LRRK2 is involved in heat exposure-induced acute lung injury and alveolar type II epithelial cell dysfunction.

Heat exposure induces excessive hyperthermia associated with systemic inflammatory response that leads to multiple organ dysfunction including acute lung injury. However, how heat impairs the lung remains elusive so far. We aimed to explore the underlying mechanism by focusing on leucine-rich repeat kinase 2 (LRRK2), which was associated with lung homeostasis. Both in vivo and in vitro models were induced by heat exposure. Firstly, heat exposure exerted core temperature (Tc) disturbance, pulmonary dysfunction, atelectasis, inflammation, impaired energy metabolism, and reduced surfactant proteins in the lung of mice. In addition, decreased LRRK2 expression and increased heat shock proteins (HSPs) 70 were observed with heat exposure in both the lung of mice and alveolar type II epithelial cells (AT2). Furthermore, LRRK2 inhibition aggravated heat exposure-initiated Tc dysregulation, injury in the lung and AT2 cells, and enhanced HSP70 expression. In conclusion, LRRK2 is involved in heat-induced acute lung injury and AT2 cell dysfunction.

Unveiling the Therapeutic Potential of Herba Epimedii: Enhancing Bone Healing Through Cytoskeletal Regulation of RhoA/Rock1 Pathway.

Herba Epimedii is widely used to promote bone healing, and their active ingredients are total flavonoids of Epimedium (TFE). Ras homolog gene family member A / Rho-associated protein kinase (RhoA/Rock), an important pathway regulating the cytoskeleton, has been proven to affect bone formation. However, whether TFE promotes bone healing via this pathway remains unclear. In this study, the therapeutic effects of TFE were estimated using micro-computed tomography and hematoxylin and eosin staining of pathological sections. F-actin in osteoblasts was stained to investigate the protective effects of TFE on the cytoskeleton. Its regulatory effects on the RhoA/Rock1 pathway were explored using RT-qPCR and Western blot analysis. Besides, flow cytometry, alkaline phosphatase and nodule calcification staining were performed to evaluate the effects on osteogenesis. The bone healing in rats was improved, the cytoskeletal damage in osteoblasts was reduced, the RhoA/Rock1 pathway was downregulated, and osteogenesis was enhanced after TFE treatment. Thus, TFE can promote bone formation at least partially by regulating the expression of key genes and proteins in the cytoskeleton. The findings of this study provided evidence for clinical applications and would contribute to a better understanding of Epimedium's mechanisms in treating bone defects.

HER2-positive advanced biliary tract cancer responds to second-line pyrotinib therapy: a case report.

Biliary tract cancers are solid tumors with poor prognosis and over 70% of patients present in advanced stages. The efficacy of second-line treatment for patients who progressed on GC chemotherapy is limited. Median OS of these patients is less than 1 year with palliative treatment. Despite the success of anti-HER2 therapy in HER2-positive breast cancer, the targeted therapy of HER2 mutations in BTCs is still being explored. This case report is the first report suggesting a 15-month PFS and partial response of pyrotinib in HER2-positive BTC. We report a 64-year-old female with HER2-positive biliary tract cancer. She was diagnosed with AJCC clinical stage IV (cT3N1M1) intrahepatic biliary tract cancer and got PD after 3 cycles of systemic chemotherapy of gemcitabine plus cisplatin. Due to the HER2-positive signature, pyrotinib (400 mg daily in 21-day cycles), an oral irreversible pan-ErbB TKI was prescribed in September 2021, with her informed consent. The tumor shrank significantly after this treatment and imaging assessments conducted on 24 September 2022 showed PR. Until the writing of the case draft, the patient had achieved 15 months of PFS. The present case suggests that Pyrotinib might be a potential effective treatment for HER2-positive advanced BTC.

Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL-33/ST2 axis.

