower extremity varicose veins with 207,055 European participants. First, a univariable MR was performed to identify the causality from SHBG and sex hormone levels to lower extremity varicose veins with several sensitivity analyses being performed. Then, a multivariable MR (MVMR) was performed to further assess whether the causal effects were independent. Finally, we performed a gender-stratified MR to understand the role of genders on lower extremity varicose veins. Results: Genetically predicted higher serum SHBG levels significantly increased the risk of lower extremity varicose veins in the univariable MR analysis (OR=1.39; 95% CI: 1.13-1.70; P=1.58×10-3). Sensitivity analyses and MVMR (OR=1.50; 95% CI:1.13-1.99; P=5.61×10-3) verified the robustness of the causal relationships. Gender-stratified MR revealed that higher serum SHBG levels were associated with lower extremity varicose veins in both sexes. However, the OR of serum SHBG levels on lower extremity varicose veins risk in females (OR=1.51; 95% CI: 1.23-1.87; P=1.00×10-4) was greater than in males (OR=1.26; 95% CI: 1.04-1.54; P=1.86×10-2). Conclusions: Serum SHBG levels are positively related to lower extremity varicose veins risk in both sexes, especially in females. This may partly explain the higher prevalence of varicose vines among females.

MEGF6 prevents sepsis-induced acute lung injury in mice.

OBJECTIVE: Acute lung injury (ALI) is featured as excessive inflammatory response and oxidative damage, and results in high death rate of septic patients. This research intends to determine the function of multiple EGF like domains 6 (MEGF6) in sepsis-induced ALI. METHODS: Mice were intratracheally treated with adenovirus to knock down or overexpress MEGF6 in lung tissues, and then were subjected to cecum ligation and puncture (CLP) operation to induce ALI. Primary peritoneal macrophages were isolated, and were knocked down or overexpressed with MEGF6, and then, were stimulated with lipopolysaccharide (LPS) to confirm its role in vitro. RESULTS: Serum and lung MEGF6 levels were significantly elevated in septic mice. MEGF6 knockdown exacerbated, while MEGF6 overexpression prevented inflammation, oxidative damage and ALI in CLP mice. Meanwhile, LPS-elicited inflammatory response and oxidative damage in primary macrophages were reduced by MEGF6 overexpression, but were further aggravated by MEGF6 knockdown. Mechanistic studies revealed that MEGF6 reduced cluster of differentiation 38 (CD38) expression and subsequently elevated intracellular nicotinamide adenine dinucleotide levels, thereby activating sirtuin 1 (SIRT1) without affecting the protein expression. SIRT1 suppression or CD38 overexpression with either genetic or pharmacologic methods remarkably blunted the lung protective effects of MEGF6 in CLP mice. CONCLUSION: MEGF6 prevents CLP-induced ALI through CD38/SIRT1 pathway, and it might be a valuable therapeutic candidate for the management of sepsis-induced ALI.

Limonin, a novel AMPK activator, protects against LPS-induced acute lung injury.

AMP-activated protein kinase (AMPK) activation plays crucial roles in the treatment of many oxidative stress- and inflammation-induced diseases, including acute lung injury (ALI). Limonin is a naturally occurring tetracyclic triterpenoid extracted from the plants of Rutaceae and Meliaceae. Limonin also serves as an AMPK activator with anti-inflammatory and anti-oxidation effects. However, the potential beneficial effects of limonin on ALI and the possible mechanisms have never been disclosed till now. Here, the effects of limonin on lipopolysaccharide (LPS)-induced ALI in C57 BL/6 mice, plus bone marrow-derived macrophages (BMDM) stimulated with LPS to induce in vitro ALI model were investigated. Limonin significantly improved pulmonary function and alleviated lung pathological injury in LPS-induced mice. Meanwhile, limonin also markedly decreased inflammation and oxidative stress in lung tissues from LPS-treated mice. In vitro experiments also unveiled that limonin could decrease inflammation and oxidative stress in LPS-induced BMDM in a concentration-dependent manner. Mechanically, limonin could promote the activation of AMPKα and upregulate the expression of nuclear factor erythroid 2-related factor 2 (NRF2) in lung tissues and BMDM. Pharmacological inhibition of AMPKα by Compound C or AMPKα knockout could abolish the pulmonary protection from limonin during ALI. In conclusion, limonin mediates the activation of AMPKα/NRF2 pathway, providing an attractive therapeutic target for ALI in the future.

Nesfatin-1, a novel energy-regulating peptide, alleviates pulmonary fibrosis by blocking TGF-ß1/Smad pathway in an AMPKα-dependent manner.

Pulmonary fibrosis is a chronic progressive disease which steadily causes a critical public health concern. Nesfatin-1, a novel energy-regulating peptide discovered in 2006, could increase the level of AMPK phosphorylation. Previous studies have unveiled that Nesfatin-1 possessed many pharmacological effects including anti-inflammation, anti-oxidative stress, anti-fibrosis, and the regulation of lipid metabolism. Here, we investigated the impact of Nesfatin-1 on pulmonary fibrosis. Male C57BL/6J mice were intraperitoneally injected with Nesfatin-1 (10 µg·kg-1·day-1) for 21 days since mice were intratracheally administrated with bleomycin (BLM) (2 U/kg). Primary murine lung fibroblasts were stimulated with TGF-ß1 (10 ng/ml) for 48 h. The results showed that Nesfatin-1 treatment significantly improved pulmonary function and decreased the production of collagen in BLM-treated mice. Meantime, Nesfatin-1 treatment also inhibited oxidative stress and inflammation in lung tissues from BLM-treated mice. Mechanically, Nesfatin-1 blocked the activation of TGF-ß1/Smad2/3 signaling pathway in lung tissues challenged with BLM. In addition, we found that Nesfatin-1 enhanced the phosphorylation of AMPKα during pulmonary fibrosis. However, pharmacological inhibition or genetic deletion of AMPKα could both offset the pulmonary protection mediated by Nesfatin-1 during pulmonary fibrosis. Our experimental results firstly show Nesfatin-1 might serve as a novel treatment or adjuvant against pulmonary fibrosis by blocking TGF-ß1/Smad pathway in an AMPKα-dependent manner.

