Predictive modeling of frailty status in elderly abdominal surgery patients by preoperative quadriceps ultrasound testing.

OBJECTIVE: To develop a predictive model based on preoperative quadriceps ultrasound measurements to determine frailty status in elderly patients undergoing abdominal surgery. METHODS: The clinical data of 148 elderly patients who underwent abdominal surgery from July 2018 to June 2022 were retrospectively analyzed. The patients were assessed for frailty using the Fried Frailty Phenotype Assessment Scale after operation and divided into a no-frailty group (n=89) and a frailty group (n=59). The differences in the patient's clinical data, perioperative indexes, and imaging indexes were compared. The risk factors affecting the frailty status of elderly patients undergoing abdominal surgery were analyzed by logistic regression. The efficacy of the prediction model was evaluated by receiver operating characteristic (ROC) curve, with model validity confirmed through calibration curves and decision curve analysis (DCA). RESULTS: The proportion of patients with age ≥80 and BMI ≥23 kg/m2 in the frailty group was significantly higher than that in the no-frailty group (both P<0.01). The operation duration and postoperative hospital stay in the frail group were significantly longer the non-frail group, and the complication rate within postoperative 7 days was significantly higher than that in the non-frail group (all P<0.05). The cross-sectional area of rectus femoris muscle, vastus medialis muscle thickness, vastus intermedius muscle thickness, rectus femoris muscle thickness, and lateral femoris muscle thickness were significantly less in the frail group than those of the no-frail group (all P<0.001). Multifactorial logistic regression analysis showed that BMI, surgical duration, vastus medialis muscle thickness, vastus intermedius muscle thickness, rectus femoris muscle thickness, and lateral femoral muscle thickness were independent risk factors affecting frailty status in elderly patients undergoing abdominal surgery (all P<0.05). The predictive model demonstrated high accuracy with an AUC of 0.926. CONCLUSION: BMI and thickness of all quadriceps muscle components were significant factors affecting the frailty status of elderly patients undergoing abdominal surgery. In addition, the developed model, with excellent accuracy, offers a potential tool for preoperative risk assessment in this patient population.

CXCL1/IGHG1 signaling enhances crosstalk between tumor cells and tumor-associated macrophages to promote MC-LR-induced colorectal cancer progression.

Microcystin-leucine arginine (MC-LR) is a common cyantotoxin produced by hazardous cyanobacterial blooms, and eutrophication is increasing the contamination level of MC-LR in drinking water supplies and aquatic foods. MC-LR has been linked to colorectal cancer (CRC) progression associated with tumor microenvironment, however, the underlying mechanism is not clearly understood. In present study, by using GEO, KEGG, GESA and ImmPort database, MC-LR related differentially expressed genes (DEGs) and pathway- and gene set-enrichment analysis were performed. Of the three identified DEGs (CXCL1, GUCA2A and GDF15), CXCL1 was shown a positive association with tumor infiltration, and was validated to have a dominantly higher upregulation in MC-LR-treated tumor-associated macrophages (TAMs) rather than in MC-LR-treated CRC cells. Both CRC cell/macrophage co-culture and xenograft mouse models indicated that MC-LR stimulated TAMs to secrete CXCL1 resulting in promoted proliferation, migration, and invasion capability of CRC cells. Furtherly, IP-MS assay found that interaction between TAMs-derived CXCL1 and CRC cell-derived IGHG1 may enhance CRC cell proliferation and migration after MC-LR treatment, and this effect can be attenuated by silencing IGHG1 in CRC cell. In addition, molecular docking analysis, co-immunoprecipitation and immunofluorescence further proved the interactions between CXCL1 and IGHG1. In conclusion, CXCL1 secreted by TAMs can trigger IGHG1 expression in CRC cells, which provides a new clue in elucidating the mechanism of MC-LR-mediated CRC progression.

Application of a WeChat Mini Program to provide pharmaceutical care for cancer pain patients: A randomized controlled trial.