Lupus nephritis (LN) is a type of immune-complex nephritis caused by systemic lupus erythematosus and is a major contributor to mortality and morbidity. Honokiol (HNK) has been found to have a therapeutic effect on LN, but its action mechanism remains unclear. In this study, we first demonstrated that HNK attenuates kidney injury in MRL/lpr mice. Results from RNA sequencing combined with ingenuity pathway analysis suggested that HNK plays an anti-LN role through inhibition of the NLRP3 inflammasome and IL33. GEO chip data, single-cell data, and clinical samples from LN patients demonstrated that the pyroptosis and IL-33/ST2 pathways are abnormally activated during the stage of LN. In vivo, similar to the results of the AAV-mediated NLRP3 shRNA MRL/lpr model, HNK downregulated serum and renal IL-33 levels, and suppressed NLRP3 inflammasome and the IL-33/ST2 axis in the kidney. In vitro, co-culturing NLRP3-overexpressing or IL-33 knocked-down rat renal macrophages with NRK-52E cells confirmed that NLRP3 activation in resident macrophages directly upregulates IL-33, which in turn mediates the IL-33/ST2/NF-κB pathway to promote the inflammatory response of renal tubular epithelial cells. Furthermore, a molecular docking model and surface plasmon resonance analysis were utilized to demonstrate a direct interaction between HNK and NLRP3. In conclusion, this study provides a novel anti-LN treatment strategy in which HNK plays a preventive and therapeutic role against LN by suppressing the abnormal crosstalk between renal resident macrophages and renal tubular epithelial cells by inhibiting the activation of the NLRP3/IL-33/ST2 axis.

Fabrication, Characterization and In Planta Uptake of Engineered Surfactant Nanovesicles for the Delivery of the Biostimulant Sodium Copper Chlorophyllin.

Effective delivery of agrochemicals requires control over bioactive release kinetics coupled with effective penetration of the bioactive into plants. Herein, we demonstrate the fabrication of hybrid nanovesicles based on sodium dodecylbenzenesulfonate (SDBS) and cetyltrimethylammonium bromide (CTAB) for enabling effective delivery of the biostimulant sodium copper chlorophyllin (Cu-chl) into plants. SDBS-CTAB nanovesicles exhibited a particle size of 107 nm with a well-defined spherical morphology, while modified formulations that included small fractions of the unsaturated dopant Span 80 yielded larger nanovesicles that were softer and more irregular in shape. All nanovesicles maintained high colloidal stability over >4 weeks and enabled sustained Cu-chl release, with the incorporation of Span 80 into the membranes enabling controllable acceleration of the release rate. Nanovesicle encapsulation improved the photostability of Cu-chl bioactive 3-4 × relative to that of free Cu-chl and enabled significant penetration of Cu-chl into the plant root without inducing any significant phytotoxicity.

Chang qing formula ameliorates colitis-associated colorectal cancer via suppressing IL-17/NF-κB/STAT3 pathway in mice as revealed by network pharmacology study.

Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer (CRC) with high mortality and morbidity, the chronic inflammation in the intestinal mucosal is the characteristic of CAC. Chang Qing formula (CQF) is a Chinese herbal formula used clinically for the treatment of CAC with remarkable clinical efficacy, but its mechanism remains unclear. In the present work, Combined network pharmacology and transcriptomics were used to analyze the potential active ingredients and elucidate molecular mechanism of CQF in treating CAC. Firstly, the constituents migrating to blood of CQF were analyzed and identified by UPLC-Q-TOF-MS/MS, and core genes and pathways were screened by network pharmacology analysis. Encyclopedia of Genes and Genomes (KEGG) analysis showed that the IL-17 signaling pathway involved in CAC may be closely associated with the potential mechanismof action of CQF. Subsequently, the results from animal studies indicated that CQF profoundly reduced tumor numbers and tumor size in AOM/DSS mice. The RNA-seq data was analysed utilizing Ingenuity Pathway Analysis (IPA), and the results supported the idea that CQF exerts a tumour-suppressive effect via the IL-17 signalling pathway. Further studies demonstrated that CQF significantly reduced IL-17A levels, which in turn inhibited NF-κB/IL-6/STAT3 signaling cascade, suppressed MMP9 expression and promoted tumor cell apoptosis. In conclusion, the current study demonstrated that CQF remarkably improved inflammatory tumor microenvironment, and hindered the transformation of inflammation into cancer. These findings may help to design future strategies for the treatment of CAC.

