GIHP: Graph convolutional neural network based interpretable pan-specific HLA-peptide binding affinity prediction.

Accurately predicting the binding affinities between Human Leukocyte Antigen (HLA) molecules and peptides is a crucial step in understanding the adaptive immune response. This knowledge can have important implications for the development of effective vaccines and the design of targeted immunotherapies. Existing sequence-based methods are insufficient to capture the structure information. Besides, the current methods lack model interpretability, which hinder revealing the key binding amino acids between the two molecules. To address these limitations, we proposed an interpretable graph convolutional neural network (GCNN) based prediction method named GIHP. Considering the size differences between HLA and short peptides, GIHP represent HLA structure as amino acid-level graph while represent peptide SMILE string as atom-level graph. For interpretation, we design a novel visual explanation method, gradient weighted activation mapping (Grad-WAM), for identifying key binding residues. GIHP achieved better prediction accuracy than state-of-the-art methods across various datasets. According to current research findings, key HLA-peptide binding residues mutations directly impact immunotherapy efficacy. Therefore, we verified those highlighted key residues to see whether they can significantly distinguish immunotherapy patient groups. We have verified that the identified functional residues can successfully separate patient survival groups across breast, bladder, and pan-cancer datasets. Results demonstrate that GIHP improves the accuracy and interpretation capabilities of HLA-peptide prediction, and the findings of this study can be used to guide personalized cancer immunotherapy treatment. Codes and datasets are publicly accessible at: https://github.com/sdustSu/GIHP.

Raspberry Ketone Attenuates Hepatic Fibrogenesis and Inflammation via Regulating the Crosstalk of FXR and PGC-1α Signaling.

Hepatic fibrosis is a compensatory response to chronic liver injury and inflammation, and dietary intervention is recommended as one of the fundamental prevention strategies. Raspberry ketone (RK) is an aromatic compound first isolated from raspberry and widely used to prepare food flavors. The current study investigated the hepatoprotection and potential mechanism of RK against hepatic fibrosis. In vitro, hepatic stellate cell (HSC) activation was stimulated with TGF-ß and cultured with RK, farnesoid X receptor (FXR), or peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) agonist or inhibitor, respectively. In vivo, C57BL/6 mice were injected intraperitoneally with thioacetamide (TAA) at 100/200 mg/kg from the first to the fifth week. Mice were intragastrically administrated with RK or Cur once a day from the second to the fifth week. In activated HSCs, RK inhibited extracellular matrix (ECM) accumulation, inflammation, and epithelial-mesenchymal transition (EMT) process. RK both activated FXR/PGC-1α and regulated their crosstalk, which were verified by their inhibitors and agonists. Deficiency of FXR or PGC-1α also attenuated the effect of RK on the reverse of activated HSCs. RK also decreased serum ALT/AST levels, liver histopathological change, ECM accumulation, inflammation, and EMT in mice caused by TAA. Double activation of FXR/PGC-1α might be the key targets for RK against hepatic fibrosis. Above all, these discoveries supported the potential of RK as a novel candidate for the dietary intervention of hepatic fibrosis.

Diallyl disulfide, the bioactive component of Allium species, ameliorates pulmonary fibrosis by mediating the crosstalk of farnesoid X receptor and yes-associated protein 1 signaling pathway.