Objective: This study aimed to develop an individual WeChat Mini Program to provide pharmaceutical care to better manage cancer pain patients and to evaluate its feasibility and the differences in analgesic efficacy, medication adherence and safety versus conventional pharmacy interventions. Methods: In this parallel randomized clinical trial, 42 cancer pain patients were equally allocated into the experimental group and the control group. The experimental group received individualized pharmaceutical care based on the "Yao Nin You Wo" WeChat Mini Program, while the control group received conventional care during the 4-week period. Main outcomes contained pain scores, medication adherence, incidences and relief rates of breakthrough pain, and incidences of adverse events. Relief rates of pain were also calculated according to pain scores. Results: At the beginning of intervention, none of the pain scores and medication adherence showed relevant differences between the two groups (all P > .05). After intervention, the experimental group had significantly lower pain scores compared to the control group (P = .003). Breakthrough pain of both groups was alleviate; not only the incidence of breakthrough pain considerably was lower at 4 weeks than at baseline, but the relief rate of breakthrough in the experimental group was higher than that in the control group. Compared with the control group, the medication adherence rate of the experimental group was significantly improved (P = .02). Types of adverse events that happened in experimental and groups were similar, but the total incidence of adverse events in the experimental group was lower than that in the control group. Conclusions: WeChat Mini Program is a useful and facilitative tool with the potential to improve cancer pain self-management ability in discharged patients. In addition, pharmacists could play a key role through the Mini Program to connect with patients successfully by providing personalized pharmaceutical services.

Activation of the IL-6/STAT3 pathway contributes to the pathogenesis of membranous nephropathy and is a target for Mahuang Fuzi and Shenzhuo Decoction (MFSD) to repair podocyte damage.

BACKGROUND: Primary membranous nephropathy (PMN) is an autoimmune glomerular disease. IL-6 is a potential therapeutic target for PMN. Previous clinical studies have demonstrated the effectiveness of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in treating membranous nephropathy. However, the mechanism of action of MFSD remains unclear. METHODS: Serum IL-6 levels were measured in patients with PMN and healthy subjects. The passive Heymann nephritis (PHN) rat model was established, and high and low doses of MFSD were used for intervention to observe the repair effect of MFSD on renal pathological changes and podocyte injury. RNA-seq was used to screen the possible targets of MFSD, and the effect of MFSD targeting IL-6/STAT3 was further verified by combining the experimental results. Finally, the efficacy of tocilizumab in PHN rats was observed. RESULTS: Serum IL-6 levels were significantly higher in PMN patients than in healthy subjects. These levels significantly decreased in patients in remission after MFSD treatment. MFSD treatment improved laboratory indicators in PHN rats, as well as glomerular filtration barrier damage and podocyte marker protein expression. Renal transcriptome changes showed that MFSD-targeted differential genes were enriched in JAK/STAT and cytokine-related pathways. MFSD inhibits the IL6/STAT3 pathway in podocytes. Additionally, MFSD significantly reduced serum levels of IL-6 and other cytokines in PHN rats. However, treatment of PHN with tocilizumab did not achieve the expected effect. CONCLUSION: The IL-6/STAT3 signaling pathway is activated in podocytes of experimental membranous nephropathy. MFSD alleviates podocyte damage by inhibiting the IL-6/STAT3 pathway.

Differences in influencing mechanism of clinicians' adoption behavior for liver cancer screening technology between the leading and subordinate hospitals within medical consortiums.

BACKGROUND: Medical consortiums have been extensively established to facilitate the integration of health resources and bridge the technical gap among member institutions. However, some commonly appropriate technologies remain stagnant in subordinate hospitals, although they have been routinely applied in leading hospitals. Besides, the mechanism underlying differences in clinicians' adoption behavior at different levels of institutions was unknown. Therefore, this study aimed to investigate the differences in influencing mechanisms of clinicians' hepatic contrast-enhanced ultrasound technology (CEUS) utilization behavior between leading and subordinate hospitals within medical consortiums, thus providing clues for expanding effective and appropriate technologies within integrated care systems. METHODS: A self-designed scale was developed based on the theory of planned behavior (TPB). A multistage sampling method was applied to investigate clinicians who were aware of CEUS and worked in liver disease-related departments within the sampled medical institutions. The final sample size was 289. AMOS 24.0 software was used to construct multi-group structural equation modeling (SEM) to validate the hypotheses and determine the mechanism of hepatic CEUS utilization. RESULTS: It revealed that behavioral intention significantly influenced adoption behavior, regardless of whether it was in leading hospitals or subordinate hospitals (ß = 0.283, p < 0.001). Furthermore, behavioral attitude (ß = 0.361, p < 0.001) and perceived behavioral control (ß = 0.582, p < 0.001) exerted significant effects on adoption behavior through behavioral intention. However, in leading hospitals, subjective norm had a significant positive effect on behavioral intention (ß = 0.183, p < 0.01), while it had a significant negative impact on behavioral intention in the subordinate hospitals (ß = -0.348, p < 0.01). CONCLUSION: To effectively translate the adoption intention into actual behavior, it is recommended to elucidate the demand and facilitators involved in the process of health technology adoption across leading and subordinate hospitals. Additionally, bolstering technical support and knowledge dissemination within subordinate hospitals while harnessing the influential role of key individuals can further enhance this transformative process.

