Establishment and study of a rat internal haemorrhoid model.

To establish a relatively stable internal haemorrhoid model in rats. A total of 48 SPF SD rats were selected and randomly divided into a blank group of 16 and a model group of 32. The model was created by croton oil-mixed liquid stimulation combined with standing and swimming experiments, and the modelling times were 1 week and 2 weeks, respectively. By observing the symptoms and signs of rats, pathological morphology and immunohistochemical staining of anorectal tissue, anorectal laser speckle blood-flow imaging and defecation contrast, etc., the effect of different modelling times was evaluated. The stability of the model was evaluated after feeding for 2 weeks. Both model-formation times caused rats to produce local symptoms of tissue bulging in the haemorrhoid area. Microscopy showed that the rectal submucosal interstitial blood vessels were dilated, and inflammatory cell infiltration and other manifestations were observed. Laser speckle blood-flow imaging revealed increased anorectal blood perfusion and capillary dilatation, and defecography showed a longitudinal and continuous rectal mucosa. After 2 weeks of normal feeding, lifting of the haemorrhoidal tissue was still present. The effect of modelling for 1 week was most in line with the clinical manifestations of internal haemorrhoids. The 1-week modelling scheme in this study can effectively establish a rat internal haemorrhoid model that closely approximates clinical internal haemorrhoid symptoms and pathological manifestations. The operation is simple, the success rate is high, and the model has certain stability. This model can be used as an important basis for studying various treatment methods for internal haemorrhoids.

Forecasting education expenditure with a generalized conformable fractional-order nonlinear grey system model.

As an important human capital investment, education is an effective means to improve the comprehensive quality of people. Education expenditure is an important material guarantee for the development of educational undertakings. Education expenditure data is highly susceptible to numerous economic and social factors that complicate its nonlinear structure. In order to model the complex nonlinear problems of the system, this paper proposes a generalized conformable fractional-order nonlinear grey prediction model for the first time by analyzing the traditional time series-based modeling method in a nonlinear grey domain. The proposed model expands on the classical grey Bernoulli model by introducing the generalized conformable fractional accumulation as a new accumulation generator and utilizes error minimization principles in the modeling process. By altering the optimal order of the model and the cumulative generation operator, this model can adapt to various time series and reduce errors. Finally, the model is applied to education expenditure forecasting, and it is proved that the proposed model achieved good results and has higher accuracy than other models.

Venous malformations of the lower limb with severe localized intravascular coagulopathy treated with radiofrequency ablation and resection.

Diffuse venous malformations (VMs) are relatively rare, especially the lesions locting special anatomical sites, and they are prone to casuse localized intravascular coagulopathy (LIC). Diffuse VMs can also cause bleeding and life-threatening disseminated intravascular coagulopathy (DIC) from trauma, surgery, and improper treatments. Thus, the treatment of diffuse VMs with LIC is quite tough. We report of a diffuse VMs with severe LIC that was treated with the combined use of minimally invasive treatment and open surgery.

Rhubarb Peony Decoction Downregulates the Expression of c-Fos after Intestinal Epithelial Cells Hypoxia-reoxygenation Injury.

BACKGROUND: Intestinal ischemia-reperfusion (I/R) injury occurs in several clinical situations and after intestinal transplantation. This study aimed to examine the role of rhubarb peony decoction (RPD) in intestinal I/R injury. METHODS: Different concentrations of RPD were set to treat IEC-6 and Caco-2 cells. Cell proliferation and apoptosis were measured by CCK-8 and flow cytometry assays. High-throughput transcriptome sequencing was performed on IEC-6 cells treated with hypoxia-reoxygenation (HR) or HR and RPD. RESULTS: RPD treatment significantly promoted the proliferation of IEC-6 and Caco-2 cells and inhibited apoptosis. Sequencing results identified 109 significantly up-regulated genes and 36 significantly down-regulated genes in the RPD group. In addition, the results of western blot suggested that HR induced the expression of c-Fos, and the treatment of RPD prevented the HR-induced c- Fos expression. Importantly, knockdown of c-Fos rescued the HR-inhibited cell proliferation and HR-induced apoptosis. CONCLUSIONS: In conclusion, RPD was beneficial in protecting the survival of intestinal epithelial cells under HR stress. Furthermore, the increase in c-Fos expression after HR stress was closely related to the proliferation and apoptosis of intestinal epithelial cells.

