Identification and analysis of differently expressed transcription factors in aristolochic acid nephropathy.

BACKGROUND: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy caused by Aristolochic acid (AA). AAN is associated with the development of nephropathy and urothelial carcinoma. It is estimated that more than 100 million people worldwide are at risk of developing AAN. However, the underlying mechanisms driving renal deterioration in AAN remain poorly understood, and the treatment options are limited. METHODS: We obtained GSE27168 and GSE136276 series matrix data from the Gene Expression Omnibus (GEO) related to AAN. Using the R Studio environment, we applied the limma package and WGCNA package to identify co-differently expressed genes (co-DEGs). By GO/KEGG/GSVA analysis, we revealed common biological pathways. Subsequently, co-DEGs were subjected to the String database to construct a protein-protein interaction (PPI) network. The MCC algorithms implemented in the Cytohubba plugin were employed to identify hub genes. The hub genes were cross-referenced with the transcription factor (TF) database to identify hub TFs. Immune infiltration analysis was performed to identify key immune cell groups by utilizing CIBERSORT. The expressions of AAN-associated hub TFs were verified in vivo and in vitro. Finally, siRNA intervention was performed on the two TFs to verify their regulatory effect in AAN. RESULTS: Our analysis identified 88 co-DEGs through the "limma" and "WGCNA" R packages. A PPI network comprising 53 nodes and 34 edges was constructed with a confidence level >0.4. ATF3 and c-JUN were identified as hub TFs potentially linked to AAN. Additionally, expressions of ATF3 and c-JUN positively correlated with monocytes, basophils, and vessels, and negatively correlated with eosinophils and endothelial cells. We observed a significant increase in protein and mRNA levels of these two hub TFs. Furthermore, it was found that siRNA intervention targeting ATF3, but not c-JUN, alleviated cell damage induced by AA. The knockdown of ATF3 protects against oxidative stress and inflammation in the AAN cell model. CONCLUSION: This study provides novel insights into the role of ATF3 in AAN. The comprehensive analysis sheds light on the molecular mechanisms and identifies potential biomarkers and drug targets for AAN treatment.

Barriers and Implications of 5G Technology Adoption for Hospitals in Western China: Integrated Interpretive Structural Modeling and Decision-Making Trial and Evaluation Laboratory Analysis.

BACKGROUND: 5G technology is gaining traction in Chinese hospitals for its potential to enhance patient care and internal management. However, various barriers hinder its implementation in clinical settings, and studies on their relevance and importance are scarce. OBJECTIVE: This study aimed to identify critical barriers hampering the effective implementation of 5G in hospitals in Western China, to identify interaction relationships and priorities of the above-identified barriers, and to assess the intensity of the relationships and cause-and-effect relations between the adoption barriers. METHODS: This paper uses the Delphi expert consultation method to determine key barriers to 5G adoption in Western China hospitals, the interpretive structural modeling to uncover interaction relationships and priorities, and the decision-making trial and evaluation laboratory method to reveal cause-and-effect relationships and their intensity levels. RESULTS: In total, 14 barriers were determined by literature review and the Delphi method. Among these, "lack of policies on ethics, rights, and responsibilities in core health care scenarios" emerged as the fundamental influencing factor in the entire system, as it was the only factor at the bottom level of the interpretive structural model. Overall, 8 barriers were classified as the "cause group," and 6 as the "effect group" by the decision-making trial and evaluation laboratory method. "High expense" and "organizational barriers within hospitals" were determined as the most significant driving barrier (the highest R-C value of 1.361) and the most critical barrier (the highest R+C value of 4.317), respectively. CONCLUSIONS: Promoting the integration of 5G in hospitals in Western China faces multiple complex and interrelated barriers. The study provides valuable quantitative evidence and a comprehensive approach for regulatory authorities, hospitals, and telecom operators, helping them develop strategic pathways for promoting widespread 5G adoption in health care. It is suggested that the stakeholders cooperate to explore and solve the problems in the 5G medical care era, aiming to achieve the coverage of 5G medical care across the country. To our best knowledge, this study is the first academic exploration systematically analyzing factors resisting 5G integration in Chinese hospitals, and it may give subsequent researchers a solid foundation for further studying the application and development of 5G in health care.

Trends in characteristics and outcomes among US adults hospitalised with COVID-19 throughout 2020: an observational cohort study.

