Genomic adaptations for arboreal locomotion in Asian flying treefrogs.

SignificanceTo adapt to arboreal lifestyles, treefrogs have evolved a suite of complex traits that support vertical movement and gliding, thus presenting a unique case for studying the genetic basis for traits causally linked to vertical niche expansion. Here, based on two de novo-assembled Asian treefrog genomes, we determined that genes involved in limb development and keratin cytoskeleton likely played a role in the evolution of their climbing systems. Behavioral and morphological evaluation and time-ordered gene coexpression network analysis revealed the developmental patterns and regulatory pathways of the webbed feet used for gliding in Rhacophorus kio.

Fibroblast growth factor receptor 4 deficiency in macrophages aggravates experimental colitis by promoting M1-polarization.

OBJECTIVE AND DESIGN: Compelling evidence indicates that dysregulated macrophages may play a key role in driving inflammation in inflammatory bowel disease (IBD). Fibroblast growth factor (FGF)-19, which is secreted by ileal enterocytes in response to bile acids, has been found to be significantly lower in IBD patients compared to healthy individuals, and is negatively correlated with the severity of diarrhea. This study aims to explore the potential impact of FGF19 signaling on macrophage polarization and its involvement in the pathogenesis of IBD. METHODS: The dextran sulfate sodium (DSS)-induced mouse colitis model was utilized to replicate the pathology of human IBD. Mice were created with a conditional knockout of FGFR4 (a specific receptor of FGF19) in myeloid cells, as well as mice that overexpressing FGF19 specifically in the liver. The severity of colitis was measured using the disease activity index (DAI) and histopathological staining. Various techniques such as Western Blotting, quantitative PCR, flow cytometry, and ELISA were employed to assess polarization and the expression of inflammatory genes. RESULTS: Myeloid-specific FGFR4 deficiency exacerbated colitis in the DSS mouse model. Deletion or inhibition of FGFR4 in bone marrow-derived macrophages (BMDMs) skewed macrophages towards M1 polarization. Analysis of transcriptome sequencing data revealed that FGFR4 deletion in macrophages significantly increased the activity of the complement pathway, leading to an enhanced inflammatory response triggered by LPS. Mechanistically, FGFR4-knockout in macrophages promoted complement activation and inflammatory response by upregulating the nuclear factor-κB (NF-κB)-pentraxin3 (PTX3) pathway. Additionally, FGF19 suppressed these pathways and reduced inflammatory response by activating FGFR4 in inflammatory macrophages. Liver-specific overexpression of FGF19 also mitigated inflammatory responses induced by DSS in vivo. CONCLUSION: Our study highlights the significance of FGF19-FGFR4 signaling in macrophage polarization and the pathogenesis of IBD, offering a potential new therapeutic target for IBD.

Retention time prediction and MRM validation reinforce the biomarker identification of LC-MS based phospholipidomics.

Dysfunctional lipid metabolism plays a crucial role in the development and progression of various diseases. Accurate measurement of lipidomes can help uncover the complex interactions between genes, proteins, and lipids in health and diseases. The prediction of retention time (RT) has become increasingly important in both targeted and untargeted metabolomics. However, the potential impact of RT prediction on targeted LC-MS based lipidomics is still not fully understood. Herein, we propose a simplified workflow for predicting RT in phospholipidomics. Our approach involves utilizing the fatty acyl chain length or carbon-carbon double bond (DB) number in combination with multiple reaction monitoring (MRM) validation. We found that our model's predictive capacity for RT was comparable to that of a publicly accessible program (QSRR Automator). Additionally, MRM validation helped in further mitigating the interference in signal recognition. Using this developed workflow, we conducted phospholipidomics of sorafenib resistant hepatocellular carcinoma (HCC) cell lines, namely MHCC97H and Hep3B. Our findings revealed an abundance of monounsaturated fatty acyl (MUFA) or polyunsaturated fatty acyl (PUFA) phospholipids in these cell lines after developing drug resistance. In both cell lines, a total of 29 lipids were found to be co-upregulated and 5 lipids were co-downregulated. Further validation was conducted on seven of the upregulated lipids using an independent dataset, which demonstrates the potential for translation of the established workflow or the lipid biomarkers.