Immunogenic Cell Death-related Signature Evaluates the Tumor Microenvironment and Predicts the Prognosis in Diffuse Large B-Cell Lymphoma.

Current literatures suggest a growing body of evidence highlighting the pivotal role of Immunogenic Cell Death (ICD) in multiple tumor types. Nevertheless, the potential and mechanisms of ICD in diffuse large B-cell lymphoma (DLBCL) remain inadequately studied. To address this gap, our current study aims to examine the impact of ICD on DLBCL and identify a corresponding gene signature in DLBC. Using the expression profiles of ICD-associated genes, the gene expression omnibus (GEO) samples were segregated into ICD-high and ICD-low subtypes utilizing non-negative matrix factorization clustering. Next, univariate and LASSO Cox regression analyses were employed to establish the ICD-related gene signature. Subsequently, the CIBERSORT tool, ssGSEA, and ESTIMATE algorithm were utilized to examine the association between the signature and tumor immune microenvironment of DLBC. Finally, the oncoPredict algorithm was implemented to evaluate the drug sensitivity prediction of DLBCL patients. These findings suggest that the immune microenvironment of the ICD-high group with a poor prognosis was significantly suppressed. An 8-gene ICD-related signature was identified and validated to prognosticate and evaluate the tumor immune microenvironment in DLBCL. Similarly, the high-risk group exhibited a worse prognosis compared to the low-risk group, and the immune function was considerably suppressed. Moreover, the results of oncoPredict algorithm indicated that patients in the high-risk group exhibited higher sensitivity to Cisplatin, Cytarabine, Epirubicin, Oxaliplatin, and Vincristine with low IC50. In conclusion, the present study provides novel insights into the role of ICD in DLBCL by identifying a new biomarker for the disease and may have implications for the development of immune-targeted therapies for the tumor.

GCN2-eIF2α signaling pathway negatively regulates the growth of triploid crucian carp.

GCN2-eIF2α signaling pathway plays crucial roles in cell growth,development, and protein synthesis. However, in polyploid fish, the function of this pathway is rarely understood. In this study, genes associated with the GCN2-eIF2α pathway (pkr, pek, gcn2, eif2α) are founded lower expression levels in the triploid crucian carp (3nCC) muscle compared to that of the red crucian carp (RCC). In muscle effect stage embryos of the 3nCC, the mRNA levels of this pathway genes are generally lower than those of RCC, excluding hri and fgf21. Inhibiting gcn2 in 3nCC embryos downregulates downstream gene expression (eif2α, atf4, fgf21), accelerating embryonic development. In contrast, overexpressing of eif2α can alter the expression levels of downstream genes (atf4 and fgf21), and decelerates the embryonic development. These results demonstrate the GCN2-eIF2α pathway's regulatory impact on 3nCC growth, advancing understanding of fish rapid growth genetics and offering useful molecular markers for breeding of excellent strains.

Biomarkers and coptis chinensis activity for rituximab-resistant diffuse large B-cell lymphoma: Combination of bioinformatics analysis, network pharmacology and molecular docking.