OBJECTIVES: To examine the temporal patterns of patient characteristics, treatments used and outcomes associated with COVID-19 in patients who were hospitalised for the disease between January and 15 November 2020. DESIGN: Observational cohort study. SETTING: COVID-19 subset of the Optum deidentified electronic health records, including more than 1.8 million patients from across the USA. PARTICIPANTS: There were 51 510 hospitalised patients who met the COVID-19 definition, with 37 617 in the laboratory positive cohort and 13 893 in the clinical cohort. PRIMARY AND SECONDARY OUTCOME MEASURES: Incident acute clinical outcomes, including in-hospital all-cause mortality. RESULTS: Respectively, 48% and 49% of the laboratory positive and clinical cohorts were women. The 50- 65 age group was the median age group for both cohorts. The use of antivirals and dexamethasone increased over time, fivefold and twofold, respectively, while the use of hydroxychloroquine declined by 98%. Among adult patients in the laboratory positive cohort, absolute age/sex standardised incidence proportion for in-hospital death changed by -0.036 per month (95% CI -0.042 to -0.031) from March to June 2020, but remained fairly flat from June to November, 2020 (0.001 (95% CI -0.001 to 0.003), 17.5% (660 deaths /3986 persons) in March and 10.2% (580/5137) in October); in the clinical cohort, the corresponding changes were -0.024 (95% CI -0.032 to -0.015) and 0.011 (95% CI 0.007 0.014), respectively (14.8% (175/1252) in March, 15.3% (189/1203) in October). Declines in the cumulative incidence of most acute clinical outcomes were observed in the laboratory positive cohort, but not for the clinical cohort. CONCLUSION: The incidence of adverse clinical outcomes remains high among COVID-19 patients with clinical diagnosis only. Patients with COVID-19 entering the hospital are at elevated risk of adverse outcomes.

User Behaviors and User-Generated Content in Chinese Online Health Communities: Comparative Study.

BACKGROUND: Online health communities (OHCs) have increasingly gained traction with patients, caregivers, and supporters globally. Chinese OHCs are no exception. However, user-generated content (UGC) and the associated user behaviors in Chinese OHCs are largely underexplored and rarely analyzed systematically, forfeiting valuable opportunities for optimizing treatment design and care delivery with insights gained from OHCs. OBJECTIVE: This study aimed to reveal both the shared and distinct characteristics of 2 popular OHCs in China by systematically and comprehensively analyzing their UGC and the associated user behaviors. METHODS: We concentrated on studying the lung cancer forum (LCF) and breast cancer forum (BCF) on Mijian, and the diabetes consultation forum (DCF) on Sweet Home, because of the importance of the 3 diseases among Chinese patients and their prevalence on Chinese OHCs in general. Our analysis explored the key user activities, small-world effect, and scale-free characteristics of each social network. We examined the UGC of these forums comprehensively and adopted the weighted knowledge network technique to discover salient topics and latent relations among these topics on each forum. Finally, we discussed the public health implications of our analysis findings. RESULTS: Our analysis showed that the number of reads per thread on each forum followed gamma distribution (HL=0, HB=0, and HD=0); the number of replies on each forum followed exponential distribution (adjusted RL2=0.946, adjusted RB2=0.958, and adjusted RD2=0.971); and the number of threads a user is involved with (adjusted RL2=0.978, adjusted RB2=0.964, and adjusted RD2=0.970), the number of followers of a user (adjusted RL2=0.989, adjusted RB2=0.962, and adjusted RD2=0.990), and a user's degrees (adjusted RL2=0.997, adjusted RB2=0.994, and adjusted RD2=0.968) all followed power-law distribution. The study further revealed that users are generally more active during weekdays, as commonly witnessed in all 3 forums. In particular, the LCF and DCF exhibited high temporal similarity (ρ=0.927; P<.001) in terms of the relative thread posting frequencies during each hour of the day. Besides, the study showed that all 3 forums exhibited the small-world effect (mean σL=517.15, mean σB=275.23, and mean σD=525.18) and scale-free characteristics, while the global clustering coefficients were lower than those of counterpart international OHCs. The study also discovered several hot topics commonly shared among the 3 disease forums, such as disease treatment, disease examination, and diagnosis. In particular, the study found that after the outbreak of COVID-19, users on the LCF and BCF were much more likely to bring up COVID-19-related issues while discussing their medical issues. CONCLUSIONS: UGC and related online user behaviors in Chinese OHCs can be leveraged as important sources of information to gain insights regarding individual and population health conditions. Effective and timely mining and utilization of such content can continuously provide valuable firsthand clues for enhancing the situational awareness of health providers and policymakers.

Characteristics and outcomes of hospitalised adults with COVID-19 in a Global Health Research Network: a cohort study.