Increased OIT3 in macrophages promotes PD-L1 expression and hepatocellular carcinogenesis via NF-κB signaling.

Oncoprotein-induced transcript 3 (OIT3) facilitates macrophage M2 polarization and hepatocellular carcinoma (HCC) progression, however, whether OIT3 regulates tumor immunity remains largely unknown. Here we found that OIT3 was upregulated in HCC-associated macrophages, which inhibited CD4+ and CD8+ T-cell infiltration in the tumor microenvironment (TME). Mechanistically, OIT3 increased the expression of PD-L1 on tumor-associated macrophages (TAMs) by activating NF-κB signaling, blockade of NF-κB reversed the immunosuppressive activity of TAMs and dampens HCC tumorigenesis. Our findings provide the molecular basis for OIT3 enhancing tumor immunosuppression and highlighted a potential therapeutic strategy for targeting the TAMs of HCC.

Equivalent carbon number-based targeted odd-chain fatty acyl lipidomics reveals triacylglycerol profiling in clinical colon cancer.

Odd-chain FAs (OCFAs) are present in very low level at nearly 1% of total FAs in human plasma, and thus, their functions were usually ignored. Recent epidemiological studies have shown that OCFAs are inversely associated with a variety of disease risks. However, the contribution of OCFAs incorporated into complex lipids remains elusive. Here, we developed a targeted odd-chain fatty acyl-containing lipidomics method based on equivalent carbon number and retention time prediction. The method displayed good reproducibility and robustness as shown by peak width at half height within 0.7 min and coefficient of variation under 20%. A total number of 776 lipid species with odd-chain fatty acyl residues could be detected in the ESI mode of reverse-phase LC-MS, of which 309 lipids were further validated using multiple reaction monitoring transitions. Using this method, we quantified odd-chain fatty acyl-containing lipidome in tissues from 12 colon cancer patients, revealing the remodeling of triacylglycerol. The dynamics of odd-chain fatty acyl lipids were further consolidated by the association with genomic and proteomic features of altered catabolism of branched-chain amino acids and triacylglycerol endogenous synthesis in colon cancer. This lipidomics approach will be applicable for screening of dysregulated odd-chain fatty acyl lipids, which enriches and improves the methods for diagnosis and prognosis evaluation of cancer using lipidomics.

Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation.

BACKGROUND: Chronic kidney disease (CKD) involves a variety of pathological processes, and ferroptosis plays a vital role in CKD progression. Targeting ferroptosis is a promising strategy for the treatment of CKD. However, inhibitors of ferroptosis have not been used in the clinical treatment of CKD. Vitexin is a natural flavonoid with many biological activities and protective effects against various diseases. However, whether vitexin can prevent the progression of CKD is not known. METHODS: In vivo, the effect of vitexin on CKD was evaluated by using mouse models of unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion (UIR). Western blotting, Sirius red staining and transmission electron microscopy were used to analyze renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. In vitro, CCK8 assays and lipid peroxidation assays were performed to analyze cell viability and lipid peroxidation in human renal tubular epithelial cells (HK2 cells) induced by erastin. The activation of renal fibroblasts (NRK-49 F cells) was also analyzed. Additionally, an in-silico protein-drug docking model and coimmunoprecipitation were performed to determine the direct substrate of vitexin. RESULTS: In vivo, vitexin treatment significantly ameliorated renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. Additionally, our results showed that vitexin significantly attenuated UUO- and UIR-induced ferroptosis in renal tubular epithelial cells by upregulating glutathione peroxidase 4 (GPX4) protein levels and inhibiting lipid peroxidation in mouse kidneys. In vitro, treatment with vitexin inhibited erastin-induced ferroptosis in HK2 cells. Moreover, vitexin inhibited the expression of collagen I and α-SMA (alpha-smooth muscle actin) in NRK-49 F cells induced by the supernatant of erastin-treated HK2 cells. Mechanistically, our results suggested that vitexin could activate the NRF2/heme oxygenase-1 (HO-1) pathway by inhibiting the KEAP1- and ubiquitination-mediated degradation of NRF2, thereby increasing the expression of GPX4, and further inhibiting lipid peroxidation and ferroptosis. Additionally, knockout of NRF2 greatly inhibited the antiferroptotic effects of vitexin. CONCLUSIONS: Taken together, our results indicate that vitexin can protect against renal tubular epithelial cell ferroptosis in CKD by activating the KEAP1/NRF2/HO-1 pathway and is a promising drug to treat CKD.