BACKGROUND: Rituximab resistance is one of the great challenges in the treatment of diffuse large B-cell lymphoma (DLBCL), but relevant biomarkers and signalling pathways remain to be identified. Coptis chinensis and its active ingredients have antitumour effects; thus, the potential bioactive compounds and mechanisms through which Coptis chinensis acts against rituximab-resistant DLBCL are worth exploring. OBJECTIVE: To elucidate the core genes involved in rituximab-resistant DLBCL and the potential therapeutic targets of candidate monomers of Coptis chinensis. METHODS: Using the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), the Similarity Ensemble Approach and Swiss Target Prediction, the main ingredients and pharmacological targets of Coptis chinensis were identified through database searches. Through the overlap between the pharmacological targets of Coptis chinensis and the core targets of rituximab-resistant DLBCL, we identified the targets of Coptis chinensis against rituximab-resistant DLBCL and constructed an active compound-target interaction network. The targets and their corresponding active ingredients of Coptis chinensis against rituximab-resistant DLBCL were molecularly docked. RESULTS: Berberine, quercetin, epiberberine and palmatine, the active components of Coptis chinensis, have great potential for improving rituximab-resistant DLBCL via PIK3CG. CONCLUSION: This study revealed biomarkers and Coptis chinensis-associated molecular functions for rituximab-resistant DLBCL.

Purine salvage-associated metabolites as biomarkers for early diagnosis of esophageal squamous cell carcinoma: a diagnostic model-based study.

Esophageal squamous cell carcinoma (ESCC) remains an important health concern in developing countries. Patients with advanced ESCC have a poor prognosis and survival rate, and achieving early diagnosis remains a challenge. Metabolic biomarkers are gradually gaining attention as early diagnostic biomarkers. Hence, this multicenter study comprehensively evaluated metabolism dysregulation in ESCC through an integrated research strategy to identify key metabolite biomarkers of ESCC. First, the metabolic profiles were examined in tissue and serum samples from the discovery cohort (n = 162; ESCC patients, n = 81; healthy volunteers, n = 81), and ESCC tissue-induced metabolite alterations were observed in the serum. Afterward, RNA sequencing of tissue samples (n = 46) was performed, followed by an integrated analysis of metabolomics and transcriptomics. The potential biomarkers for ESCC were further identified by censoring gene-metabolite regulatory networks. The diagnostic value of the identified biomarkers was validated in a validation cohort (n = 220), and the biological function was verified. A total of 457 dysregulated metabolites were identified in the serum, of which 36 were induced by tumor tissues. The integrated analyses revealed significant alterations in the purine salvage pathway, wherein the abundance of hypoxanthine/xanthine exhibited a positive correlation with HPRT1 expression and tumor size. A diagnostic model was developed using two purine salvage-associated metabolites. This model could accurately discriminate patients with ESCC from normal individuals, with an area under the curve (AUC) (95% confidence interval (CI): 0.680-0.843) of 0.765 in the external cohort. Hypoxanthine and HPRT1 exerted a synergistic effect in terms of promoting ESCC progression. These findings are anticipated to provide valuable support in developing novel diagnostic approaches for early ESCC and enhance our comprehension of the metabolic mechanisms underlying this disease.

Temperature-resilient superior performances by coupling partial nitritation/anammox and iron-based denitrification with granular formation.

Partial nitritation-anammox (PN/A), an energy-neutral process, is widely employed in the treatment of nitrogen-rich wastewater. However, the intrinsic nitrate accumulation limits the total nitrogen (TN) removal, and the practical application of PN/A continues to face a significant challenge at low temperatures (<15 °C). Here, an integrated partial nitritation-anammox and iron-based denitrification (PNAID) system was developed to address the concern. Two up-flow bioreactors were set up and operated for 400 days, with one as the control group and the other as the experiment group with the addition of Fe0. In comparison to the control group, the experiment group with the Fe0 supplement showed better nitrogen removal during the entire course of the experiment at different temperature levels. Specifically, the TN removal efficiency of the control group decreased from 82.9 % to 53.9 % when the temperature decreased from 30 to 12 °C, while in stark contrast, the experiment group consistently achieved 80 % of TN removal in the same condition. Apart from the enhanced nitrogen removal, the experiment group also exhibited better phosphorus removal (10.6 % versus 74.1 %) and organics removal (49.5 % versus 65.1 %). The enhanced and resilient nutrient removal performance of the proposed integrated process under low temperatures appeared to be attributed to the compact structure of granules and the increased microbial metabolism with Fe0 supplement, elucidated by a comprehensive analysis including microbial-specific activity, apparent activation energy, characteristics of granular sludge, and metagenomic sequencing. These results clearly confirmed that Fe0 supplement not only improved nitrogen removal of PN/A process, but also conferred a certain degree of robustness to the system in the face of temperature fluctuations.

Excessive linoleic acid induces muscle oxidative stress through 5-lipoxygenase-dependent peroxidation.