OBJECTIVE: To examine age, gender, and temporal differences in baseline characteristics and clinical outcomes of adult patients hospitalised with COVID-19. DESIGN: A cohort study using deidentified electronic medical records from a Global Research Network. SETTING/PARTICIPANTS: 67 456 adult patients hospitalised with COVID-19 from the USA; 7306 from Europe, Latin America and Asia-Pacific between February 2020 and January 2021. RESULTS: In the US cohort, compared with patients 18-34 years old, patients ≥65 had a greater risk of intensive care unit (ICU) admission (adjusted HR (aHR) 1.73, 95% CI 1.58 to 1.90), acute respiratory distress syndrome(ARDS)/respiratory failure (aHR 1.86, 95% CI 1.76 to 1.96), invasive mechanical ventilation (IMV, aHR 1.93, 95% CI, 1.73 to 2.15), and all-cause mortality (aHR 5.6, 95% CI 4.36 to 7.18). Men appeared to be at a greater risk for ICU admission (aHR 1.34, 95% CI 1.29 to 1.39), ARDS/respiratory failure (aHR 1.24, 95% CI1.21 to 1.27), IMV (aHR 1.38, 95% CI 1.32 to 1.45), and all-cause mortality (aHR 1.16, 95% CI 1.08 to 1.24) compared with women. Moreover, we observed a greater risk of adverse outcomes during the early pandemic (ie, February-April 2020) compared with later periods. In the ex-US cohort, the age and gender trends were similar; for the temporal trend, the highest proportion of patients with all-cause mortality were also in February-April 2020; however, the highest percentages of patients with IMV and ARDS/respiratory failure were in August-October 2020 followed by February-April 2020. CONCLUSIONS: This study provided valuable information on the temporal trends of characteristics and outcomes of hospitalised adult COVID-19 patients in both USA and ex-USA. It also described the population at a potentially greater risk for worse clinical outcomes by identifying the age and gender differences. Together, the information could inform the prevention and treatment strategies of COVID-19. Furthermore, it can be used to raise public awareness of COVID-19's impact on vulnerable populations.

Resveratrol inactivates PI3K/Akt signaling through upregulating BMP7 in human colon cancer cells.

Colon cancer is common worldwide and accounts for the significant cancer related morbidity and mortality in patients. Although extensive advancement has been made in colon cancer treatment and diagnosis in the last decades, there is still a giant gap between the clinical expectation. It has been reported that resveratrol (Res) may be a potential candidate for cancer treatment. However, the specific mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Res in human colon cancer cells, and unveiled the possible mechanism for this effect. With cell viability, flow cytometry, PCR and western blot analysis, we demonstrated the efficacious anticancer activity of Res in HCT116 cells. Mechanically, we found that Res greatly upregulates BMP7 in HCT116 cells. Exogenous BMP7 enhances the anticancer effect of Res in HCT116 cells, which was almost reversed by the BMP7 specific antibody. Res does not activate the BMPs/Smads signaling, but decreases the phosphorylation of Akt1/2/3 substantially in HCT116 cells. Exogenous BMP7 enhances the inhibitory effect of Res on the phosphorylation of Akt1/2/3, while BMP7 immunodepletion reverses this effect notably. Res markedly decreases the phosphorylation of PTEN, which can be enhanced by exogenous BMP7 but partly reversed by the BMP7 antibody. Our findings suggested that Res may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating BMP7 to decrease, at least, the phosphorylation of PTEN.

TGF-ß1/PTEN/PI3K signaling plays a critical role in the anti-proliferation effect of tetrandrine in human colon cancer cells.

The diagnosis and treatment for colon cancer have been greatly developed, but the prognosis remains unsatisfactory. There is still a great clinical need to explore new efficacious drugs for colon cancer treatment. Tetrandrine (Tet) is a bis-benzylisoquinoline alkaloid. It has been shown that Tet may be a potential candidate for cancer treatment, but the explicit mechanism underlying this activity remains unclear. In this study, we investigated the anticancer activity of Tet in human colon cancer cells and dissected the possible mechanism. With cell viability assay and flow cytometry analysis, we confirmed that Tet can effectively inhibit the proliferation and induce apoptosis in HCT116 cells. Mechanically, we found that Tet greatly increases the mRNA and protein level of TGF-ß1 in HCT116 cells. Exogenous TGF-ß1 enhances the anti-proliferation and apoptosis inducing effect of Tet in HCT116 cells, which has been partly reversed by TGF-ß1 inhibitor. Tet decreases the phosphorylation of Akt1/2/3 in HCT116 cells. This effect can be enhanced by exogenous TGF-ß1, but partly reversed by TGF-ß1 inhibitor. Tet exhibits no effect on total level of PTEN, but decreases the phosphorylation of PTEN; exogenous TGF-ß1 enhances the effect of Tet on decreasing the phosphorylation of PTEN, which was partly reversed by TGF-ß1 inhibitor. Our findings suggested that Tet may be a promising candidate for colon cancer treatment, and the anticancer activity may be mediated by inactivating PI3K/Akt signaling through upregulating TGF-ß1 to decrease the phosphorylation of PTEN.