RNA-Seq approach to investigate the effects of melatonin on bone marrow-derived dendritic cells from dextran sodium sulfate-induced colitis mice.

Melatonin (MLT) was reported to have therapeutic effects on inflammatory bowel disease (IBD) such as ulcerative colitis (UC) and Crohn's disease (CD) due to its anti-inflammatory and immunomodulatory properties. However, whether the beneficial effects of melatonin on colitis are through altering the immune response of bone marrow-derived dendritic cells (BMDCs) has not been well characterized. Here, we propose that MLT alleviates dextran sulfate sodium (DSS)-induced colitis in mice through its regulation of the immune response of BMDCs, in which some lncRNA, circRNA, miRNA, and mRNA may be involved. We at first established a DSS-induced colitis mouse model and found that the concentration of MLT in the serum of DSS-induced colitis mice was significantly lower than that in the control mice. Supplementation with MLT alleviated DSS-induced colitis in mice, which was reflected by preventing mouse body weight loss, colon length shortening, inflammation, and epithelial tissue destruction and abscission in the colon. We then isolated and cultured BMDCs and found that MLT could inhibit the activation of BMDCs from the colitis mice, which was reflected by reducing the phagocytotic ability of the cells, inhibiting their migration, and decreasing their secretion of pro-inflammatory cytokines. RNA sequencing results showed that MLT promoted the transformation of BMDCs into immune tolerant phenotypes in DSS-induced colitis mice through affecting non-coding RNAs (ncRNAs). Among them, lncRNA ENSMUST00000226323, circRNA-0520, and circRNA-2243 were predicted to interact with miRNA-709, and mRNAs of Ywhaz and Ccl9 were the targets of miRNA-709, all of which were involved in MLT-induced alteration of BMDCs functions in DSS-induced colitis mice via PI3K-Akt pathway. Our findings may provide some clues for understanding MLT inhibiting inflammatory response in DSS-induced colitis, which may be through alteration of BMDCs function.

Application of CTU-Assisted Doppler Ultrasound Puncture in Nontube Percutaneous Nephrolithotomy, Its Effect on Patients' Complications, and Its Clinical Value.

Objective: To research the application of CTU-assisted Doppler ultrasound puncture in uncatheterized PCNL, its influence on patients' complications, and its clinical value in a case-control study. Methods: One hundred and forty-four patients who went through percutaneous nephrolithotomy (PCNL) from March 2019 to June 2021 in our hospital were arbitrarily assigned into the CTU group (n = 72) and CT plain scan group (n = 72). CTA+CTU was adopted to determine the puncture passage in the CTU group, and CT scan was employed in the CT group. The intraoperative blood loss, postoperative blood loss, operation time, hospital stay, primary stone removal rate, and the incidence of intraoperative and postoperative complications were compared. The visual analogue score (VAS) was employed to assess the degree of postoperative wound pain. Results: The first-stage stone removal rate in the CTU group was 95.83% (69/72), which was remarkably higher compared to the CT plain scan group, which was 81.94% (59/72), and the difference was statistically significant (P < 0.05). The overall rates of intraoperative complications were 6.94% (5/72) in the CTU group and 18.06% (13/72) in the CT plain scan group, respectively, which exhibited great differences (P < 0.05). In addition, the overall rates of intraoperative complications were 2.78% (2/72) in the CTU and 13.89% (10/72) in the CT plain scan group, respectively, and the difference was statistically significant (P < 0.05). The operation time and postoperative hospital stays in the CTU group were remarkably shorter compared to the CT group, and the difference was statistically significant (P < 0.05). The intraoperative and postoperative blood loss of CTU group displayed obvious less than that of the CT group, and the difference was statistically significant (P < 0.05). The VAS were compared 24 hours after surgery. After operation, the VAS of 24 hours after operation in the CTU group (0.92 ± 0.12) were remarkably lower compared to the CT group (1.22 ± 0.15), and the difference was statistically significant (P < 0.05). Discussion. PCNL is constantly being optimized by CTU-assisted Doppler ultrasound puncture to improve stone clearance rates, reduce postoperative bleeding, be less painful, provide rapid recovery, and provide safe and feasible results. It is therefore worthwhile to standardize and then widely promote it in clinical practice.