Oxidative stress in muscles is closely related to the occurrence of insulin resistance, muscle weakness and atrophy, age-related sarcopenia, and cancer. Aldehydes, a primary oxidation intermediate of polyunsaturated fatty acids, have been proven to be an important trigger for oxidative stress. However, the potential role of linoleic acid (LA) as a donor for volatile aldehydes to trigger oxidative stress has not been reported. Here, we reported that excessive dietary LA caused muscle redox imbalance and volatile aldehydes containing hexanal, 2-hexenal, and nonanal were the main metabolites leading to oxidative stress. Importantly, we identified 5-lipoxygenase (5-LOX) as a key enzyme mediating LA peroxidation in crustaceans for the first time. The inhibition of 5-LOX significantly suppressed the content of aldehydes produced by excessive LA. Mechanistically, the activation of the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway facilitated the translocation of 5-LOX from the nucleus to the cytoplasm, where 5-LOX oxidized LA, leading to oxidative stress through the generation of aldehydes. This study suggests that 5-LOX is a potential target to prevent the production of harmful aldehydes.

Bioaccumulation and Male Reproductive Toxicity of the New Brominated Flame Retardant Tetrabromobisphenol A-Bis(2,3-dibromo-2-methylpropyl ether) in Comparison with Hexabromocyclododecane.

Tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) (TBBPA-DBMPE) has come into use as an alternative to hexabromocyclododecane (HBCD), but it is unclear whether TBBPA-DBMPE has less hazard than HBCD. Here, we compared the bioaccumulation and male reproductive toxicity between TBBPA-DBMPE and HBCD in mice following long-term oral exposure after birth. We found that the concentrations of TBBPA-DBMPE in livers significantly increased with time, exhibiting a bioaccumulation potency not substantially different from HBCD. Lactational exposure to 1000 µg/kg/d TBBPA-DBMPE as well as 50 µg/kg/d HBCD inhibited testis development in suckling pups, and extended exposure up to adulthood resulted in significant molecular and cellular alterations in testes, with slighter effects of 50 µg/kg/d TBBPA-DBMPE. When exposure was extended to 8 month age, severe reproductive impairments including reduced sperm count, increased abnormal sperm, and subfertility occurred in all treated animals, although 50 µg/kg/d TBBPA-DBMPE exerted lower effects than 50 µg/kg/d HBCD. Altogether, all data led us to conclude that TBBPA-DBMPE exerted weaker male reproductive toxicity than HBCD at the same doses but exhibited bioaccumulation potential roughly equivalent to HBCD. Our study fills the data gap regarding the bioaccumulation and toxicity of TBBPA-DBMPE and raises concerns about its use as an alternative to HBCD.

Interaction between Wnt/ß-catenin signaling pathway and EMT pathway mediates the mechanism of sunitinib resistance in renal cell carcinoma.

BACKGROUND: Targeted drugs are the main methods of RCC treatment. However, drug resistance is common in RCC patients, in-depth study of the drug-resistant mechanism is essential. METHODS: We constructed sunitinib resistant and Twist overexpressed A498 cells, and studied its mechanisms in vitro and in vivo. RESULTS: In cell research, we found that either sunitinib resistance or Twist overexpression can activate Wnt/ß-catenin and EMT signaling pathway, and the sunitinib resistance may work through ß-catenin/TWIST/TCF4 trimer. In zebrafish research, we confirmed the similarity of Twist overexpression and sunitinib resistance, and the promoting effect of Twist overexpression on drug resistance. CONCLUSIONS: Sunitinib resistance and Twist overexpression can activate Wnt/ß-catenin signaling pathway and EMT to promote the growth and metastasis of RCC cells.

MSCs-derived extracellular vesicles alleviate sepsis-associated liver dysfunction by inhibiting macrophage glycolysis-mediated inflammatory response.