Risk factors and prevalence of cognitive impairment in maintenance haemodialysis patients: A systematic review and meta-analysis of observational studies.

AIMS: To systematically identify the risk factors for cognitive impairment in maintenance haemodialysis patients and to assess its prevalence in included studies. DESIGN: Systematic review and meta-analysis about observational studies. DATA SOURCES: Systematic search of seven databases, including PubMed, Web of Science, Scope, Wanfang Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and Weipu Chinese Science and Technology Journal Database, from inception until October 2021. REVIEW METHODS: Observational studies reporting the risk factors for cognitive impairment in maintenance haemodialysis patients in English and Chinese language were included. Meta-analysis was performed to identify risk factors and prevalence of cognitive impairment in maintenance haemodialysis patients with STATA 15.0 software. RESULTS: Overall, 37 eligible studies encompassing 129,849 cases were included. The risk factors with statistical significance after meta-analysis were older age, female sex, fewer years of education, hypertension, diabetes, cerebrovascular accident, multiple comorbid conditions, systolic blood pressure variability, arterial stiffness and low haemoglobin and albumin level. The overall prevalence of cognitive impairment in maintenance haemodialysis patients was 49.1%. CONCLUSION: The current analysis indicated a high prevalence of cognitive impairment in maintenance haemodialysis patients. Eleven risk factors for cognitive impairment in maintenance haemodialysis patients were identified, among which more attention should be paid to modifiable factors such as cardiovascular disease risk factors and specific kidney and dialysis-related factors. IMPACT: This paper provides an updated estimate of the pooled prevalence of cognitive impairment in maintenance haemodialysis patients. Identification of risk factors associated with cognitive impairment may assist in developing targeted prevention strategies for maintenance haemodialysis patients at high risk. NO PATIENT OR PUBLIC CONTRIBUTION: This study was a systematic review completed by the authors in accordance with relevant guidelines and processes and did not include the participation of patients, service users, caregivers or the general public.

The intricate role of annexin A2 in kidney: a comprehensive review.

Annexin A2 (Anxa2) is a calcium (Ca2+)-regulated phospholipid binding protein composed of a variable N-terminus and a conserved core domain. This protein has been widely found in many tissues and fluids, including tubule cells, glomerular epithelial cells, renal vessels, and urine. In acute kidney injury, the expression level of this protein is markedly elevated in response to acute stress. Moreover, Anxa2 is a novel biomarker and potential therapeutic target with prognostic value in chronic kidney disease. In addition, Anxa2 is associated not only with clear-cell renal cell carcinoma differentiation but also the formation of calcium-related nephrolithiasis. In this review, we discuss the characteristics and functions of Anxa2 and focus on recent reports on the role of Anxa2 in the kidney, which may be useful for future research.

Exposure to multiple metals and diabetes mellitus risk in dong ethnicity in China: from the China multi-ethnic cohort study.

