Endometrial injury is the main fact leading to the damage of endometrial basal layer.It is usually caused by traumatic treatment,inflammatory injury,radiation,chemical drug-related injury,and delivery-related divertic-ulum.The use of hyaluronic acid,decellularized matrix,amniotic membrane,platelet-rich plasma,mesenchymal stem cells(especially scaffold-based therapeutic delivery)has been proved to reduce post-injury scar formation and promote endometrial growth and repair,which provides a new therapeutic strategy for repairing the damaged endo-metrium with improved tolerability and fertility outcomes.

Objective:To explore mechanism of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction in treatment of post-stroke depression(PSD)based on network pharmacology,molecular docking and animal experiment.Methods:TCMSP and other databases were used to predict active components and targets of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction.Targets of PSD were retrieved from PharmGKB and other databases,and"component-intersection target-disease"network was constructed by Cytoscape(v3.9.1)software.PPI network was constructed by String(v11.5)database,and GO enrichment and KEGG pathway analy-sis of intersection targets were performed by DAVID6.8 database.AutoDock vina(v1.1.2)software was used for molecular docking.Pymol(v 2.5)and other softwares were used to visualize optimal docking results.Animal experiments were setup in control group,model group,fluoxetine group,TCM group and TCM+fluoxetine group,neurobehavioral scores and expressions of neurotransmitters and inflammatory factors in brain tissues were detected.mRNA and protein expressions of key genes PPARG,MAPK3,AKT1,PIK3CA were detected by RT-qPCR and Western blot.Results:A total of 225 kinds of active ingredients of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction were obtained,which acted on 119 targets of PSD,among which key targets included MAPK3,AKT1,PIK3CA and PPARG,key pathways including MAPK signaling pathway,PI3K-Akt signaling pathway and etc.Compared with model group,MAPK3 mRNA and protein expressions were decreased,AKT1,PIK3CA,PPARG mRNA and protein expressions were increased in TCM group and TCM+fluoxetine group(P<0.05).Conclusion:Mechanism of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction in treatment of PSD may be related to inhibition of MAPK3 expression,promotion of AKT1,PIK3CA,PPARG expressions,alleviation of inflammatory response and oxidative stress in brain tissues.

PiT2 is an inorganic phosphate (Pi) transporter whose mutations are linked to primary familial brain calcification (PFBC). PiT2 mainly consists of two ProDom (PD) domains and a large intracellular loop region (loop7). The PD domains are crucial for the Pi transport, but the role of PiT2-loop7 remains unclear. In PFBC patients, mutations in PiT2-loop7 are mainly nonsense or frameshift mutations that probably cause PFBC due to C-PD1131 deletion. To date, six missense mutations have been identified in PiT2-loop7; however, the mechanisms by which these mutations cause PFBC are poorly understood. Here, we found that the p.T390A and p.S434W mutations in PiT2-loop7 decreased the Pi transport activity and cell surface levels of PiT2. Furthermore, we showed that these two mutations attenuated its membrane localization by affecting adenosine monophosphate-activated protein kinase (AMPK)- or protein kinase B (AKT)-mediated PiT2 phosphorylation. In contrast, the p.S121C and p.S601W mutations in the PD domains did not affect PiT2 phosphorylation but rather impaired its substrate-binding abilities. These results suggested that missense mutations in PiT2-loop7 can cause Pi dyshomeostasis by affecting the phosphorylation-regulated cell-surface localization of PiT2. This study helps understand the pathogenesis of PFBC caused by PiT2-loop7 missense mutations and indicates that increasing the phosphorylation levels of PiT2-loop7 could be a promising strategy for developing PFBC therapies.
Humans ; Cell Membrane ; Mutation, Missense ; Phosphates/metabolism* ; Sodium-Phosphate Cotransporter Proteins, Type III/genetics*

Age-dependent loss of skeletal muscle mass and function is a feature of sarcopenia, and increases the risk of many aging-related metabolic diseases. Here, we report phenotypic and single-nucleus transcriptomic analyses of non-human primate skeletal muscle aging. A higher transcriptional fluctuation was observed in myonuclei relative to other interstitial cell types, indicating a higher susceptibility of skeletal muscle fiber to aging. We found a downregulation of FOXO3 in aged primate skeletal muscle, and identified FOXO3 as a hub transcription factor maintaining skeletal muscle homeostasis. Through the establishment of a complementary experimental pipeline based on a human pluripotent stem cell-derived myotube model, we revealed that silence of FOXO3 accelerates human myotube senescence, whereas genetic activation of endogenous FOXO3 alleviates human myotube aging. Altogether, based on a combination of monkey skeletal muscle and human myotube aging research models, we unraveled the pivotal role of the FOXO3 in safeguarding primate skeletal muscle from aging, providing a comprehensive resource for the development of clinical diagnosis and targeted therapeutic interventions against human skeletal muscle aging and the onset of sarcopenia along with aging-related disorders.
Animals ; Humans ; Sarcopenia/metabolism* ; Forkhead Box Protein O3/metabolism* ; Muscle, Skeletal/metabolism* ; Aging/metabolism* ; Primates/metabolism*