F2RL3 Methylation in the Peripheral Blood as a Potential Marker for the Detection of Coronary Heart Disease: A Case-Control Study.

Background and Aims: Previous work has shown the association between blood-based methylation of coagulation factor II receptor-like 3 gene (F2RL3) and cardiovascular mortality in Caucasians. However, the diagnostic value of F2RL3 methylation for CHD is still unknown. The aim of our study was to evaluate the association between blood-based F2RL3 methylation and the risk of CHD in the Chinese population. Methods: The methylation level of F2RL3 was quantified by mass spectrometry in a case-control study with 180 CHD cases and 184 controls. The association between F2RL3 methylation intensity and CHD was assessed by logistic regression models, controlling confounding factors. Results: The hypomethylation in F2RL3_A amplicon was significantly associated with CHD (odds ratio (ORs) per -10% methylation: 1.22-1.42, p < 0.035 for six out of seven CpG loci). Specifically, this significant association was observed in elderly CHD patients (≥60 years), myocardial infarction (MI) patients, heart failure patients and the patients with minor to medium cardiac function impairment (NYHA Ⅰ&Ⅱ CHD cases) (ORs per -10% methylation: 1.35-1.58, 1.32-2.00, 1.29-1.43, 1.25-1.44; p < 0.024, 0.033, 0.035, 0.025, respectively). However, F2RL3_B CpG sites showed no or very weak association with CHD. The combination of F2RL3_A_CpG_1 and F2RL3_A_CpG_3 methylation levels could efficiently discriminate CHD, MI, heart failure, NYHA I&II CHD, and elderly CHD patients from controls (area under curve (AUC) = 0.75, 0.79, 0.75, 0.76, and 0.82, respectively). Conclusion: We propose blood-based F2RL3 methylation as a potential biomarker for CHD, especially for people with older age or with the status of MI. The combination of F2RL3 methylation and conventional risk factors might be an approach to evaluate CHD at early stage.

Venous malformations with severe localized intravascular coagulopathy treated with microwave ablation.

OBJECTIVES: To evaluate the safety and feasibility of microwave ablation for treating venous malformations (VMs) with severe localized intravascular coagulopathy (LIC). PATIENTS AND METHODS: Data for patients with the diagnosis of VMs coupled with severe LIC who underwent color Doppler-guided microwave dynamic ablation between January 2017 and June 2019 were retrospectively reviewed and analyzed. All patients had previously received sclerotherapy or other treatments with poor outcomes and gradual aggravation of coagulation abnormalities. Microwave treatment with "dynamic ablation" was performed with real-time color Doppler monitoring and was repeated if necessary after 3 months. Low-molecular-weight heparin (LMWH) was used to control consumptive coagulopathy. The therapeutic efficacy including coagulation function and lesion size was evaluated using the four-level scale developed by Achauer. RESULTS: Among 15 patients with extensive diffuse or multiple VMs, 10 patients presented with lesions in a single lower extremity, one in both lower extremities and the perineum, one in both upper extremities and the trunk, and three with multiple lesions. The patients underwent a total of 74 microwave ablation sessions, with an average of 4.9 sessions per person. Coagulation abnormalities were temporarily aggravated in 59 sessions within the first seven days post-ablation but improved to grade II (fair) a week later. From six months to three years after the ablation, the lesions improved to grade IV (excellent) in one patient, grade III (good) in six patients, and grade II (fair) in eight patients. Moreover, the coagulation function improved to grade IV in four patients, grade III in eight patients, and grade II in three patients, resulting in an efficiency rate of 80% (12/15). Post-ablation complications included fever, hemoglobinuria, and elevations in aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase. The patients with fever and hemoglobinuria recovered after specific therapeutic measures, but elevations in aspartate aminotransferase, lactate dehydrogenase, and alanine aminotransferase recovered spontaneously without further interventions. CONCLUSIONS: Ablation coupled with anticoagulation can effectively treat VMs in patients with severe LIC and improve the long-term coagulation function.