Investigating the Mechanisms of Jieduquyuziyin Prescription Improves Lupus Nephritis and Fibrosis via FXR in MRL/lpr Mice.

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE) and one of the leading causes of death. An alternative effective treatment to ameliorate and relieve LN and delay the process of renal tissue fibrosis is urgently needed in the clinical setting. Jieduquyuziyin prescription (JP) has been successfully used to treat SLE, but its potential mechanisms are not sufficiently understood. In this study, we treated MRL/lpr mice with JP for 8 weeks and treated human renal tubular epithelial cells (human kidney 2 (HK-2)) with drug-containing serum to observe the antagonistic effects of JP on inflammation and fibrosis, as well as to investigate the possible mechanisms. Results demonstrated that JP significantly reduced urinary protein and significantly improved pathological abnormalities. Metabolomics combined with ingenuity pathway analysis illustrated that the process of kidney injury in lupus mice may be closely related to farnesoid X receptor (FXR) pathway abnormalities. Microarray biomimetic analysis and LN patients indicated that FXR may play a protective role as an effective therapeutic target for LN and renal fibrosis. JP significantly increased the expression of FXR and inhibited the expression of its downstream targets, namely, nuclear transcription factor κB (NF-κB) and α-smooth muscle actin (α-SMA), in the kidney of MRL/lpr mice and HK-2 cells, as confirmed by in vitro and in vivo experiments. In conclusion, JP may mediate the activation of renal FXR expression and inhibit NF-κB and α-SMA expression to exert anti-inflammatory and antifibrotic effects for LN prevention and treatment.

Expression and Predictive Value of Serum NLR, PLR Combined with SAA in Patients with Different Stages of Colorectal Cancer.

Colorectal cancer (CRC) is one of the major causes of death in the world, and has become a serious threat to human life. The prognosis of CRC patients in different pathological stages is quite different, so it is necessary to evaluate the clinical stages of CRC patients before surgery. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), serum amyloid A (SAA) and other indicators have been widely proved to play the role of early diagnosis and prognosis monitoring in chronic inflammatory diseases and cancers. In this study, we collected clinical data of 103 patients with CRC confirmed by pathology in Yiwu Central Hospital from January 2019 to December 2021. In addition, it aims to explore the expression and predictive value of NLR, PLR combined with SAA in patients with different stages of CRC, so as to provide reference for patients to choose a reasonable treatment plan. The results show that serum NLR, PLR combined with SAA can predict CRC staging effectively, which has certain auxiliary value for clinical decision-making.

Inoscavin A, a pyrone compound isolated from a Sanghuangporus vaninii extract, inhibits colon cancer cell growth and induces cell apoptosis via the hedgehog signaling pathway.