Environmental pollution, virus infection, allergens, and other factors may cause respiratory disease, which could be improved by dietary therapy. Allium species are common daily food seasoning and have high nutritional and medical value. Diallyl disulfide (DADS) is the major volatile oil compound of Allium species. The present study aims to explore the preventive effect and potential mechanism of DADS on pulmonary fibrosis. C57BL/6J mice were intratracheally injected with bleomycin (BLM) to establish pulmonary fibrosis and then administrated with DADS. Primary lung fibroblasts or A549 were stimulated with BLM, followed by DADS, farnesoid X receptor (FXR) agonist (GW4064), yes-associated protein 1 (YAP1) inhibitor (verteporfin), or silencing of FXR and YAP1. In BLM-stimulated mice, DADS significantly ameliorated histopathological changes and interleukin-1ß levels in bronchoalveolar lavage fluid. DADS decreased fibrosis markers, HIF-1α, inflammatory cytokines, and epithelial-mesenchymal transition in pulmonary mice and activated fibroblasts. DADS significantly enhanced FXR expression and inhibited YAP1 activation, which functions as GW4064 and verteporfin. A deficiency of FXR or YAP1 could result in the increase of these two protein expressions, respectively. DADS ameliorated extracellular matrix deposition, hypoxia, epithelial-mesenchymal transition, and inflammation in FXR or YAP1 knockdown A549. Taken together, targeting the crosstalk of FXR and YAP1 might be the potential mechanism for DADS against pulmonary fibrosis. DADS can serve as a potential candidate or dietary nutraceutical supplement for the treatment of pulmonary fibrosis.

Angelica dahurica extract and its effective component bergapten alleviated hepatic fibrosis by activating FXR signaling pathway.

Angelica dahurica (A. dahurica) has a wide range of pharmacological effects, including analgesic, anti-inflammatory and hepatoprotective effects. In this study, we investigated the effect of A. dahurica extract (AD) and its effective component bergapten (BG) on hepatic fibrosis and potential mechanisms. Hepatic fibrosis was induced by intraperitoneal injection with carbon tetrachloride (CCl4) for 1 week, and mice were administrated with AD or BG by gavage for 1 week before CCl4 injection. Hepatic stellate cells (HSCs) were stimulated by transforming growth factor-ß (TGF-ß) and cultured with AD, BG, GW4064 (FXR agonist) or Guggulsterone (FXR inhibitor). In CCl4-induced mice, AD significantly decreased serum aminotransferase, reduced excess accumulation of extracellular matrix (ECM), inhibited caspase-1 and IL-1ß, and increased FXR expressions. In activated HSCs, AD suppressed the expressions of α-SMA, collagen I, and TIMP-1/MMP-13 ratio and inflammatory factors, functioning as FXR agonist. In CCl4-induced mice, BG significantly improved serum transaminase and histopathological changes, reduced ECM excessive deposition, inflammatory response, and activated FXR expression. BG increased FXR expression and inhibited α-SMA and IL-1ß expressions in activated HSCs, functioning as GW4064. FXR deficiency significantly attenuated the decreasing effect of BG on α-SMA and IL-1ß expressions in LX-2 cells. In conclusion, AD could regulate hepatic fibrosis by regulating ECM excessive deposition and inflammation. Activating FXR signaling by BG might be the potential mechanism of AD against hepatic fibrosis.

Sesamol as a potential candidate for the treatment of hepatic fibrosis, based on its regulation of FXR/LXR axis-mediated inhibition of autophagy through crosstalk between hepatic cells and macrophage.

