Endothelin-1 is a peptide derived from endothelial cells, consisting of 21 amino acid residues. In recent years, research has found that endothelin-1 not only plays a key role in vascular tone regulation but also participates in the occurrence and development of various types of pathological pain, including inflammatory pain, neuropathic pain, and cancer pain. Endothelin-1 binds to its receptors and activates multiple signaling pathways such as protein kinase C, calcium ion channels, and the phosphoinositide pathway, thereby influencing neuronal excitability and nociceptive information transmission. This article briefly reviews the current understanding of the mechanisms and potential roles of endothelin-1 in the development of pain, as well as commonly used endothelin-1 receptor antagonists, aiming to provide clues for better utilizing endothelin-1 and its receptors to alleviate and treat pathological pain.
Humans ; Endothelin-1/physiology* ; Pain/physiopathology* ; Signal Transduction/physiology* ; Animals ; Neuralgia/physiopathology* ; Cancer Pain/physiopathology* ; Endothelin Receptor Antagonists

In this study, we explored the pharmacological effects of Siwu Decoction in treating premature ovarian insufficiency(POI) and its molecular mechanism based on the mitophagy pathway modulated and mediated by estrogen receptor(ER) subtypes. Female Balb/c mice were divided into a control group, model group, as well as high-dose and low-dose groups of Siwu Decoction. The POI mice model was constructed by intraperitoneal injection of cisplatin. The high-dose and low-dose groups of Siwu Decoction were administered intragastrically with Siwu Decoction each day for 14 days. During this period, we monitored the estrous cycle and body weight of the mice and calculated the ovarian index. The morphology of the ovaries was detected by hematoxylin-eosin(HE) staining, and the number of primordial follicles was counted. The apoptosis of the ovarian tissue was detected by TUNEL staining. The expression levels of anti-Müllerian hormone(AMH), apoptosis-associated and mitophagy-associated proteins, ER subtypes, and the expression levels of key proteins of its mediated molecular pathways were detected by Western blot and immunohistochemistry. KGN cells were divided into a control group, model group, Siwu Decoction group, and gene silencing group. The apoptosis model was induced by H_2O_2, and PTEN-induced putative kinase 1(PINK1) gene silencing was induced by siRNA transfection. The Siwu Decoction group and gene silencing group were added to the medium containing Siwu Decoction. Cell viability was detected by CCK-8 assay. Cell senescence was detected by senescence-associated-β-galactosidase. The expression levels of apoptosis-associated and mitophagy-associated proteins were detected by Western blot. The results of in vivo experiments showed that compared with the model group, the mice in the high-dose and low-dose groups of Siwu Decoction significantly recovered the rhythm of the estrous cycle, and the levels of ovarian index, number of primordial follicles, and expression of AMH, representative indexes of ovarian function, were significantly higher, suggesting that the level of ovarian function was significantly improved. The expression levels of the apoptosis-related proteins, cytochrome C(Cyt C), cysteinyl aspartate specific proteinase 3(caspase 3), B-cell lymphoma-2(Bcl-2)-associated X(Bax), and mitophagy-associated indicator(Beclin 1) were significantly decreased, and the expression levels of Bcl-2 was significantly elevated. The positive area of TUNEL was significantly reduced, suggesting that the apoptosis level of the ovaries was significantly reduced. The expression levels of PINK1, Parkin, and sequestosome 1(p62) were significantly reduced, suggesting that the level of ovarian mitophagy was significantly down-regulated. The expression levels of ERα and ERβ were significantly elevated, and the ratio of ERα/ERβ was significantly reduced. The expression levels of key proteins in the pathway, phosphoinositide 3-kinase(PI3K) and protein kinase B(Akt), were significantly reduced, suggesting that the regulation of ER subtypes and the mediation of PI3K/Akt pathway were the key mechanisms. In vitro experiments showed that compared with the model group, the proportion of senescent cells in the Siwu Decoction group was significantly reduced. Cyt C, caspase 3, Beclin 1, Parkin, and p62 were significantly reduced, which was in line with in vivo experimental results. The proportion of senescent cells and the expression level of the above proteins were further significantly reduced after PINK1 silencing. It can be seen that Siwu Decoction can regulate the expression level and proportion of ER subtypes in KGN cells, then mediate the PI3K/Akt pathway to inhibit excessive mitophagy and apoptosis, and exert therapeutic effects of POI.
Animals ; Female ; Drugs, Chinese Herbal/administration & dosage* ; Mitophagy/drug effects* ; Primary Ovarian Insufficiency/physiopathology* ; Mice ; Mice, Inbred BALB C ; Humans ; Receptors, Estrogen/genetics* ; Apoptosis/drug effects* ; Ovary/metabolism* ; Signal Transduction/drug effects* ; Anti-Mullerian Hormone/genetics*