BACKGROUND: Sanghuangporus vaninii, a large precious medicinal fungus called Sanghuang in China, has significant antitumor activity. We previously reported that a Sanghuangporus vaninii extract could lead to apoptosis in HT-29 cells through the intrinsic apoptotic pathway. We further found that Inoscavin A exhibited anti-colon cancer activity, but its specific mechanisms have not been fully elucidated. METHODS: Inoscavin A was obtained from Sanghuangporus vaninii by the classic phytochemical separation technology. The male BALB/c nude mice were injected with HT-29 colon cancer cells as animal model. In order to observe the pathological changes of tumor section, the hematoxylin-eosin(H&E) staining was applied in the histological analysis. Metabolomics was utilized for the investigation of the overall changes of serum metabolites in animal model, and the potential targets of Inoscavin A were analyzed by Ingenuity Pathway Analysis (IPA). We further employed a molecular docking approach to predict the degree of combination of Inoscavin A and Smo. Then we further performed Western blotting and immunofluorescence analysis to investigate the expression of proteins involved in Hh-related pathways in tumor tissues. In addition, the colony formation assay, scratch-wound assay and transwell migration and invasion assay were conducted to evaluate the anti-colon-cancer activity of Inoscavin A. Concurrently, the mitochondrial membrane potential assay and TUNEL apoptosis assay were detected to demonstrate the effect of Inoscavin A on promoting HT-29 cells apoptosis. Western blot experiments verified the anti-tumor effects of Inoscavin A were modulated the protein expression of Shh, Ptch1, Smo and Gli1 in HT-29 cells. RESULTS: We showed that Inoscavin A, a pyrone compound isolated from the Sanghuangporus vaninii extract, exerted its antitumor activity in an HT-29 colon cancer cell xenograft mouse model. Subsequently, we first time prove that the antitumor effects of Inoscavin A were related to the hedgehog (Hh) signaling pathway. Furthermore, we demonstrated that Smo, the core receptor of the Hh pathway, was critical for the induction of apoptosis of Inoscavin A and that overexpression of this target could significantly rescue cell apoptosis induced by Inoscavin A treatment. CONCLUSION: Thus, our studies first propose that the natural outgrowth Inoscavin A exerted its anti-cancer effects by inhibiting Smo to suppress the activity of the Hh pathway though inhibiting cell proliferation and promoting apoptosis. These findings further indicate that Inoscavin A will be expected to be a prospective remedical compound for the treatment of colon cancer.

Unraveling metabolic alterations in transgenic mouse model of Alzheimer's disease using MALDI MS imaging with 4-aminocinnoline-3-carboxamide matrix.

Revealing the metabolic abnormalities of central and peripheral systems in Alzheimer's disease (AD) mouse model is of paramount importance for understanding AD disease. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is a powerful label-free technique that has been extensively utilized for the interrogation of spatial changes of various metabolites in neurodegenerative disease. However, technical limitations still exist in MALDI MS, and there is a need to improve the performance of traditional MALDI for a deeper investigation of metabolic alterations in the AD mouse model. In this work, 4-aminocinnoline-3-carboxamide (4-AC) was developed into a novel dual-polarity MALDI matrix. Compared with traditionally used MALDI matrices such as 2,5-dihydroxybenzoic acid (DHB) and 9-aminoacridine (9-AA), 4-AC exhibited superior performance in UV absorption at 355 nm, ion yields, background interference, and vacuum stability, making it an ideal MALDI matrix for comprehensive evaluation of metabolic alteration in the brain and serum of APP/PS1 transgenic mouse model of AD. In total, 93 metabolites exhibited different levels of regional changes in the brain of AD mice as compared to the age-matched controls. Moreover, in the serum of AD mice, 81 altered metabolites distinguishing the AD group from the control were observed by using multivariate statistical analysis. It is expected that the application of the MALDI MSI method developed in this work to visualize the spatio-chemical change of various metabolites may improve our understanding of the etiopathogenesis of AD.

Erxian herbal pair enhances bone formation in infected bone nonunion models and attenuates lipopolysaccharide-induced osteoblastinhibition by regulating miRNA-34a-5p.

Bacterium-induced inflammatory responses cause bone nonunion. Although antibiotics suppress infection, bone loss after antibacterial treatment remains a critical challenge. Erxian herbal pair (EHP) has been proven effective in promoting bone formation. Our study aimed to investigate the effect of EHP on bone repair after anti-infection treatment, explore its effect on a lipopolysaccharide (LPS)-induced osteoblast. We evaluated effects of EHP on bone repair with Micro-CT, and morphology detecting. Chemical constituents of EHP and EHP-containing serum (EHP-CS) were identified by UHPLC-Q/TOF-MS. In addition, osteoblast induced by LPS was established and administrated with EHP-CS. Cell proliferationwas assessed by MTT. Target prediction identified SMAD2 as a potential target of miRNA-34a-5p. MiRNA mimic, inhibitor and siRNA were transiently transfected into osteoblasts. The mRNA levels and protein expressions of miRNA-34a-5p, BMP2, Runx2, SMAD2 were assessed. The results showed that the main biocactivity ingredients in EHP-CS were Baohuoside Ι and Orcinol Glucoside. EHP could promote bone remolding after anti-infection therapy and restore the activity of LPS-induced osteoblasts. Moreover, miRNA-34a-5p was dramatically downregulated and SMAD2 was upregulated after LPS stimulation, while EHP resisted the inhibition of LPS by promoting miRNA-34a-5p, ALP, and BMP2 expressions. Whereas downregulation of miRNA-34a-5p reversed these effects. Silencing endogenous SMAD2 expression markedly promoted BMP2 and ALP activity and enhanced osteogenesis. Taken together, EHP restored LPS-induced bone loss by regulating miRNA-34a-5p levels and repressing its target gene SMAD2. EHP might be a potential adjuvant herbal remedy for the treatment of bone nonunion, and miRNA-34a-5p is a novel target for controlling bone and metabolic diseases.