BACKGROUND: Sesamol (SEM), a natural lignan compound isolated from sesame, has strong anti-oxidant property, regulating lipid metabolism, decreasing cholesterol and hepatoprotection. However, its anti-hepatic fibrosis effect and mechanisms have not been comprehensively elucidated. HYPOTHESIS/PURPOSE: This study aims to investigate the anti-hepatic fibrosis of SEM and its underlying mechanisms. METHOD: C57BL/6 mice with hepatic fibrosis were induced by TAA, then administrated with SEM or curcumin, respectively. HSCs were stimulated by TGF-ß or conditioned medium, and then cultured with SEM, GW4064, GW3965, Rapamycin (RA) or 3-methyladenine (3-MA), respectively. Mice with hepatic fibrosis also were administrated with SEM, RA or 3-MA to estimate the effect of SEM on autophagy. RESULTS: In vitro, SEM significantly inhibited extracellular matrix deposition, P2 × 7r-NLRP3, and inflammatory cytokines. SEM increased FXR and LXRα/ß expressions and decreased MAPLC3α/ß and P62 expressions, functioning as 3-MA (autophagy inhibitor). In vivo, SEM reduced serum transaminase, histopathology changes, fibrogenesis, autophagy markers and inflammatory cytokines caused by TAA. LX-2 were activated with conditioned medium from LPS-primed THP-1, which resulted in significant enhance of autophagy markers and inflammatory cytokines and decrease of FXR and LXRα/ß expressions. SEM could reverse above these changes and function as 3-MA, GW4064, or GW3965. Deficiency of FXR or LXR attenuated the regulation of SEM on α-SMA, MAPLC3α/ß, P62 and IL-1ß in activated LX-2. In activated THP-1, deficiency of FXR could decrease the expression of LXR, and vice versa. Deficiency of FXR or LXR in activated MΦ decreased the expressions of FXR and LXR in activated LX-2. Deficiency FXR or LXR in activated MΦ also attenuated the regulation of SEM on α-SMA, MAPLC3α/ß, P62, caspase-1 and IL-1ß. In vivo, SEM significantly reversed hepatic fibrosis via FXR/LXR and autophagy. CONCLUSION: SEM could regulate hepatic fibrosis by inhibiting fibrogenesis, autophagy and inflammation. FXR/LXR axis-mediated inhibition of autophagy contributed to the regulation of SEM against hepatic fibrosis, especially based on involving in the crosstalk of HSCs-macrophage. SEM might be a prospective therapeutic candidate, and its mechanism would be a new direction or strategy for hepatic fibrosis treatment.

BiVO4 Photoanodes Enhanced with Metal Phosphide Co-Catalysts: Relevant Properties to Boost Photoanode Performance.

Achieving highly performant photoanodes for oxygen evolution is key to developing photoelectrochemical devices for solar water splitting. In this work, BiVO4 photoanodes are enhanced with a series of core-shell structured bimetallic nickel-cobalt phosphides (MPs), and key insights into the role of co-catalysts are provided. The best BiVO4 /Ni1.5 Co0.5 P and BiVO4 /Ni0.5 Co1.5 P photoanodes achieve a 3.5-fold increase in photocurrent compared with bare BiVO4 . It is discovered that this enhanced performance arises from a synergy between work function, catalytic activity, and capacitive ability of the MPs. Distribution of relaxation times analysis reveals that the contact between the MPs, BiVO4 , and the electrolyte gives rise to three routes for hole injection into the electrolyte, all of which are significantly improved by the presence of a second metal cation in the co-catalyst. Kinetic studies demonstrate that the significantly improved interfacial charge injection is due to a lower charge-transfer resistance, enhanced oxygen-evolution reaction kinetics, and larger surface hole concentrations, providing deeper insights into the carrier dynamics in these photoanode/co-catalyst systems for their rational design.

Application of Micro-Percutaneous Nephrolithotomy (Micro-PCNL) combined with FURL in 1-2 cm symptomatic, refractory lower calyceal stones.

Objective: To investigate the safety and efficacy of Micro-Percutaneous Nephrolithotomy (Micro-PCNL) combined with flexible ureteroscopic lithotomy (FURL) in the treatment of 1-2 cm symptomatic, refractory lower calyceal stones. Methods: A retrospective analysis was performed concerning the clinical data of 28 patients with 1-2 cm symptomatic, refractory lower calyceal stones. When there was a difficulty in performing FURL in Affiliated Hospital of Hebei University from January 2019 to February 2022, ultrasound-guided F4.8 visual puncture was performed on the lower calyceal stone,with a holmium laser was then used to treat the remaining stones, followed by drainage using a flexible ureteroscopic sheath and postoperative indwelling of the ureteral stent without a nephrostomy tube. The surgery time, intraoperative bleeding and stone-free rate(SFR) were recorded, and the VAS score was used to evaluate the patients' pain status. Results: The surgery was completed successfully in an average of 43.46 ± 10.04 minutes, and the puncture time was 3.46 ± 0.69 minutes. The SFR was 85.71%(24/28) and 92.86%(26/28) at one day and 30 days after surgery, respectively. Two patients with residual stones greater than 0.6 cm in size underwent extracorporeal shock wave lithotripsy four weeks after surgery. Patients were followed up for three months after surgery, and the SFR was revised to 96.43%(27/28). In addition, the VAS scores of all patients decreased significantly from before to after surgery, and the difference was statistically significant(p< 0.05). Conclusion: Micro-Percutaneous Nephrolithotomy (Micro-PCNL) combined with FURL is safe and effective in the treatment of 1-2 cm symptomatic, refractory lower calyceal stones.