Sepsis-associated liver dysfunction (SALD) aggravates the disease progression and prognosis of patients. Macrophages in the liver play a crucial role in the occurrence and development of SALD. Human umbilical cord mesenchymal stem cells (MSCs), by secreting extracellular vesicles (EVs), show beneficial effects in various inflammatory diseases. However, whether MSC-derived EVs (MSC-EVs) could ameliorate the inflammatory response in liver macrophages and the underlying mechanisms remain unclear. In this study, a mouse model of sepsis induced by lipopolysaccharide (LPS) challenge was used to investigate the immunomodulatory functions of MSC-EVs in SALD. LPS-stimulated primary Kupffer cells (KCs) and Raw264.7 were used to further explore the potential mechanisms of MSC-EVs in regulating the inflammatory response of macrophages. The results showed that MSC-EVs alleviated liver tissue injury and facilitated the polarization of M1 to M2 macrophages. Further in vitro studies confirmed that MSC-EVs treatment significantly downregulated the expression of several enzymes related to glycolysis and reduced the glycolytic flux by inhibiting hypoxia-inducible factor 1α (HIF-1α) expression, thus effectively inhibiting the inflammatory responses of macrophages. These findings reveal that the application of MSC-EVs might be a potential therapeutic strategy for treating SALD.

Metabolism, antioxidant and immunity in acute and chronic hypoxic stress and the improving effect of vitamin C in the channel catfish (Ictalurus punctatus).

Hypoxia is the most significant factor that threatens the health and even survival of freshwater and marine fish. Priority should be given to the investigation of hypoxia adaptation mechanisms and their subsequent modulation. Acute and chronic studies were designed for the current study. Acute hypoxia comprised of normoxia dissolved oxygen (DO) 7.0 ± 0.5 mg/mL (N0), low-oxygen 5.0 ± 0.5 mg/mL(L0), and hypoxia 1.0 ± 0.1 mg/mL (H0) and 300 mg/L Vc for hypoxia regulation (N300, L300, H300). Chronic hypoxia comprised of normoxia (DO 7.0 ± 0.5 mg/mL) with 50 mg/kg Vc in the diet (N50) and low oxygen (5.0 ± 0.5 mg/mL) with 50, 250, 500 mg/kg Vc in the diet (L50, L250, L500) to assess the effect of Vc in hypoxia. The growth, behavior, hematological parameters, metabolism, antioxidants, and related inflammatory factors of channel catfish were investigated, and it was found that channel catfish have a variety of adaptive mechanisms in response to acute and chronic hypoxia. Under acute 5 mg/mL DO, the body color lightened (P < 0.05) and reverted to normal with 300 mg/mL Vc. PLT was significantly elevated after 300 mg/L Vc (P < 0.05), indicating that Vc can effectively restore hemostasis following oxygen-induced tissue damage. Under acute hypoxia, the significantly increased of cortisol, blood glucose, the gene of pyruvate kinase (pk), and phosphofructokinase (pfk), together with the decreased expression of fructose1,6-bisphosphatase (fbp) and the reduction in myoglycogen, suggested that Vc might enhance the glycolytic ability of the channel catfish. And the enzyme activities of superoxide dismutase (SOD) and catalase (CAT) and the gene expression of sod rose significantly, showing that Vc might improve the antioxidant capacity of the channel catfish. The significant up-regulation of tumor necrosis factor-alpha (tnf-α), interleukin-1ß (il-1ß), and cd68 under acute hypoxia implies that hypoxia may generate inflammation in channel catfish, whereas the addition of Vc and down-regulation of these genes suggests that Vc suppresses inflammation under acute hypoxia. We found that the final weight, WGR, FCR, and FI of channel catfish were significantly reduced under chronic hypoxia, and that feeding 250 mg/kg of Vc in the diet was effective in alleviating the growth retardation caused by hypoxia. The significant increase in cortisol, blood glucose, myoglycogen, and the expression of tnf-α, il-1ß, and cd68 (P < 0.05) and the significant decrease in lactate (P < 0.05) under chronic hypoxia indicated that the channel catfish had gradually adapted to the survival threat posed by hypoxia and no longer relied on carbohydrates as their primary source of energy. While the addition of Vc did not appear to increase the energy supply of the fish under hypoxia in terms of glucose metabolism, but the significantly decreased expression of tnf-α, il-1ß, and cd68 (P < 0.05) also were found, indicating that chronic hypoxia, similar acute hypoxia, may increase inflammation in the channel catfish. This study indicates that under acute stress, channel catfish withstand stress by raising energy supply through glycolysis, and acute hypoxic stress significantly promotes inflammation in channel catfish, but Vc assists the channel catfish resist stress by raising glycolysis, antioxidant capacity, and decreasing the production of inflammatory markers. Under chronic hypoxia, the channel catfish no longer utilize carbohydrates as their primary energy source, and Vc may still effectively reduce inflammation in the channel catfish under hypoxia.