OBJECTIVES: This systematic review examines recent pharmacoeconomic literature on denosumab' cost-effectiveness for bone metastasis treatment, providing evidence-based insights to guide healthcare policy decisions. METHODS: A comprehensive literature search was performed across Cochrane, PubMed, EMBASE (Ovid), CNKI, and Wanfang databases to identify original articles published between 2017 and 2023. Key words consisted of bone metastases, denosumab, and cost-effectiveness in the search strategy. The methodological quality of the included studies was assessed utilizing the revised Consolidated Health Economic Evaluation Reporting Standards (CHEERS 2022). Data was extracted regarding methodological characteristics and cost-effectiveness analyses. RESULTS: A total of 111 studies were retrieved, of which 6 met the inclusion criteria. All included studies were based on clinical trials and published literature data and exhibited high methodological quality. Up to 83% (5 out of 6) of comparisons demonstrated that denosumab was more cost-effective or dominant compared to zoledronic acid. The adjusted incremental cost-effectiveness ratios varied substantially by tumor type, ranging from CZK 436,339.09 to USD 136,234 per skeletal-related event avoided and from CZK 61,580.95 to USD 118,392.11 per quality-adjusted life year gained. CONCLUSIONS The majority of the included studies support denosumab as a more cost-effective treatment option for bone metastases in solid tumors compared to zoledronic acid. The application of CHEER (2022) enhances the reliability of pharmacoeconomic evaluations.
Denosumab/therapeutic use* ; Humans ; Bone Neoplasms/economics* ; Cost-Benefit Analysis

The outer membrane composed predominantly of lipopolysaccharide (LPS) is an essential biological barrier for most Gram-negative (G^-) bacteria. Lipopolysaccharide transport protein (Lpt) complex LptDE is responsible for the critical final stage of LPS transport and outer membrane assembly. The structure and function of LptDE are highly conserved in most G^- bacteria but absent in mammalian cells, and thus LptDE complex is regarded as an attractive antibacterial target. In recent 10 years, the deciphering of the three-dimensional structure of LptDE protein facilities the drug discovery based on such "non-enzyme" proteins. Murepavadin, a peptidomimetic compound, was reported to be the first compound able to target LptD, enlightening a new class of antibacterial molecules with novel mechanisms of action. This article is devoted to summarize the molecular characteristics, structure-function of LptDE protein complex and review the development of murepavadin and related peptidomimetic compounds, in order to provide references for relevant researches.

Lipopolysaccharides (LPS) are major outer membrane components of Gram-negative bacteria. Unlike most Gram-negative bacteria, Acinetobacter baumannii can still survive and acquire polymyxin resistance after complete loss of LPS. Previous studies of LPS-deficient Acinetobacter baumannii mostly focused on LPS-deficient strains induced by polymyxin, whose background was complex and unstable. To investigate LPS loss-mediated polymyxin resistant-Acinetobacter baumannii, this study constructed a stable and clear background LPS-deficient strain by knocking out lpxC gene in Acinetobacter baumannii ATCC 19606 with CIRSPR/Cas9, and then studied the phenotypic changes of the lpxC-deficient strain including morphology, growth rate, antibiotic susceptibility, virulence, membrane permeability, and membrane potential. Animal experiments were approved by the Animal Care and Welfare Committee Institute of Medicinal Biotechnology, CAMS and PUMC (approval number: IMB-20240119D₉). The results indicated that the lpxC gene of Acinetobacter baumannii ATCC 19606 was successfully knocked out. After losing the lpxC, the strain underwent the morphological change from rod-shaped to spherical. Furthermore, it leads to reduced growth rate, enhanced membrane permeability, decreased membrane potential, lower virulence, and increased antibiotic susceptibility to β-lactams, quinolones, aminoglycosides, macrolides, glycopeptides. The lpxC deletion results in significant changes in membrane homeostasis and adaptability of Acinetobacter baumannii. Understanding the phenotypic changes of colistin-resistant Acinetobacter baumannii mediated by LPS loss is useful for exploring the resistance mechanism of Acinetobacter baumannii and developing new therapeutic strategies.