Prediction of allergic reaction risk of Shenmai injection based on real-world evidence coupled with UPLC-Q-TOF-MS.

The allergic reaction (AR) of Chinese herbal injection (CHI) has become one of the most noticeable focuses of public health in China. However, it still remains a considerable controversy as to whether low-molecular-weight components in CHI have potential sensitization. In this study, the relationship between AR and low-molecular-weight component profile of Shenmai injection was explored by an interdisciplinary technology integrating real-world evidence and ultra-performance liquid chromatography-quadrupole time-of-flight mass spectroscopy (UPLC-Q-TOF-MS). The AR information of hospitalized patients was obtained by comprehensively analyzing real-world evidence from January 2015 to June 2019 at two Chinese hospitals. The UPLC-Q-TOF-MS was exploited to systematically investigate the low-molecular-weight component profile with 50-1500 m/z mass range, and 3725 MS1 peaks were detected. The optimized partial least squares discriminant analysis model was established to map the influence of low-molecular-weight components on AR. The results of this study showed that high levels of organic acids administered intravenously might be a potential risk factor for inducing AR. By using this method, Shenmai injection with high AR risk could be recognized precisely with 100% accuracy before clinical use.

Association of long-chain non-coding RNA GAS5 gene polymorphisms with prostate cancer risk and prognosis in Chinese Han population.

BACKGROUND: To investigate the correlation between growth arrest-specific transcript 5 (GAS5) gene polymorphism and the risk and prognosis of prostate cancer in Chinese Han population. METHODS: Sanger sequencing was used to analyze genotypes at the rs17359906 and rs1951625 loci of the GAS5 gene in 218 prostate cancer patients and 220 healthy controls. The follow-up period was from August 2016 to August 2019, and the relationships between GAS5 gene polymorphisms at the rs17359906 and rs1951625 loci and the recurrence-free survival rate of prostate cancer patients were analyzed. RESULTS: GAS5 A-allele carriers at the rs17359906 locus were 3.44 times more likely to develop prostate cancer than G-allele carriers (95% confidence interval (CI): 2.38-4.96, P < .001). Carriers of the GAS5 A allele at the rs1951625 locus had a 1.40-fold higher risk of prostate cancer than carriers of the G allele (95% CI: 1.05-1.86, P = .027). Plasma prostate-specific antigen (PSA), body mass index (BMI), and rs17359906 and rs1951625 loci were independent risk factors for prostate cancer. GAS5 AA genotype and A-allele carriers (GA + AA) at the rs1951625 locus were significantly correlated with Gleason scores ≤7 (P < .05). GAS5 genes rs17359906 G > A and rs1951625 G > A were associated with high plasma PSA levels. The recurrence-free survival rate of patients with prostate cancer with AA genotype at the rs17359906 locus of GAS5 (66.67%) was significantly lower than that of the GA genotype (76.47%), whereas the GG genotype was the highest (91.96%), and the difference was statistically significant (P = .002). The recurrence-free survival rate of patients with prostate cancer with the AA genotype at the rs1951625 locus of GAS5 (75.00%) was significantly lower than that of the GA genotype (81.82%), whereas the GG genotype was the highest (87.76%) with a statistically significant difference (P = .025). CONCLUSION: GAS5 rs17359906 G > A and rs1951625 G > A are significantly associated with an increased risk of prostate cancer and a reduction in three-year relapse-free survival.