Can vitamin B6 alleviate the adverse reactions of quadruple anti-Helicobacter pylori regimen? : randomized controlled trial.

BACKGROUND: Vitamin B6 is an essential water-soluble vitamin for humans. It is often used to prevent a variety of neuropathies, relieve vomiting, and relieve symptoms such as hand and foot neuritis. AIM: To evaluate whether vitamin B6 can alleviate the adverse reactions caused by the quadruple anti-Helicobacter pylori treatment regimen containing minocycline and metronidazole. METHODS: In this randomized controlled trial, 280 patients with H. pylori infection were randomly placed into one of two treatment groups-the conventional treatment group and the vitamin B6 supplement treatment group-for 2 weeks. The primary endpoint was the total incidence of adverse reactions up to 2 weeks after treatment initiation. The study was designed according to CONSORT Medicinal Interventions. And it was registered with Chinese Clinical Trial Registry under the number ChiCTR2100053833. RESULTS: In terms of efficacy, vitamin B6 does not affect the efficacy of conventional regimen. In the vitamin B6 supplement treatment group, the incidence of adverse reactions was 56.92%, which was significantly lower than the 74.62% observed in the conventional treatment group. In addition, the severity of adverse reactions was also significantly reduced. The proportion of moderate to severe central nervous system symptoms decreased from 58.7 to 14.63%. And, the proportion of moderate to severe gastrointestinal reactions decreased from 33.33 to 0%. We speculate that the mechanism of vitamin B6 of reducing adverse reaction may be related to the production of GABA in the brain. CONCLUSIONS: Vitamin B6 can alleviate adverse reactions of the quadruple anti-H. pylori regimen containing minocycline and metronidazole.

Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways.

Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 µM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1ß and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.

Preparation of water-dispersed monolayer LDH nanosheets by SMA intercalation to hinder the restacking upon redispersion in water.

We present a novel method for preparing water-dispersed monolayer layered double hydroxide (LDH) nanosheets (m-LDH). By intercalating styrene-maleic anhydride copolymer (SMA) into LDH, we obtained m-LDH through a simple aging step that produced stable, translucent colloidal solutions. After drying, the resulting powder can be redispersed in water to recover the m-LDH monolayer structure. To our knowledge, this is the first report of immediate recovery of the m-LDH monolayer structure from dried powder after redispersion in water. Our method may have significant implications for preparing and utilizing m-LDH nanosheets in various applications.

The therapeutic and prognostic role of cuproptosis-related genes in triple negative breast cancer.

BACKGROUND: This study aimed to observe the potential impact of known cuproptosis-related genes (CRGs) on triple negative breast cancer (TNBC) development, as well as their associated molecular mechanisms, immune infiltration mechanisms and potential therapeutic agents. RESULTS: Based on the Cox Proportional Hazard Model, 11 CRGs may be especially important in TNBC development and progression (considered as the Key-TNBC-CRGs). The expression of several Key-TNBC-CRGs (e.g., ATP7A, PIK3CA, LIAS, and LIPT) are associated with common mutations. The SCNA variation of 11 Key-TNBC-CRGs are related to differences immune infiltration profiles. In particular, depletion of ATP7A, ATP7B, CLS, LIAS, and SCL31A1 and while high amplification of NLRP3 and LIPT2 are correlated with decreased immune infiltration. In our Cox proportional hazards regression model, there is a significant difference in the overall survival between high-risk and low-risk groups. The HR in the high-risk group is 3.891 versus the low-risk group. And this model has a satisfactory performance in Prediction of 5-15-year survival, in particular in the 10-year survival (AUC = 0.836). Finally, we discovered some potential drugs for TNBC treatment based on the strategy of targeting 11 Key-TNBC-CRGs, such as Dasatinib combined with ABT-737, Erastin or Methotrexate, and Docetaxel/Ispinesib combination. CONCLUSION: In conclusion, CRGs may play important roles in TNBC development, and they can impact tumor immune microenvironment and patient survival. The Key-TNBC-CRGs interact mutually and can be influenced by common BC-related mutations. Additionally, we established a 11-gene risk model with a robust performance in prediction of 5-15-year survival. As well, some new drugs are proposed potentially effective in TNBC based on the CRG strategy.