Network of Interactions Between Gut Microbiome, Host Biomarkers, and Urine Metabolome in Carotid Atherosclerosis.

Comprehensive analyses of multi-omics data may provide insights into interactions between different biological layers concerning distinct clinical features. We integrated data on the gut microbiota, blood parameters and urine metabolites of treatment-naive individuals presenting a wide range of metabolic disease phenotypes to delineate clinically meaningful associations. Trans-omics correlation networks revealed that candidate gut microbial biomarkers and urine metabolite feature were covaried with distinct clinical phenotypes. Integration of the gut microbiome, the urine metabolome and the phenome revealed that variations in one of these three systems correlated with changes in the other two. In a specific note about clinical parameters of liver function, we identified Eubacteriumeligens, Faecalibacteriumprausnitzii and Ruminococcuslactaris to be associated with a healthy liver function, whereas Clostridium bolteae, Tyzzerellanexills, Ruminococcusgnavus, Blautiahansenii, and Atopobiumparvulum were associated with blood biomarkers for liver diseases. Variations in these microbiota features paralleled changes in specific urine metabolites. Network modeling yielded two core clusters including one large gut microbe-urine metabolite close-knit cluster and one triangular cluster composed of a gut microbe-blood-urine network, demonstrating close inter-system crosstalk especially between the gut microbiome and the urine metabolome. Distinct clinical phenotypes are manifested in both the gut microbiome and the urine metabolome, and inter-domain connectivity takes the form of high-dimensional networks. Such networks may further our understanding of complex biological systems, and may provide a basis for identifying biomarkers for diseases. Deciphering the complexity of human physiology and disease requires a holistic and trans-omics approach integrating multi-layer data sets, including the gut microbiome and profiles of biological fluids. By studying the gut microbiome on carotid atherosclerosis, we identified microbial features associated with clinical parameters, and we observed that groups of urine metabolites correlated with groups of clinical parameters. Combining the three data sets, we revealed correlations of entities across the three systems, suggesting that physiological changes are reflected in each of the omics. Our findings provided insights into the interactive network between the gut microbiome, blood clinical parameters and the urine metabolome concerning physiological variations, and showed the promise of trans-omics study for biomarker discovery.

Transcriptional landscape in rat intestines under hypobaric hypoxia.

Oxygen metabolism is closely related to the intestinal homeostasis environment, and the occurrence of many intestinal diseases is as a result of the destruction of oxygen gradients. The hypobaric hypoxic environment of the plateau can cause dysfunction of the intestine for humans, such as inflammation. The compensatory response of the small intestine cells to the harsh environment definitely changes their gene expression. How the small intestine cells response the hypobaric hypoxic environment is still unclear. We studied the rat small intestine under hypobaric hypoxic conditions to explore the transcriptional changes in rats under acute/chronic hypobaric hypoxic conditions. We randomly divided rats into three groups: normal control group (S), acute hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 2 weeks (W2S) and chronic hypobaric hypoxia group, exposing to hypobaric hypoxic condition for 4 weeks (W4S). The RNA sequencing was performed on the small intestine tissues of the three groups of rats. The results of principal component analysis showed that the W4S and W2S groups were quite different from the control group. We identified a total of 636 differentially expressed genes, such as ATP binding cassette, Ace2 and Fabp. KEGG pathway analysis identified several metabolic and digestive pathways, such as PPAR signaling pathway, glycerolipid metabolism, fat metabolism, mineral absorption and vitamin metabolism. Cogena analysis found that up-regulation of digestive and metabolic functions began from the second week of high altitude exposure. Our study highlights the critical role of metabolic and digestive pathways of the intestine in response to the hypobaric hypoxic environment, provides new aspects for the molecular effects of hypobaric hypoxic environment on intestine, and raises further questions about between the lipid metabolism disorders and inflammation.