Objective To explore the effects of standardized environmental enrichment(EE)on cognitive function and serum brain-derived neurotrophic factor(BDNF)levels in patients with post-stroke dementia.Methods A prospective study was conducted,including 80 patients with post-stroke dementia admitted to Department of Traditional Chinese Medicine Rehabilitation,910th Hospital of the Joint Logistics Support Force of Chinese PLA from January 2021 to May 2023.Patients were randomly divided into control group,cognitive training(COG)group,aerobic exercise training(AE)group and environmental enrichment(EE)group,with 20 cases in each group.All patients received routine treatment,with COG group receiving additional cognitive function training(30 minutes each time),AE group receiving additional aerobic exercise training(30 minutes each time),and EE group receiving both aerobic exercise and cognitive function training(15 minutes of aerobic exercise training and 15 minutes of cognitive training each time).The training was conducted once a day,5 days a week,for a total of 8 weeks.The patients'mini-mental state scale(MMSE),modified Barthel index(MBI),Hamilton depression scale(HAMD),stroke-specific quality of life(SS-QOL)score and serum levels of BDNF were assessed before treatment,at 4 weeks and 8 weeks of treatment,respectively.Results Before treatment,there were no significant differences in general information,MMSE,MBI,HAMD,SS-QOL scores,and serum levels of BDNF among the four groups(P＞0.05).After 4 and 8 weeks of treatment,the above indicators of the four groups were improved compared with those before treatment,with all differences being statistically significant(P＜0.05).Inter-group comparison showed that after 4 and 8 weeks of treatment,MMSE,MBI,SS-QOL scores,and serum BDNF levels in COG,AE and EE groups were significantly higher than those in control group,and HAMD scores were significantly lower than those in control group(P＜0.05).In addition,MMSE,MBI,SS-QOL scores and BDNF levels of group EE were better than those of other 3 groups,while HAMD scores were lower than those of other 3 groups,with all differences being statistically significant(P＜0.05).There was no significant difference in above outcome indicators between COG group and AE group after 4 and 8 weeks of treatment(P＞0.05).Conclusion Standardized enrichment environment can significantly enhance cognitive function,daily living abilities of post-stroke dementia patients,alleviate depression symptoms,and improve the quality of life,which may be related to the increase in serum BDNF levels.

To conduct timely surveillance of the seasonal characteristics and disease burden of Human Respiratory Syncytial Virus (HRSV) in various geographical regions of China, and further develop more precise and effective prevention and intervention strategies, there is an urgent need for China to establish a nationwide, effective, and stable HRSV surveillance system. Through combining the current status of domestic and international HRSV surveillance systems and the existing surveillance framework in China, this study proposed an HRSV surveillance type applicable to China based on different surveillance purposes, and considering the feasibility of implementation. This article aimed to provide solid scientific and technical support to monitor the dynamic changes of HRSV epidemic timely, carry out a risk assessment and early warning, and further understand the disease burden of HRSV in China. It also helps to improve the diagnosis, prevention, and control of the HRSV diseases research and development, use, and evaluation of HRSV vaccines and drugs in China.