Metals play an important role in the development of diabetes mellitus (DM). The association of metals with diabetes among the Dong ethnicity in China remains poorly understood. The current study aimed to evaluate the association of single metal exposure and multi-metal co-exposure with DM risk. Urinary concentrations of arsenic, cadmium, chromium, copper, iron, lead, manganese, mercury, molybdenum, nickel, strontium, vanadium, and zinc were measured using inductively coupled plasma-mass spectrometry (ICP-MS) among 4479 Dong ethnic participants aged 30-79 years from the China Multi-Ethnic Cohort (CMEC) study. Based on tertiles, the metal exposure can be divided into three groups: low, middle, and high exposure. Multivariate logistic regression models and principal component analysis were performed to determine exposure to single-metal and multi-metal co-exposure in relation to DM. A decrease in risk of DM was associated with iron (OR = 0.78, 95% CI: 0.61-1.00 and 0.68, 0.53-0.88 for the middle and high vs. low) and strontium (OR = 0.87, 95% CI: 0.69-1.12 and 0.67, 0.51-0.86 for the middle and high vs. low), respectively. A principal component 3 (PC3) characterized by iron and strontium showed an inverse association with DM. A principal component 4 (PC4) characterized by manganese and lead positively associated with DM. Exposure to high concentrations of urinary iron and strontium may reduce the risk of diabetes mellitus. This study revealed an increase in the risk of diabetes mellitus by co-exposure to high concentrations of urinary manganese and lead.

Identification of DELLA gene family in head cabbage and analysis of mRNA transport in the heterograft.

DELLA gene family is involved in the regulation of signal transduction of plant hormones. mRNAs of GA insensitive (GAI), the member of DELLA gene family, are also signaling molecules of long-distance transport in plants. Genome-wide identification and mRNA transport analysis of the members of DELLA gene family in head cabbage (Brassica oleracea var. capitata) can provide basic data for their application in head cabbage. In this study, five members of DELLA gene family (BoRGA1, BoRGA2, BoRGL1, BoRGL2, and BoRGL3) were identified in head cabbage using genome and transcriptome data. However, head cabbage lacked a GAI gene in its genome. The scion (head cabbage, inbred line G27) and the rootstock Chinese flowering cabbage (Brassica campestris L. ssp. chinensis var. utilis Tsen et Lee) (sijiucaixin) were cleft-grafted together to produce the heterograft. Inflorescence stem of the rootstock and the corresponding inflorescence stem in Chinese flowering cabbage seedlings (as controls) were purified and analyzed with transcriptome sequencing. The total of 8, 9, 3, 5, and 1 exogenous read(s), derived respectively from BoRGA1, BoRGA2, BoRGL1, BoRGL2, and BoRGL3, were identified in the transcriptomes of the rootstocks. Nevertheless, mRNA transport of DELLA family genes from scion to rootstock did not increase the transcriptional level of the members of DELLA gene family in the rootstocks. Correlation analysis suggested that mRNA transport efficiency of the DELLA family genes was correlated with the sequence and the transcriptional level of the respective DELLA gene in the scion (head cabbage). This study lays the foundation for further investigation on the molecular mechanism of mRNA transport of the members of DELLA gene family in head cabbage.

[Research Progress of High-intensity Interval Training in Cardiac Rehabilitation of Patients with Acute Coronary Syndrome].

Acute coronary syndrome (ACS),with increasing mortality year by year,has become a major public health problem in China.Exercise rehabilitation as an important part of the out-of-hospital rehabilitation for the patients with heart diseases can further reduce the mortality of patients on the basis of drug treatment.The available studies have proved that high-intensity interval training (HIIT) is more effective and efficient than moderate-intensity continuous training (MICT) such as walking and jogging on chronic cardiovascular diseases such as heart failure,stable coronary heart disease,and hypertension and has high security.According to the latest research,HIIT can reduce the platelet response,mitigate myocardial ischemia-reperfusion injury,and increase the exercise compliance of ACS patients more significantly than MICT.Moreover,it does not increase the risk of thrombotic adverse events or malignant arrhythmia.Therefore,HIIT is expected to become an important part of exercise prescription in out-of-hospital cardiac rehabilitation strategy for the patients with ACS.

Effect modification of greenness on PM2.5 associated all-cause mortality in a multidrug-resistant tuberculosis cohort.