Panorama of Breakthrough Infection Caused by SARS-CoV-2: A Review.

Since the outbreak of the novel coronavirus disease 2019 (COVID-19) in 2019, many countries have successively developed a variety of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, with the continuous spread of SARS-CoV-2, it has evolved several variants; as a result, prevention and control of the pandemic of SARS-CoV-2 has become more important. Among these variants, the Omicron variant has higher transmissibility and immune escape ability and is the main variant causing a large number of COVID-19 breakthrough infection, thus, presenting new challenges to pandemic prevention and control. Hence, we review the biological characteristics of the Omicron variant and discuss the current status and possible mechanism of breakthrough infection caused by the Omicron variant in order to provide insights into the prevention and control of the pandemic of SARS-CoV-2.

Surface Reduction Stabilizes the Single-Crystalline Ni-Rich Layered Cathode for Li-Ion Batteries.

The surface of the layered transition metal oxide cathode plays an important role in its function and degradation. Modification of the surface structure and chemistry is often necessary to overcome the debilitating effect of the native surface. Here, we employ a chemical reduction method using CaI2 to modify the native surface of single-crystalline layered transition metal oxide cathode particles. High-resolution transmission electron microscopy shows the formation of a conformal cubic phase at the particle surface, where the outmost layer is enriched with Ca. The modified surface significantly improves the long-term capacity retention at low rates of cycling, yet the rate capability is compromised by the impeded interfacial kinetics at high voltages. The lack of oxygen vacancy generation in the chemically induced surface phase transformation likely results in a dense surface layer that accounts for the improved electrochemical stability and impeded Li-ion diffusion. This work highlights the strong dependence of the electrode's (electro)chemical stability and intercalation kinetics on the surface structure and chemistry, which can be further tailored by the chemical reduction method.

Li Alginate-Based Artificial SEI Layer for Stable Lithium Metal Anodes.

Lithium metal anodes (LMAs) are critical for high-energy-density batteries such as Li-S and Li-O2 batteries. The spontaneously formed solid electrolyte interface on LMAs is fragile, which may not accommodate the cyclic Li plating/stripping. This usually will result in a low coulombic efficiency (CE), short cycle life, and potential safety hazards induced by the uncontrollable growth of lithium dendrites. In this study, we fabricate a Li alginate-based artificial SEI (ASEI) layer that is chemically stable and allows easy Li ion transport on the surface of LMAs, thus enabling the stable operation of lithium metal anodes. Compared to bare LMAs, the ASEI layer-protected LMAs exhibit a more stable Li plating/stripping behavior and present effective dendrite suppression. The symmetric Li∥Li cells with the ASEI layer-protected LMAs can stably run for 850 and 350 h at current densities of 0.5 and 1 mA cm-2, respectively. Additionally, the LiFePO4∥Li full cell with the ASEI layer-protected LMA exhibits a capacity retention of about 94.0% coupled with a CE of 99.6% after 1000 cycles at 4 C. We believe that this study of engineering an ASEI brings a new and promising approach to the stabilization of LMAs for high-performance lithium metal batteries.

Superior Stability Secured by a Four-Phase Cathode Electrolyte Interface on a Ni-Rich Cathode for Lithium Ion Batteries.

A multifunctional coating with high ionic and electronic conductivity is constructed on the surface of LiNi0.8Co0.1Mn0.1O2 (NCM) to boost the battery stability upon cycling and during storage as well. Phosphoric acid reacts with residual lithium species on the pristine NCM to form a Li3PO4 coating with extra carbon nanotubes (CNTs) penetrating through, which shows high ionic and electronic conductivity. NCM, Li3PO4, CNTs, and the electrolyte jointly form a four-phase cathode electrolyte interface, which plays a key role in the great enhancement of capacity retention, from 50.3% for pristine NCM to 84.8% for the modified one after 500 cycles at 0.5C at room temperature. The modified NCM also delivers superior electrochemical performances at a high cut-off voltage (4.5 V), high temperature (55 °C), and high rate (10C). Furthermore, it can deliver 154.2 mA h g-1 at the 500th cycle after exposed to air with high humidity for 2 weeks. These results demonstrate that the well-constructed multifunctional coating can remarkably enhance the chemical and electrochemical performances of NCM. The improved cycling, storage, and rate performance are attributed to the four-phase cathode electrolyte interface delivering high electron and ionic conductivity and securing the cathode against attack. This work broadens the horizon for constructing effective electrode/electrolyte interfaces for electrochemical energy storage and conversion.

Two new acylated flavonol glycosides from the seeds of Lepidium sativum.

Two new acylated flavonol glycosides named kaempferol-3-O-(2-O-sinapoyl)-ß-D-galactopyranosyl-(1 → 2)-ß-D-glucopyranoside-7-O-α-L-rhamnopyranoside (1) and quercetin-3-O-(6-O-benzoyl)-ß-D-glucopyranosyl-(1 → 3)-ß-D-galactopyranoside-7-O-α-L-rhamnopyranoside (2), were isolated together with six known compounds from the seeds of L. sativum. Their structures were elucidated on the basis of spectroscopic analysis and chemical methods. In vitro 1 and 2 inhibited nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, with IC50 values of 25.36 and 25.08 µM, respectively.