Analysis of 18 complex diffuse arteriovenous malformation cases treated with percutaneous radiofrequency ablation.

BACKGROUND: The aim of the present study is to evaluate the short-term efficacy and feasibility of radiofrequency ablation in the treatment of complex diffuse arteriovenous (AV) malformations. METHODS: The data of 18 patients (8 male and 10 female) with complex AV malformations treated between December 2014 and June 2019 were analyzed retrospectively. The lesion area was 10 × 7 cm ~ 28 × 30 cm. Under duplex ultrasound guidance, the site with the most abundant blood flow signals in the lesion was percutaneously punctured with the radiofrequency ablation needle (electrode). The impedance automatic adjustment mode was adopted, and ablation was monitored usingduplex ultrasoundduring the entire process. RESULTS: Of the included patients, 1 had a high fever after two rounds of treatment, 2 had transient hemoglobinuria, and 1 had tissue necrosis in the original ruptured tumor area as well as a penetrating defect in the cheek, which was repaired with a pedicled trapezius myocutaneous flap. In 9 patients who experienced bleeding, the bleeding stopped after one round of treatment. During the follow-up period of 1-5 years, there were 0 grade I (poor) cases, 0 grade II (medium) cases, 7 grade III (good) cases, and 11 grade IV (excellent) cases. CONCLUSION: The "high power and continuous" radiofrequency ablation technique conducted under real-time duplex ultrasoundmonitoring can completely destroy the deep core lesions of AV malformations and effectively control life-threatening massive hemorrhage; it is an effective alternative treatment method for complex diffuse AV malformations in which interventional embolization, sclerotherapy, and surgery are ineffective.

Functional analyses unveil the involvement of moso bamboo (Phyllostachys edulis) group I and II NIN-LIKE PROTEINS in nitrate signaling regulation.

For rapid growth, moso bamboo (Phyllostachys edulis) requires large amounts of nutrients. Nitrate is an indispensable molecular signal to regulate nitrogen absorption and assimilation, which are regulated by group III NIN-LIKE PROTEINs (NLPs). However, no Phyllostachys edulis NLP (PeNLP) has been characterized. Here, eight PeNLPs were identified, which showed dynamic expression patterns in bamboo tissues. Nitrate did not affect PeNLP mRNA levels, and PeNLP1, -2, -5, -6, -7, and -8 successfully restored nitrate signaling in Arabidopsis atnlp7-1 protoplasts through recovering AtNiR and AtNRT2.1 expression. Four group I and II PeNLPs (PeNLP1, -2, -5, and -8) interacted with the nitrate-responsive cis-element of PeNiR. Moreover, nitrate triggered the nuclear retention of PeNLP8. PeNLP8 overexpression in Arabidopsis significantly increased the primary root length, lateral root number, leaf area, and dry and wet weight of the transgenic plants, and PeNLP8 expression rescued the root architectural defect phenotype of atnlp7-1 mutants. Interestingly, PeNLP8 overexpression dramatically reduced nitrate content but elevated total amino acid content in Arabidopsis. Overall, the present study unveiled the potential involvement of group I and II NLPs in nitrate signaling regulation and provided genetic resources for engineering plants with high nitrogen use efficiency.