A modified triangular Double-J stent for retrograde intrarenal surgery improvement of free-stone rate, and quality of life: a randomized controlled, multiple centers, perspective trial.

PURPOSE: The goal of this study is to evaluate the efficacy and safety of modified triangular double-J (DJ) stent in 1-2 cm renal or ureter calculi after retrograde intrarenal surgery (RIRS) via a randomized, controlled clinical study. METHODS: A total of 196 patients with 1-2 cm renal or ureter calculi who were performed RIRS and received 7Fr modified triangular DJ stents (100 cases) or 6Fr normal DJ stents (96 cases). All operations were performed by experienced surgeons. The clinical characteristics and outcomes were analyzed. RESULTS: There were no significant differences between two groups in terms of age, gender, BMI, location, hydronephrosis, urea WBC, urea RBC, BUN, Cr, laser emission time, operation time, Hb loss, postoperative BUN, postoperative Cr. Patients who received modified triangular DJ stents were shown to have higher stone-free rate (p = 0.038), but lower general health (p = 0.004). CONCLUSION: The modified triangular 7Fr DJ stents were more efficient for patients underwent RIRS than 6Fr normal DJ stents.

Demulsifier-Inspired Superhydrophilic/Underwater Superoleophobic Membrane Modified with Polyoxypropylene Polyoxyethylene Block Polymer for Enhanced Oil/Water Separation Properties.

Demulsifiers are considered the key materials for oil/water separation. Various works in recent years have shown that demulsifiers with polyoxypropylen epolyoxyethylene branched structures possess better demulsification effects. In this work, inspired by the chemical structure of demulsifiers, a novel superhydrophilic/underwater superoleophobic membrane modified with a polyoxypropylene polyoxyethylene block polymer was fabricated for enhanced separation of O/W emulsion. First, a typical polyoxypropylene polyoxyethylene triblock polymer (Pluronic F127) was grafted onto the poly styrene-maleic anhydride (SMA). Then, the Pluronic F127-grafted SMA (abbreviated as F127@SMA) was blended with polyvinylidene fluoride (PVDF) for the preparation of the F127@SMA/PVDF ultrafiltration membrane. The obtained F127@SMA/PVDF ultrafiltration membrane displayed superhydrophilic/underwater superoleophobic properties, with a water contact angle of 0° and an underwater oil contact angle (UOCA) higher than 150° for various oils. Moreover, it had excellent separation efficiency for SDS-stabilized emulsions, even when the oil being emulsified was crude oil. The oil removal efficiency was greater than 99.1%, and the flux was up to 272.4 L·m-2·h-1. Most importantly, the proposed F127@SMA/PVDF membrane also exhibited outstanding reusability and long-term stability. Its UOCA remained higher than 150° in harsh acidic, alkaline, and high-salt circumstances. Overall, the present work proposed an environmentally friendly and convenient approach for the development of practical oil/water separation membranes.

Effect of Hypertension on EPR effect Induced by Polymer Nanomicelles in Renal Cell Carcinoma in vitro.