Effects of a high-fat and high-carbohydrate diet on appetite regulation and central AMPK in the hypothalamus of blunt snout bream (Megalobrama amblycephala).

Adenosine monophosphate-activated protein kinase (AMPK) is a sensor of cellular energy changes and controls food intake. This study investigates the effect of a high-calorie diet (high fat diet [HFD], high carbohydrate diet [HCD] and high energy diet [HED]) on appetite and central AMPK in blunt snout bream. In the present study, fish (average initial weight 45.84 ± 0.07 g) were fed the control, HFD, HCD and HED in four replicates for 12 weeks. At the end of the feeding trial, the result showed that body mass index, specific growth rate, feed efficiency ratio and feed intake were not affected (p > 0.05) by dietary treatment. However, fish fed the HFD obtained a significantly higher (p < 0.05) lipid productive value, lipid gain and lipid intake than those fed the control diet, but no significant difference was attributed to others. Also, a significantly higher (p < 0.05) energy intake content was found in fish-fed HFD, HCD and HED than those given the control diet. Long-term HFD and HCD feeding significantly increased (p < 0.05) plasma glucose, glycated serum protein, advanced glycation end product, insulin and leptin content levels than the control group. Moreover, a significantly lower (p < 0.05) complex 1, 2 and 3 content was found in fish-fed HFD and HCD than in the control, but no differences (p > 0.05) were attributed to those in HED. Fish-fed HED significantly upregulated (p < 0.05) hypothalamic ampα 1 and ampα 2 expression, whereas the opposite trend was observed in the hypothalamic mammalian target of rapamycin than those in HFD and HCD compared to the control. However, hypothalamic neuropeptide y, peroxisome proliferator-activated receptor α (pparα), acetyl-coa oxidase and carnitine palmitoyltransferase 1 were significantly upregulated (p < 0.05) in the HCD group, while the opposite was seen in cholecystokinin expression compared to those in the control group. Our findings indicated that the central AMPK signal pathway and appetite were modulated according to the diet's energy level to regulate nutritional status and maintain energy homoeostasis in fish.

The Terminalia chebula Retz extract treats hyperuricemic nephropathy by inhibiting TLR4/MyD88/NF-κB axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperuricemic nephropathy (HN) is a renal injury caused by hyperuricemia and is the main cause of chronic kidney disease and end-stage renal disease. ShiWeiHeZiSan, which is composed mainly of components of Terminalia chebula Retz. And is recorded in the Four Medical Tantras, is a typical traditional Tibetan medicinal formula for renal diseases. Although T. chebula has been reported to improve renal dysfunction and reduce renal cell apoptosis, the specific mechanism of the nephroprotective effects of T. chebula on HN is still unclear. AIM OF THE STUDY: This study was conducted to evaluate the effects and specific mechanism of T. chebula extract on HN through network pharmacology and in vivo and in vitro experiments. MATERIALS AND METHODS: Potassium oxalate (1.5 g/kg) and adenine (50 mg/kg) were combined for oral administration to establish the HN rat model, and the effects of T. chebula extract on rats in the HN model were evaluated by renal function indices and histopathological examinations. UPLC-Q-Exactive Orbitrap/MS analysis was also conducted to investigate the chemical components of T. chebula extract, and the potential therapeutic targets of T. chebula in HN were predicted by network pharmacology analysis. Moreover, the activation of potential pathways and the expression of related mRNAs and proteins were further observed in HN model rats and uric acid-treated HK-2 cells. RESULTS: T. chebula treatment significantly decreased the serum uric acid (SUA), blood urea nitrogen (BUN) and serum creatinine (SCr) levels in HN rats and ameliorated renal pathological injury and fibrosis. A total of 25 chemical components in T. chebula extract were identified by UPLC-Q-Exactive Orbitrap/MS analysis, and network pharmacology analysis indicated that the NF-κB pathway was the potential pathway associated with the therapeutic effects of T. chebula extract on HN. RT‒PCR analysis, immunofluorescence staining and ELISA demonstrated that the mRNA and protein levels of TLR4 and MyD88 were significantly decreased in the renal tissue of HN rats after treatment with T. chebula extract at different concentrations, while the phosphorylation of P65 and the secretion of TNF-α and IL-6 were significantly inhibited. The results of in vitro experiments showed that T. chebula extract significantly decreased the protein levels of TLR4, MyD88, p-IκBα and p-P65 in uric acid-treated HK-2 cells and inhibited the nuclear translocation of p65 in these cells. In addition, the expression of inflammatory factors (IL-1ß, IL-6 and TNF-α) and fibrotic genes (α-SMA and fibronectin) was significantly downregulated by T. chebula extract treatment, while E-cadherin expression was significantly upregulated. CONCLUSION: T. chebula extract exerts nephroprotective effects on HN, such as anti-inflammatory effects and fibrosis improvement, by regulating the TLR4/MyD88/NF-κB axis, which supports the general use of T. chebula in the management of HN and other chronic kidney diseases.