RATIONALE: Evidence for the association between fine particulate matter (PM2.5) and mortality among patients with tuberculosis (TB) is limited. Whether greenness protects air pollution-related mortality among patients with multidrug-resistant tuberculosis (MDR-TB) is completely unknown. METHODS: 2305 patients reported in Zhejiang and Ningxia were followed up from MDR-TB diagnosis until death, loss to follow-up or end of the study (31 December 2019), with an average follow-up of 1724 days per patient. 16-day averages of contemporaneous Normalised Difference Vegetation Index (NDVI) in the 500 m buffer of patient's residence, annual average PM2.5 and estimated oxidant capacity Ox were assigned to patients regarding their geocoded home addresses. Cox proportional hazards regression models were used to estimate HRs per 10 µg/m3 exposure to PM2.5 and all-cause mortality among the cohort and individuals across the three tertiles, adjusting for potential covariates. RESULTS: HRs of 1.702 (95% CI 1.680 to 1.725) and 1.169 (1.162 to 1.175) were observed for PM2.5 associated with mortality for the full cohort and individuals with the greatest tertile of NDVI. Exposures to PM2.5 were stronger in association with mortality for younger patients (HR 2.434 (2.432 to 2.435)), female (2.209 (1.874 to 2.845)), patients in rural (1.780 (1.731 to 1.829)) and from Ningxia (1.221 (1.078 to 1.385)). Cumulative exposures increased the HRs of PM2.5-related mortality, while greater greenness flattened the risk with HRs reduced in 0.188-0.194 on average. CONCLUSIONS: Individuals with MDR-TB could benefit from greenness by having attenuated associations between PM2.5 and mortality. Improving greener space and air quality may contribute to lower the risk of mortality from TB/MDR-TB and other diseases.

OIT3 mediates macrophage polarization and facilitates hepatocellular carcinoma progression.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality; however, effective immunotherapy strategies are limited because of the immunosuppressive tumor microenvironment. Macrophages are essential components of the HCC microenvironment and are related to poor prognosis. Here, we evaluated the attributes of paracancer tissues in tumor immunity and progression using public databases. Based on the abundance of immune cells estimated by CIBERSORT, we performed weighted gene co-expression network analysis and found a specific module associated with M2 macrophages. Through analyzing interaction networks using Cytoscape and public datasets, we identified oncoprotein-induced transcript 3 (OIT3) as a novel marker of M2 macrophages. Overexpression of OIT3 remodeled immune features and reprogrammed the metabolism of M2 macrophages. Moreover, compared with wildtype macrophages, OIT3-overexpressing macrophages further enhanced the migration and invasion of co-cultured cancer cells. Additionally, OIT3-overexpressing macrophages promoted tumorigenesis and cancer development in vivo. Taken together, the findings demonstrate that OIT3 is a novel biomarker of alternatively activated macrophages and facilitates HCC metastasis.

Intestinal microbiota dysbiosis in acute kidney injury: novel insights into mechanisms and promising therapeutic strategies.

In recent years, the clinical impact of intestinal microbiota-kidney interaction has been emerging. Experimental evidence highlighted a bidirectional evolutionary correlation between intestinal microbiota and kidney diseases. Nonetheless, acute kidney injury (AKI) is still a global public health concern associated with high morbidity, mortality, healthcare costs, and limited efficient therapy. Several studies on the intestinal microbiome have improved the knowledge and treatment of AKI. Therefore, the present review outlines the concept of the gut-kidney axis and data about intestinal microbiota dysbiosis in AKI to improve the understanding of the mechanisms of the intestinal microbiome on the modification of kidney function and response to kidney injury. We also introduced the future directions and research areas, emphasizing the intervention approaches and recent research advances of intestinal microbiota dysbiosis during AKI, thereby providing a new perspective for future clinical trials.

Integrated LC-MS metabolomics with dual derivatization for quantification of FFAs in fecal samples of hepatocellular carcinoma patients.