Objective: To investigate the effect of hypertension on the (enhanced permeability and retention, EPR) effect induced by polymer nanomicelles in renal cell carcinoma in vitro. Methods: A total of 80 patients with renal cell carcinoma treated at the Department of Urology Surgery in the Dept. of Urology of the Affiliated Hospital of Hebei University from Oct. 2019 to Oct. 2020, were analyzed retrospectively. The hypertension group (experimental group) included 40 patients, and the normal blood pressure group (control group) included 40 patients. The diagnosis of renal clear cell carcinoma was confirmed by preoperative auxiliary examinations, such as ultrasonography and CT combined with postoperative pathological analysis. All patients underwent laparoscopic radical nephrectomy for renal cell carcinoma. Polymer nanomicelles (loaded with prolonium iodide) were perfused into the resected kidney specimens within the specified time. The iodine enrichment of polymer nanomicelles in renal tumors was assessed by CT scanning. The peak EPR effect and the time to the peak were statistically compared between the two groups. Results: No significant differences were found in age, sex, location of kidney disease, tumor location or tumor size between the two groups (p> 0.05). The peak (χ̄±S) of the EPR effect in experimental group was 3.60±0.95 ug/cm3 and 3.01±0.96 ug/cm3 in control group, respectively. There was significant difference between the two groups (p< 0.05). The time to the peak of the EPR effect was 3.76±0.75 h in experimental group and 3.82±0.93 hour in control group, respectively. No statistically significant difference was found in the time to the peak of the EPR effect between the two groups (p> 0.05). Conclusion: Hypertension has a certain effect on the EPR effect induced by polymer nanomicelles in renal cell carcinoma in vitro.

The impact of Helicobacter pylori infection and eradication therapy containing minocycline and metronidazole on intestinal microbiota.

BACKGROUND: Helicobacter pylori (H. pylori) infection is associated with remodeling of gut microbiota. Many studies have found H. pylori infection and eradication therapy can alter the gut microbiota. However, few studies explored the impact of eradication therapy containing minocycline and metronidazole on gut microbiota. AIM: The objective of the present study was to explore the changes of gut microbiota after H. pylori infection. Besides, learn more about the dynamic changes of gut microbiota during different stages of eradication treatment containing minocycline, metronidazole, bismuth agents and proton pump inhibitors. METHODS: Sixty stool samples from the patients with H. pylori infection before eradication, 14 and 42 days after eradication, and ten stool samples from non-infected individuals were collected. Subsequently, we performed 16S rRNA gene amplicon sequencing to analyze these samples, and the results were evaluated by using alpha diversity, beta diversity and microbial composition analyses. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was also used to predict the metabolic pathways according to the Kyoto Encyclopedia of Genes and Genomes database. RESULTS: The alpha and beta diversity of the microbiota changed significantly in H. pylori infected individuals, but returned to baseline 42 days after eradication therapy. At the genus level, the abundances of Bacteroidetes, [Ruminococcus]_gnavus_group, Ruminococcaceae_Incertae_Sedis, Tuzzrealla, Butyricicoccus were significantly lower in the H. pylori infected group. Bacterial abundance was also dynamically changing during eradication treatment. In addition, PICRUST analysis found the levels of uronic acid metabolism, uncharacterized transport system, and biosynthesis of unsaturated fatty acids were higher in H. pylori infected individuals than in the non-infected group. CONCLUSIONS: Intestinal microbiota diversity, composition, functional predictions altered significantly after H. pylori infection, and gradually returned to healthy control levels after the application of eradication therapy containing minocycline and metronidazole in one month and a half.

Pueraria montana (Kudzu vine) Ameliorate the Inflammation and Oxidative Stress against Fe-NTA Induced Renal Cancer.