Via an insufficient coat protein complex I (COPI) retrieval signal, the majority of SARS-CoV-2 spike (S) is resident in host early secretory organelles and a tiny amount is leaked out in cell surface. Only surface-exposed S can be recognized by B cell receptor (BCR) or anti-S therapeutic monoclonal antibodies (mAbs) that is the trigger step for B cell activation after S mRNA vaccination or infected cell clearance by S mAbs. Now, a drug strategy to promote S host surface exposure is absent. Here, we first combined structural and biochemical analysis to characterize S COPI sorting signals. A potent S COPI sorting inhibitor was then invented, evidently capable of promoting S surface exposure and facilitating infected cell clearance by S antibody-dependent cellular cytotoxicity (ADCC). Importantly, with the inhibitor as a probe, we revealed Omicron BA.1 S is less cell surface exposed than prototypes because of a constellation of S folding mutations, possibly corresponding to its ER chaperone association. Our findings not only suggest COPI is a druggable target against COVID-19, but also highlight SARS-CoV-2 evolution mechanism driven by S folding and trafficking mutations.

Animals ; Mice ; Colitis, Ulcerative/metabolism* ; beta Catenin ; Carcinogenesis ; Probiotics ; Colitis/metabolism*

Eucommiae Folium(EF),a traditional Chinese medicine,has been used to treat secondary hypertension,including renal hypertension and salt-sensitive hypertension,as well as hypertension caused by thoracic aortic endothelial dysfunction,a high-fat diet,and oxidized low-density lipoprotein.The antihyperten-sive components of EF are divided into four categories:flavonoids,iridoids,lignans,and phenyl-propanoids,such as chlorogenic acid,geniposide acid and pinoresinol diglucoside.EF regulates the occurrence and development of hypertension by regulating biological processes,such as inhibiting inflammation,regulating the nitric oxide synthase pathway,reducing oxidative stress levels,regulating endothelial vasoactive factors,and lowering blood pressure.However,its molecular antihypertensive mechanisms are still unclear and require further investigation.In this review,by consulting the relevant literature on the antihypertensive effects of EF and using network pharmacology,we summarized the active ingredients and pharmacological mechanisms of EF in the treatment of hypertension to clarify how EF is associated with secondary hypertension,the related components,and underlying mechanisms.The results of the network pharmacology analysis indicated that EF treats hypertension through a multi-component,multi-target and multi-pathway mechanism.In particular,we discussed the role of EF tar-gets in the treatment of hypertension,including epithelial sodium channel,heat shock protein70,rho-associated protein kinase 1,catalase,and superoxide dismutase.The relevant signal transduction path-ways,the ras homolog family member A(RhoA)/Rho-associated protein kinase(ROCK)and nicotinamide adenine dinucleotide phosphate(NADPH)oxidase/eNOS/NO/Ca2+pathways,are also discussed.

The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

Periprosthetic infection is a catastrophic complication after joint replacement. Choosing appropriate treatment for patients with different infection characteristics is the key to improve the success rate. The one-stage revision has been applied and studied more and more in clinical work because of its advantages in treatment cycle, functional recovery, complications and cost. Grasping the indications and contraindications, comprehensive analysis and selection of appropriate patients, considering intraoperative details and postoperative anti-infection treatment meticulously, are crucial to reduce the recurrence rate of infection. The purpose of this paper is to describe the main points of the one-stage revision in the treatment of periprosthetic infection, and to summarize the classic and recent research on the one-stage revision.

Adenocarcinoma of esophagogastric junction (AEG) has attracted more attention in recent years. Surgical method of Siewert type Ⅱ AEG is especially controversial, mainly focusing on the scope of lymph node dissection, safety of surgical margin, and digestive tract reconstruction. The abdominal transhiatal approach and right thoracoabdominal Ivor-Lewis approach are the main surgical approaches of totally laparoscopic or thoracoscopic surgery for Siewert type Ⅱ AEG, which not only need close teamwork, but also require rich experience in laparoscopic surgery. The authors has started to choose these two totally minimally invasive surgical approaches, the feasibility and safety of which are proved. The key surgical details are presented in this article for reference.