All-trans retinoic acid shifts rosiglitazone-induced adipogenic differentiation to osteogenic differentiation in mouse embryonic fibroblasts.

Rosiglitazone (RSG) is a potent drug used in the treatment of insulin resistance; however, it is associated with marked skeletal toxicity. RSG-induced osteoporosis may contribute to the promotion of adipogenic differentiation at the expense of osteogenic differentiation in bone marrow stromal cells. The aim of this study was to investigate whether RSG-induced bone toxicity can be reversed by combined treatment with all-trans retinoic acid (ATRA). We examined different osteogenic markers in mouse embryonic fibroblasts (MEFs) following treatment with RSG, ATRA, or RSG and ATRA in combination. We examined the effects of RSG and/or ATRA on ectopic bone formation, and dissected the possible molecular mechanisms underlying this process. We found that ATRA or RSG both induced alkaline phosphatase (ALP) activity in the MEFs, and that the ATRA-induced ALP activity was enhanced by RSG and vice versa. However, only the combination of RSG and ATRA increased the expression of osteopontin and osteocalcin, promoted matrix mineralization, and induced ectopic ossification in MEFs. Mechanistically, we found that the osteogenic differentiation induced by the combination of RSG and ATRA may be mediated partly by suppressing RSG-induced adipogenic differentiation and activating bone morphogenetic protein (BMP)/Smad signaling. On the whole, our findings demonstrate that RSG in combination with ATRA promotes the commitment of MEFs to the osteoblast lineage. Thus, the combination of these two agents may prove to be a promising and novel therapeutic regimen for insulin resistance without skeletal toxicity. It may also be a better strategy with which to prevent RSG-induced osteoporosis.

Ursolic acid inhibits proliferation and induces apoptosis by inactivating Wnt/ß-catenin signaling in human osteosarcoma cells.

Although multiple chemotherapeutic agents have been used for osteosarcoma (OS) treatment, their mechanisms need further study. Ursolic acid (UA), a pentacyclic triterpenoid, can reduce cell proliferation and induce apoptosis in various cancer cells, such as OS. However, the exact mechanism underlying this function remains unclear. In this study, we investigated the anti­proliferative effect of UA in human OS 143B cells and dissected the possible molecular mechanism underlying this effect. We demonstrated that UA can reduce cell proliferation, induce apoptosis and arrest cell cycle in 143B cells, as well as inhibit OS tumor growth in a mouse xenograft model. Using a luciferase reporter assay, we found that the Wnt/ß­catenin signaling is inhibited by UA in 143B cells. Correspondingly, the expression level and nuclear translocation of ß­catenin are both decreased by UA. Exogenous expression of ß­catenin attenuates the anticancer effect of UA in 143B cells, while knockdown of ß­catenin enhances this effect. UA increases the expression level of p53 in a concentration­dependent manner, and inhibition of p53 reduces the anticancer effect of UA in 143B cells. Moreover, inhibition of p53 partly reverses the UA­induced downregulation of ß­catenin, as do the targets of Wnt/ß­catenin signaling, such as c­Myc and cyclin D1. Our findings indicated that UA can inhibit the proliferation of 143B OS cells through inactivation of Wnt/ß-catenin signaling, which may be mediated partly by upregulating the expression of p53.

In vitro culture and characterization of a mammary epithelial cell line from Chinese Holstein dairy cow.

BACKGROUND: The objective of this study was to establish a culture system and elucidate the unique characteristics of a bovine mammary epithelial cell line in vitro. METHODOLOGY: Mammary tissue from a three year old lactating dairy cow (ca. 100 d relative to parturition) was used as a source of the epithelial cell line, which was cultured in collagen-coated tissue culture dishes. Fibroblasts and epithelial cells successively grew and extended from the culturing mammary tissue at the third day. Pure epithelial cells were obtained by passages culture. PRINCIPAL FINDINGS: The strong positive immunostaining to cytokeratin 18 suggested that the resulting cell line exhibited the specific character of epithelial cells. Epithelial cells cultured in the presence of 10% FBS, supraphysiologic concentrations of insulin, and hydrocortisone maintained a normal diploid chromosome modal number of 2n=60. Furthermore, they were capable of synthesizing beta-casein (CSN2), acetyl-CoA carboxylase-alpha (ACACA) and butyrophilin (BTN1A1). An important finding was that frozen preservation in a mixture of 90% FBS and 10% DMSO did not influence the growth characteristics, chromosome number, or protein secretion of the isolated epithelial cell line. CONCLUSIONS: The obtained mammary epithelial cell line had normal morphology, growth characteristics, cytogenetic and secretory characteristics, thus, it might represent an useful tool for studying the function of Chinese Holstein dairy cows mammary epithelial cell (CMECs).