FFAs display pleiotropic functions in human diseases. Short-chain FAs (SCFAs), medium-chain FAs, and long-chain FAs are derived from different origins, and precise quantification of these FFAs is critical for revealing their roles in biological processes. However, accessing stable isotope-labeled internal standards is difficult, and different chain lengths of FFAs challenge the chromatographic coverage. Here, we developed a metabolomics strategy to analyze FFAs based on isotope-free LC-MS-multiple reaction monitoring integrated with dual derivatization. Samples and dual derivatization internal standards were synthesized using 2-dimethylaminoethylamine or dansyl hydrazine as a "light" label and N,N-diethyl ethylene diamine or N,N-diethyldansulfonyl hydrazide as a "heavy" label under mild and efficient reaction conditions. General multiple reaction monitoring parameters were designed to analyze these FFAs. The limit of detection of SCFAs varied from 0.5 to 3 nM. Furthermore, we show that this approach exhibits good linearity (R2 = 0.99374-0.99929), there is no serious substrate interference, and no quench steps are required, confirming the feasibility and reliability of the method. Using this method, we successfully quantified 15 types of SCFAs in fecal samples from hepatocellular carcinoma patients and healthy individuals; among these, propionate, butyrate, isobutyrate, and 2-methylbutyrate were significantly decreased in the hepatocellular carcinoma group compared with the healthy control group. These results indicate that the integrated LC-MS metabolomics with isotope-free and dual derivatization is an efficient approach for quantifying FFAs, which may be useful for identifying lipid biomarkers of cancer.

Spatial Ecology of Asian Water Monitors Adjacent to a Sea Turtle Nesting Beach.

Nest predation is the main cause of hatching failure for many turtle populations. For green turtles (Chelonia mydas) nesting at Chagar Hutang in Redang Island, Malaysia, Asian water monitors (Varanus salvator) are a potential nest predator. However, no studies have documented the space use of this species in coastal habitat adjacent to a sea turtle nesting beach to assess its potential impact on turtle nests. Here, we used Global Positioning System (GPS) data loggers to quantify space use of Asian water monitors in order to establish the extent to which they use sea turtle nesting areas. Asian water monitors had a diurnal activity pattern and spent most of their time in rain forest habitat behind the sea turtle nesting beach. The home range occupied by Asian water monitors varied between 0.015 and 0.198 km2 calculated by the Kernel Brownian Bridge method. The space use patterns of individual Asian water monitors varied between individuals. Two males had relatively small home ranges, whereas one male and the female had a relatively large home range. Because tracked Asian water monitors in this study rarely visited the sea turtle nesting areas, it is probable that only a few individuals are responsible for opening nests.

Low-Frequency Oscillations Code Speech during Verbal Working Memory.

The way the human brain represents speech in memory is still unknown. An obvious characteristic of speech is its evolvement over time. During speech processing, neural oscillations are modulated by the temporal properties of the acoustic speech signal, but also acquired knowledge on the temporal structure of language influences speech perception-related brain activity. This suggests that speech could be represented in the temporal domain, a form of representation that the brain also uses to encode autobiographic memories. Empirical evidence for such a memory code is lacking. We investigated the nature of speech memory representations using direct cortical recordings in the left perisylvian cortex during delayed sentence reproduction in female and male patients undergoing awake tumor surgery. Our results reveal that the brain endogenously represents speech in the temporal domain. Temporal pattern similarity analyses revealed that the phase of frontotemporal low-frequency oscillations, primarily in the beta range, represents sentence identity in working memory. The positive relationship between beta power during working memory and task performance suggests that working memory representations benefit from increased phase separation.SIGNIFICANCE STATEMENT Memory is an endogenous source of information based on experience. While neural oscillations encode autobiographic memories in the temporal domain, little is known on their contribution to memory representations of human speech. Our electrocortical recordings in participants who maintain sentences in memory identify the phase of left frontotemporal beta oscillations as the most prominent information carrier of sentence identity. These observations provide evidence for a theoretical model on speech memory representations and explain why interfering with beta oscillations in the left inferior frontal cortex diminishes verbal working memory capacity. The lack of sentence identity coding at the syllabic rate suggests that sentences are represented in memory in a more abstract form compared with speech coding during speech perception and production.