The clinical implication of soluble PD-L1 (sPD-L1) in patients with breast cancer and its biological function in regulating the function of T lymphocyte.

This work investigated the clinical prognostic implications and biological function of plasma soluble programmed cell death ligand 1 in breast cancer patients. Plasma sPD-L1 levels of recurrent/metastatic breast cancer patients were determined, and the association of sPD-L1 levels and metastatic progression-free survival and metastatic overall survival was assessed. The PD-L1 expression on breast cancer cells was analyzed by flow cytometry, and the level of sPD-L1 in the supernatant of breast cancer cells was determined by enzyme-linked immunosorbent assay. Furthermore, the effect of sPD-L1 on the proliferation and apoptosis of T lymphocytes was detected by WST-1 assay and flow cytometry. The plasma sPD-L1 levels in 208 patients with recurrent/metastatic breast cancer before receiving first-line rescue therapy were measured. The optimal cutoff value of plasma sPD-L1 for predicting disease progression was 8.774 ng/ml. Univariate and multivariate analyses identified high sPD-L1 level (≥ 8.774 ng/ml) and visceral metastasis were independent factors associated with poor prognosis. Relevance analysis showed that the plasma sPD-L1 level was weaklyassociated with some systemic inflammation markers, including white cell count (WBC), absolute monocytecount, and absolute neutrophil count. Furthermore, we found sPD-L1 could be found in supernatant of culture with breast cancer cell line expressing PD-L1 on the cell surface and inhibit T lymphocyte function, playing a negative regulatory role in cellular immunity. sPD-L1 was a good tumor predictive maker in breast cancer and it may play a potentially important role in immune tolerance.

Impacts of the Plateau Environment on the Gut Microbiota and Blood Clinical Indexes in Han and Tibetan Individuals.

The intestinal microbiota is significantly affected by the external environment, but our understanding of the effects of extreme environments such as plateaus is far from adequate. In this study, we systematically analyzed the variation in the intestinal microbiota and 76 blood clinical indexes among 393 healthy adults with different plateau living durations (Han individuals with no plateau living, with plateau living for 4 to 6 days, with plateau living for >3 months, and who returned to the plain for 3 months, as well as plateau-living Tibetans). The results showed that the high-altitude environment rapidly (4 days) and continually (more than 3 months) shaped both the intestinal microbiota and clinical indexes of the Han population. With prolongation of plateau living, the general characteristics of the intestinal microbiota and clinical indexes of the Han population were increasingly similar to those of the Tibetan population. The intestinal microbiota of the Han population that returned to the plain area for 3 months still resembled that of the plateau-living Han population rather than that of the Han population on the plain. Moreover, clinical indexes such as blood glucose were significantly lower in the plateau groups than in the nonplateau groups, while the opposite result was obtained for testosterone. Interestingly, there were Tibetan-specific correlations between glucose levels and Succinivibrio and Sarcina abundance in the intestine. The results of this study suggest that a hypoxic environment could rapidly and lastingly affect both the human intestinal microbiota and blood clinical indexes, providing new insights for the study of plateau adaptability.IMPORTANCE The data presented in the present study demonstrate that the hypoxic plateau environment has a profound impact on the gut microbiota and blood clinical indexes in Han and Tibetan individuals. The plateau-changed signatures of the gut microbiota and blood clinical indexes were not restored to the nonplateau status in the Han cohorts, even when the individuals returned to the plain from the plateau for several months. Our study will improve the understanding of the great impact of hypoxic environments on the gut microbiota and blood clinical indexes as well as the adaptation mechanism and intervention targets for plateau adaptation.

Assessing inflammation in Chinese subjects with subtypes of heart failure: an observational study of the Chinese PLA Hospital Heart Failure Registry.