Renal tissue plays a crucial function in maintaining homeostasis, making it vulnerable to xenobiotic toxicity. Pueraria montana has more beneficial potential against the various diseases and has long history used as a traditional Chinese medicine. But its effect against the renal cancer not scrutinize. The goal of this study is to see if Pueraria montana can protect rats from developing kidney tumors caused by diethylnitrosamine (DEN) and ferric nitrite (Fe-NTA). Wistar rats was selected for the current study and DEN (use as an inducer) and Fe-NTA (promoter) for induction the renal cancer. For 22 weeks, the rats were given orally Pueraria montana (12.5, 25, and 50 mg/kg) treatment. At regular intervals, the body weight and food intake were calculated. The rats were macroscopically evaluated for identification of cancer in the renal tissue. The renal tumor makers, renal parameters, antioxidant enzymes, phase I and II enzymes, inflammatory cytokines and mediators were estimated at end of the experimental study. Pueraria montana treated rats displayed the suppression of renal tumors, incidence of the tumors along with suppression of tumor percentage. Pueraria montana treated rats significantly (p < 0.001) increased body weight and suppressed the renal weight and food intake. It also reduced the level of renal tumor marker ornithine decarboxylase (ODC) and [3H] thymidine incorporation along with suppression of renal parameter such as uric acid, blood urea nitrogen (BUN), urea and creatinine. Pueraria montana treatment significantly (p < 0.001) altered the level of phase enzymes and antioxidant. Pueraria montana treatment significantly (p < 0.001) repressed the level of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and improved the level of interleukin-10 (IL-10). Pueraria montana treatment suppressed the level of prostaglandin (PGE2), cyclooxygenase-2 (COX-2), nuclear kappa B factor (NF-κB) and transforming growth factor beta 1 (TGF-ß1). Pueraria montana suppressed the inflammatory necrosis, size the bowman capsules in the renal histopathology. Pueraria montana exhibited the chemoprotective effect via dual mechanism such as suppression of inflammatory reaction and oxidative stress.

Acanthoic acid, unique potential pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae): A review on its pharmacology, molecular mechanism, and structural modification.

Acanthoic acid (AA) is a pimaradiene diterpene isolated from the root bark of Acanthopanax koreanum Nakai (Araliaceae) with a wide range of pharmacological activities, including anti-cancer, anti-inflammatory, anti-diabetes, liver protection, gastrointestinal protection, and cardiovascular protection. In addition, AA promotes its pharmacological effects by targeting liver X receptors (LXRs), nuclear factor-kappa B (NF-κB), Toll-Like Receptor 4 (TLR4) and IL-1 receptor-associated kinase (IRAK) signaling pathways, or AMP-activated protein kinase (AMPK) signaling pathway, etc. Also, some studies focus on the structural modification of AA to improve its pharmacological activities. The review summarizes the pharmacological activities, molecular mechanism, and the structural modification of AA, which might supply information for the development of AA in the future.

Modulation of interleukin-36 based inflammatory feedback loop through the hepatocyte-derived IL-36R-P2X7R axis improves steatosis in alcoholic steatohepatitis.

BACKGROUND AND PURPOSE: Interleukin-36 is induced by proinflammatory cytokines and promotes inflammatory responses, creating an IL-36-based inflammation loop. Although hepatocytes, produce IL-36 responses to drug-induced liver injury, little is known about the mechanistic role of IL-36 signalling during the progression of alcoholic steatohepatitis (ASH). Regarding IL-36/IL-36R and P2X7R coregulating the inflammatory response, we elucidated that modulation of IL-36R-P2X7R-TLR axis affected hepatocyte steatosis as well as the IL-36-based inflammatory feedback loop that accompanies the onset of ASH. EXPERIMENTAL APPROACH: C57BL/6J mice were subjected to either chronic-plus-binge ethanol feeding or acute gavage with multiple doses of ethanol to establish ASH, followed by pharmacological inhibition or genetic silencing of IL-36R and P2X7R. AML12 cells or mouse primary hepatocytes were stimulated with alcohol, LPS plus ATP or Poly(I:C) plus ATP, followed by silencing of IL-36γ, IL-36R or P2X7R. KEY RESULTS: P2X7R and IL-36R deficiency blocked the inflammatory loop, specifically initiated by IL-36 cytokines, in hepatocytes of mice suffering from ASH. Pharmacological inhibition to P2X7R or IL-36R alleviated lipid accumulation and inflammatory response in ASH. IL-36R was indispensable for P2X7R modulated NLRP3 inflammasome activation in ASH, and IL-36 led to a vicious cycle of P2X7R-driven inflammation in alcohol-treated hepatocytes. TLR ligands promoted IL-36γ production in hepatocytes, based on synergism with P2X7R. CONCLUSIONS AND IMPLICATIONS: Blockade of IL-36 based inflammatory feedback loop, via IL-36R-P2X7R-TLRs-modulated NLRP3 inflammasome activation, circumvented steatosis and inflammation that accompanies the onset of ASH, suggesting that targeting IL-36 can serve as a novel therapeutic approach to combat ASH.