Objective:To construct a predictive model to assess the risk of severe respiratory syncytial virus infection among children under five years in China, conduct preliminary validation of this model by using external data, and develop an individual risk assessment tool available for their parents.Methods:The admission after RSV infection was used as a marker of severe infection. Based on the evidence of RSV hospitalization-related risk factors and real-world data, such as the prevalence of various risk factors in children under five years old in China, a Monte Carlo-based individual RSV hospitalization risk prediction model for children under five years old was constructed. Taking Suzhou City as an example, the model was externally validated, and an interactive risk prediction tool (RSV HeaRT) was developed on the WeChat mini-program platform.Results:The estimation model showed that in children under five years old in China if the population did not have any risk factors for severe RSV infection, the RSV annual hospitalization rate was 2.2/1 000 (95% CI: 0.9/1 000-7.5/1 000). Based on this baseline hospitalization rate and the prevalence of related risk factors in Suzhou, the model predicted an RSV hospitalization rate of 8.0/1 000 (95% CI: 4.6/1 000-24.4/1 000) for children under five years old annually in Suzhou, which was close to the reported RSV hospitalization rate in literature (10/1 000-20/1 000). In the developed RSV HeaRT WeChat mini-program, target users (such as parents of children) could input basic information, disease history, and social environmental factors of the child into the mini-program, and the tool could provide real-time feedback on the following predicted results: First, the relative risk of hospitalization due to RSV infection in current children compared to general children; Second, the probability of hospitalization due to RSV infection within the next year; Third, the relative risk of adverse outcomes during hospitalization in the event of RSV infection. Conclusion:This study is based on real-world evidence related to RSV hospitalization risk and constructs an RSV hospitalization risk prediction model suitable for Chinese children based on the combination of the current prevalence of risk factors in children under five years old in China. The accuracy of the prediction model results has been preliminarily demonstrated. Based on this design, the RSV HeaRT developed can facilitate parents to evaluate the hospitalization risk of children.

To conduct timely surveillance of the seasonal characteristics and disease burden of Human Respiratory Syncytial Virus (HRSV) in various geographical regions of China, and further develop more precise and effective prevention and intervention strategies, there is an urgent need for China to establish a nationwide, effective, and stable HRSV surveillance system. Through combining the current status of domestic and international HRSV surveillance systems and the existing surveillance framework in China, this study proposed an HRSV surveillance type applicable to China based on different surveillance purposes, and considering the feasibility of implementation. This article aimed to provide solid scientific and technical support to monitor the dynamic changes of HRSV epidemic timely, carry out a risk assessment and early warning, and further understand the disease burden of HRSV in China. It also helps to improve the diagnosis, prevention, and control of the HRSV diseases research and development, use, and evaluation of HRSV vaccines and drugs in China.

Objective:To construct a predictive model to assess the risk of severe respiratory syncytial virus infection among children under five years in China, conduct preliminary validation of this model by using external data, and develop an individual risk assessment tool available for their parents.Methods:The admission after RSV infection was used as a marker of severe infection. Based on the evidence of RSV hospitalization-related risk factors and real-world data, such as the prevalence of various risk factors in children under five years old in China, a Monte Carlo-based individual RSV hospitalization risk prediction model for children under five years old was constructed. Taking Suzhou City as an example, the model was externally validated, and an interactive risk prediction tool (RSV HeaRT) was developed on the WeChat mini-program platform.Results:The estimation model showed that in children under five years old in China if the population did not have any risk factors for severe RSV infection, the RSV annual hospitalization rate was 2.2/1 000 (95% CI: 0.9/1 000-7.5/1 000). Based on this baseline hospitalization rate and the prevalence of related risk factors in Suzhou, the model predicted an RSV hospitalization rate of 8.0/1 000 (95% CI: 4.6/1 000-24.4/1 000) for children under five years old annually in Suzhou, which was close to the reported RSV hospitalization rate in literature (10/1 000-20/1 000). In the developed RSV HeaRT WeChat mini-program, target users (such as parents of children) could input basic information, disease history, and social environmental factors of the child into the mini-program, and the tool could provide real-time feedback on the following predicted results: First, the relative risk of hospitalization due to RSV infection in current children compared to general children; Second, the probability of hospitalization due to RSV infection within the next year; Third, the relative risk of adverse outcomes during hospitalization in the event of RSV infection. Conclusion:This study is based on real-world evidence related to RSV hospitalization risk and constructs an RSV hospitalization risk prediction model suitable for Chinese children based on the combination of the current prevalence of risk factors in children under five years old in China. The accuracy of the prediction model results has been preliminarily demonstrated. Based on this design, the RSV HeaRT developed can facilitate parents to evaluate the hospitalization risk of children.