BACKGROUND: Inflammation is an important element of the pathophysiological process of heart failure (HF) and is correlated with subtypes of HF. The association between multiple biomarkers of inflammation and HF subtypes in Chinese subjects remains unclear. This study aimed to compare the differences in inflammation biomarkers among Chinese patients with different subtypes of HF who have been identified to date. METHODS: We included 413 consecutive patients with HF, including 262 with preserved ejection fraction (HFpEF), 55 with middle-ranged ejection fraction (HFmrEF) and 96 with reduced ejection fraction (HFrEF). Ten inflammation biomarkers were analyzed and compared according to the HF subtypes. One hundred contemporary non-HF subjects were also recruited as the control group. Moreover, the correlations between the inflammatory biomarkers and left ventricular ejection fraction of the HF subtypes were assessed. RESULTS: The mean age of the HF patients was 65.0 ± 12.0 years, 65.8% were male. Distinct subtypes of HF demonstrated different inflammation biomarker panels. IL-6, PTX-3, ANGPTL-4 and TNF-α were correlated with HFrEF; IL-1ß and PTX-3 were correlated with HFmrEF; and IL-1ß and IL-6 were correlated with HFpEF. The multivariable logistic regression showed that IL-1ß [relative ratio (RR) = 1.08, 95% CI: 1.02-1.15, P = 0.010], IL-6 (RR = 1.03, 95% CI: 1.01-1.06, P = 0.016), PTX-3 (RR = 1.31, 95% CI: 1.11-1.55, P = 0.001), and ANGPTL-4 (RR = 1.05, 95% CI: 1.02-1.07, P < 0.001) were independently associated with HF, while IL-6 (RR = 1.03, 95% CI: 1.01-1.04, P = 0.019), PTX-3 (RR = 1.23, 95% CI: 1.06-1.43, P = 0.007), and ANGPTL-4 (RR = 1.03, 95% CI: 1.01-1.06, P = 0.005) were independently associated with the HF subtype. CONCLUSIONS: Diverse inflammation biomarkers have multifaceted presentations according to the subtype of HF, which may illustrate the diverse mechanisms of inflammation in Chinese HF patients. IL-6, PTX-3, and ANGPTL-4 were independent inflammation factors associated with HFrEF and HF.

Transcriptional profiling in the livers of rats after hypobaric hypoxia exposure.

Ascent to high altitude feels uncomfortable in part because of a decreased partial pressure of oxygen due to the decrease in barometric pressure. The molecular mechanisms causing injury in liver tissue after exposure to a hypoxic environment are widely unknown. The liver must physiologically and metabolically change to improve tolerance to altitude-induced hypoxia. Since the liver is the largest metabolic organ and regulates many physiological and metabolic processes, it plays an important part in high altitude adaptation. The cellular response to hypoxia results in changes in the gene expression profile. The present study explores these changes in a rat model. To comprehensively investigate the gene expression and physiological changes under hypobaric hypoxia, we used genome-wide transcription profiling. Little is known about the genome-wide transcriptional response to acute and chronic hypobaric hypoxia in the livers of rats. In this study, we carried out RNA-Sequencing (RNA-Seq) of liver tissue from rats in three groups, normal control rats (L), rats exposed to acute hypobaric hypoxia for 2 weeks (W2L) and rats chronically exposed to hypobaric hypoxia for 4 weeks (W4L), to explore the transcriptional profile of acute and chronic mountain sickness in a mammal under a controlled time-course. We identified 497 differentially expressed genes between the three groups. A principal component analysis revealed large differences between the acute and chronic hypobaric hypoxia groups compared with the control group. Several immune-related and metabolic pathways, such as cytokine-cytokine receptor interaction and galactose metabolism, were highly enriched in the KEGG pathway analysis. Similar results were found in the Gene Ontology analysis. Cogena analysis showed that the immune-related pathways were mainly upregulated and enriched in the acute hypobaric hypoxia group.

SLC3A2 is a novel endoplasmic reticulum stress-related signaling protein that regulates the unfolded protein response and apoptosis.