Protective role of Siberian onions against toxin-induced liver dysfunction: an insight into health-promoting effects.

Siberian onions (SOs) are delicious wild vegetables. Their taste is most unique, not only like scallions but also like leeks or garlic. They also have a traditional medicinal value for anti-inflammation, anti-oxidation, and anti-pyretic analgesia, particularly facilitating hepatoprotective effects. The current study investigates the potential mechanism of SOs against toxin-induced liver dysfunction. BALB/c mice were administrated with SO or silymarin by oral gavage for one week, followed by injecting carbon tetrachloride (CCl4) to induce hepatic fibrosis. The effect of SO against hepatic fibrosis was evaluated by examining the liver tissue for serum transaminase, oxidative stress, extracellular matrix, histological alterations, cytokine levels, and apoptosis. In vitro, HSC-T6 cells were cultured with the supernatant from Raw 264.7 cells stimulated with lipopolysaccharides, followed by SO extracts or Niclosamide (Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor) at indicated time periods and doses. SO decreased serum transaminase levels and oxidative stress, and regulated the balance of ECM in CCl4-induced mice, including α-SMA, collagen-I and TIMP-1. SO reduced the release of inflammatory factors and regulated apoptosis-associated proteins, which is related to the inhibition of STAT3 phosphorylation. Moreover, SO reduced the positive expressions of α-SMA and NLRP3 by inhibiting STAT3 phosphorylation in activated HSCs. SO could show health-promoting effects for liver dysfunction by alleviating hepatic fibrogenesis, apoptosis and inflammation in the development of hepatic fibrosis potential depending on the STAT3 signaling pathway.

Circ_0037866 Contributes to the Tumorigenesis of Renal Cell Carcinoma by Sequestering miR-384 to Elevate Chromobox 5 Expression.

BACKGROUND: Circular RNAs (circRNAs) were demonstrated to have roles in the carcinogenesis of renal cell carcinoma (RCC). Hence, this work aimed to determine the functions and molecular mechanism of circ_0037866 in regulating the progression of RCC. METHODS: Quantitative real-time polymerase chain reaction and Western blotting were used to detect the levels of genes and proteins. In vitro assays, including colony formation, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell assays, and in vivo tumor formation, were conducted to investigate the effects of circ_0037866 on RCC tumorigenesis. Dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation assay were used to confirm the interaction between miR-384 and circ_0037866 or Chromobox 5 (CBX5). RESULTS: Circ_0037866 is a stable circRNA and was found to be increased in RCC tissues and cells. Functionally, circ_0037866 silencing suppressed RCC cell survival, invasion, and migration in vitro, and impeded RCC cell tumorigenesis in the subcutaneous xenograft model. Mechanistically, circ_0037866 could function as a sponge for miR-384 to elevate the expression of its target CBX5. Furthermore, a series of rescue experiments showed that miR-384 inhibition reversed the anticancer effects of circ_0037866 knockdown on RCC cells; besides that, miR-384 restoration suppressed RCC cell growth and mobility, which were attenuated by CBX5 overexpression. CONCLUSION: Circ_0037866 knockdown restrains the tumorigenesis of RCC by miR-384/CBX5, revealing a promising molecular target for RCC therapy.