APOBEC3A suppresses cervical cancer via apoptosis.

Background: Family members of Apolipoprotein B mRNA-editing enzyme catalytic 3 (APOBEC3) play critical roles in cancer evolution and development. However, the role of APOBEC3A in cervical cancer remains to be clarified. Methods: We used bioinformatics to investigate APOBEC3A expression and outcomes using The Cancer Genome Atlas (TCGA)-cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) dataset, GTEx, and GSE7803. Immunohistochemistry was then used to identify APOBEC3A's expression pattern. We performed Cell Counting Kit-8, wound-healing, Transwell, and flow cytometry assays to measure proliferation, migration, invasion, and apoptosis, respectively, using the SiHa and HeLa cell lines transfected with APOBEC3A. BALB/c nude mice were used to investigate the effects of APOBEC3A in vivo. The phosphorylated gamma-H2AX staining assay was applied to measure DNA damage. RNA sequencing (RNA-Seq) was applied to explore APOBEC3A-related signaling pathways. Results: APOBEC3A was more significantly expressed in cancer tissues than in adjacent normal tissues. Higher expression of APOBEC3A was associated with better outcomes in TCGA-CESC and GTEx. Immunohistochemistry showed that the expression of APOBEC3A was significantly higher in cancer tissues than in normal tissues. Transfection experiments showed that APOBEC3A inhibited proliferation, upregulated S-phase cells, inhibited migration and invasion, induced DNA damage, and promoted apoptosis. Overexpression of APOBEC3A inhibited tumor formation in the mouse model. RNA-seq analysis showed that ectopic expression of APOBEC3A inhibited several cancer-associated signaling pathways. Conclusions: APOBEC3A is significantly upregulated in cervical cancer, and higher expression of APOBEC3A is associated with better outcomes. APOBEC3A is a tumor suppressor whose overexpression induces apoptosis in cervical cancer.

Tanshinone IIA promotes the proliferation and differentiation ability of primary muscle stem cells via MAPK and Akt signaling.

Salvia miltiorrhiza Bunge is a widely-used traditional Chinese medicine to treat a variety of diseases including muscle disorders. The underlying pharmacological mechanisms of which active component and how it functions are still unknown. Tanshinone IIA (Tan IIA) is the main active lipophilic compound in Salvia miltiorrhiza Bunge. Muscle stem cells (MuSCs) play a crucial role in maintaining healthy physiological function of skeletal muscle. For the purpose of this study, we investigated the effects of Tan IIA on primary MuSCs as well as mechanism. The EdU staining, cell counts assay and RT-qPCR results of proliferative genes revealed increased proliferation ability of MuSCs after Tan IIA treatment. Immunofluorescent staining of MyHC and RT-qPCR results of myogenic genes found Tan IIA contributed to promoting differentiation of MuSCs. In addition, enrichment analysis of RNA-seq data and Western blot assay results demonstrated activated MAPK and Akt signaling after treatment of Tan IIA during proliferation and differentiation. The above proliferative and differentiative phonotypes could be suppressed by the combination of MAPK inhibitor U0126 and Akt inhibitor Akti 1/2, respectively. Furthermore, HE staining found significantly improved myofiber regeneration of injured muscle after Tan IIA treatment, which also contributed to muscle force and running performance recovery. Thus, Tan IIA could promote proliferation and differentiation ability of MuSCs through activating MAPK and Akt signaling, respectively. These beneficial effects also significantly contributed to muscle regeneration and muscle function recovery after muscle injury.