Endoplasmic reticulum (ER) stress results from imbalances in unfolded/misfolded proteins, contributing to a wide variety of human diseases. To better understand the mechanisms involved in the cellular response to ER stress in cardiomyocytes, we previously conducted a genome-wide screening in an in vitro ER stress model of rat cardiomyocytes, which highlighted amino acid transporter heavy chain, member 2 (SLC3A2) as an important factor in ER stress. In the present study, we characterized the role of SLC3A2 during the unfolded protein response (UPR), as one of the primary pathways activated during ER stress. First, we confirmed the induction of Slc3a2 mRNA expression following treatment with various ER stress inducers in rat cardiomyocytes (H9C2) and neural cells (PC12). Knockdown of Slc3a2 expression with small interfering RNA (siRNA) revealed that the encoded protein functions upstream of three important UPR proteins: ATF4, ATF6, and XBP1. siRNA-mediated knockdown of both SLC3A2 and mammalian target of rapamycin 1 (mTOR1) revealed that mTOR1 acts as a mediator between SLC3A2 and the UPR. RNA sequencing was then performed to gain a more thorough understanding of the function of SLC3A2, which identified 23 highly differentially regulated genes between the control and knockdown cell lines, which were related to the UPR and amino acid transport. Notably, flow cytometry further showed that SLC3A2 inhibition also enhanced the apoptosis of rat cardiomyocytes. Taken together, these results highlight SLC3A2 as a complex, multifunctional signaling protein that acts upstream of well-known UPR proteins with anti-apoptotic properties, suggesting its potential as a therapeutic target for ER stress-related diseases.

Repeated measurement of growth-differentiation factor-15 in Chinese Han patients with post-myocardial infarction chronic heart failure.

BACKGROUND: Growth-differentiation factor-15 (GDF-15) is a promising prognostic biomarker in patients with chronic heart failure (CHF). Comparatively little is known about the value of repeated measurement of GDF-15 with CHF in Chinese Han population. This study sought to identify the clinical value of repeated measurement of GDF-15 in Chinese Han patients with post-myocardial infarction CHF. METHODS: In total, 232 consecutive Chinese Han patients with post-myocardial infarction CHF were enrolled prospectively from January 2014 to June 2016.The plasma concentration of GDF-15 was determined on admission and over 12 months. Patients were followed up for all-cause death and a composite outcome of major adverse cardiac events (MACE) included all-cause death, myocardial infarction and first heart failure (HF) re-hospitalization. Association with other clinical variables and adverse outcomes of repeated measurement of GDF-15 was explored. RESULTS: The median baseline GDF-15 level was 2025 ng/L. Baseline GDF-15 was moderately associated with baseline N-terminal pro-B type natriuretic peptide (NT-proBNP) (coefficient 0.561, P < 0.001). During a median follow-up of 20 months, there were 53 deaths and 100MACE. GDF-15 remained an independent predictor of all-cause death (adjusted hazard ratio 1.826 per 1 Ln U, 95% CI: 1.037-8.360; P = 0.037) and MACE (adjusted hazard ratio 2.243 per 1 Ln U, 95% CI: 1.181-1.775; P < 0.001) adjusted for established risk factors. Repeated measurement of GDF-15 was performed in 173 survivals over 12months. Increase of GDF-15 over 12 months was associated with dilatation of left ventricle and acted as an independent predictor of subsequent all-cause death (adjusted HR = 3.164, 95% CI: 1.245-0.041; P = 0.015). In the joint model, GDF-15 was also shown to be a risk factor for all-cause death (HR = 2.749, 95% CI: 1.667-3.831; P < 0.001) and MACE (HR = 2.434, 95% CI: 1.425-3.443; P < 0.001). CONCLUSIONS: Repeated measurements of GDF-15 have promising prognostic value of the risk of all-cause death in Chinese Han patients with CHF post-myocardial infarction. GDF-15 may influence the post-myocardial infarction CHF through the path physiological pathway of myocardial remodeling.