Mitochondrial dysfunction and the AKI-to-CKD transition.

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some mechanisms of the AKI-to-CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction, and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress cross talk contribute to the AKI-to-CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.

The SP1-12LOX axis promotes chemoresistance and metastasis of ovarian cancer.

BACKGROUND: Ovarian cancer is the most lethal gynecologic cancer. Chemoresistance, especially platinum-resistance, is closely related to metastasis of ovarian cancer, however, the molecular basis by which links chemoresistance and metastasis remains vague. Disordered arachidonic acid (AA) metabolism has been shown to play an important role in the advanced ovarian cancer. This study aimed to explore the underlying mechanism involving eicosanoid metabolism that controlling chemoresistance and metastasis of ovarian cancer. METHODS: Cisplatin (DDP)-resistant SKOV3 (SKOV3-R) cells were constantly induced. Ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was performed to determine the AA metabolism in SKOV3 and SKOV3-R cells. Half maximal inhibitory concentration (IC50) and percentage of cell viability were tested using cell counting kit 8 (CCK-8). Realtime quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to evaluate indicated genes and proteins respectively. Bioinformatic analysis and chromatin immunoprecipitation (ChIP) were performed to predict and identify the co-transcription factor of interest genes. Tumor growth and metastasis in the liver were assessed with nude mice by subcutaneously injection of SKOV3-R cells. RESULTS: SKOV3-R cells expressed higher multidrug resistance-associated proteins (MRPs) MRP1 and MRP4. They showed enhanced metastatic ability and produced increased AA-derived eicosanoids. Mechanistically, MRPs, epithelial mesenchymal transition (EMT) markers Snail and Slug, as well as key enzymes involved in AA-metabolism including 12-lipoxygenase (12LOX) were transcribed by the mutual transcription factor SP1 which was consistently upregulated in SKOV3-R cells. Inhibition of SP1 or 12LOX sensitized SKOV3-R cells to DDP and impaired metastasis in vitro and in vivo. CONCLUSION: Our results reveal that SP1-12LOX axis signaling plays a key role in DDP-resistance and metastasis, which provide a new therapeutic target for ovarian cancer.

BMP1 inhibitor UK383,367 attenuates renal fibrosis and inflammation in CKD.

Renal fibrosis is a key pathological phenomenon of chronic kidney disease (CKD) contributing to the progressive loss of renal function. UK383,367 is a procollagen C proteinase inhibitor that has been selected as a candidate for dermal antiscarring agents, whereas its role in renal fibrosis is unclear. In the present study, UK383,367 was applied to a CKD mouse model of unilateral ureteral obstruction (UUO) and cell lines of renal tubular epithelial cells (mouse proximal tubular cells) and renal fibroblast cells (NRK-49F cells) challenged by transforming growth factor-ß1. In vivo, bone morphogenetic protein 1, the target of UK383,367, was significantly enhanced in UUO mouse kidneys and renal biopsies from patients with CKD. Strikingly, UK383,367 administration ameliorated tubulointerstitial fibrosis as shown by Masson's trichrome staining in line with the blocked expression of collagen type I/III, fibronectin, and α-smooth muscle actin in the kidneys from UUO mice. Similarly, the enhanced inflammatory factors in obstructed kidneys were also blunted. In vitro, UK383,367 pretreatment inhibited the induction of collagen type I/III, fibronectin, and α-smooth muscle actin in both mouse proximal tubular cells and NRK-49F cells treated with transforming growth factor-ß1. Taken together, these findings indicate that the bone morphogenetic protein 1 inhibitor UK383,367 could serve as a potential drug in antagonizing CKD renal fibrosis by acting on the maturation and deposition of collagen and the subsequent profibrotic response and inflammation.