Serum Amyloid A is a biomarker of severe Coronavirus Disease and poor prognosis.

BACKGROUND: To explore the significance of SAA in evaluating the severity and prognosis of COVID-19. METHODS: A total of 132 patients with confirmed COVID-19 who were admitted to a designated COVID-19 hospital in Wuhan, China from January 18, 2020 to February 26, 2020 were collected. The dynamic changes of blood SAA, CRP, PCT, WBC, Lymphocyte (L), PLT, CT imaging, and disease progression were studied. All patients completed at least twice laboratory data collection and clinical condition assessment at three time points indicated for this study; The length of hospital stay was longer than 14 days prior to February 26, 2020. RESULTS: COVID-19 patients had significantly increased SAA and CRP levels, while L count decreased, and PCT, WBC, and PLT were in the normal range. As disease progressed from mild to critically severe, SAA and CRP gradually increased, while L decreased, and PLT, WBC, and PCT had no significant changes; ROC curve analysis suggests that SAA/L, CRP, SAA, and L count are valuable in evaluating the severity of COVID-19 and distinguishing critically ill patients from mild ones; Patients with SAA consistently trending down during the course of disease have better prognosis, compared with the patients with SAA continuously rising; The initial SAA level is positively correlated with the dynamic changes of the serial CT scans. Patient with higher initial SAA level are more likely to have poor CT imaging. CONCLUSIONS: SAA and L are sensitive indicators in evaluating the severity and prognosis of COVID-19. Monitoring dynamic changes of SAA, combined with CT imaging could be valuable in diagnosis and treatment of COVID-19.

Metabolomics study of the hepatoprotective effect of Phellinus igniarius in chronic ethanol-induced liver injury mice using UPLC-Q/TOF-MS combined with ingenuity pathway analysis.

BACKGROUND: Phellinus igniarius (L.) Quèl as a potential medicinal mushroom possesses multiple biological activities including hepatoprotection, but the hepatoprotective mechanism is not clear. PURPOSE: To elucidate the hepatoprotective effect and potential target of P. igniarius. METHODS: The male C57BL/6 mice were fed with the Lieber-DeCarli diet containing alcohol or isocaloric maltose dextrin as control diet with or without P. igniarius decoction (PID) in the dosage of 0.65 g/kg and 2.6 g/kg. The levels of serum biomarkers were detected by an automatic biochemistry analyser. The histopathological changes of liver were observed by hematoxylin and eosin (H&E) staining. Ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was applied for investigating the dynamic changes of serum metabolites in chronic ethanol-induced liver injury mice and after treatment with PID. Ingenuity pathway analysis (IPA) was employed to identify the potential target of PID. RESULTS: PID could significantly reduce the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG) and total bile acid (TBA) in serum and improved hepatic steatosis and inflammation. In terms of metabolism, a total of 36 serum differential metabolites were identified, and PID intervention regulated 24 of them, involving the key metabolic pathways such as the biosynthesis of unsaturated fatty acids, primary bile acid biosynthesis, glycerophospholipid metabolism, fatty acids biosynthesis, ether lipid metabolism and arachidonic acid metabolism. On the mechanism, IPA showed that farnesol X receptor (FXR) was the major potential target for PID, and PID could improve chronic alcohol intake induced by the inhibition of mRNA expression of FXR in the liver and the activation of mRNA expression of FXR in the intestine in mice. CONCLUSION: The present study for the first time systematically illustrated the hepatoprotective effect of P. igniarius and preliminarily explored its potential target FXR. P. igniarius might be exploited as a promising therapeutic option for alcoholic liver injury.

Correction: Zhao, L.S., et al. Protective Effect of the Total Flavonoids from Rosa laevigata Michx Fruit on Renal Ischemia-Reperfusion Injury through Suppression of Oxidative Stress and Inflammation. Molecules 2016, 21, 952.

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A Combined Phytochemistry and Network Pharmacology Approach to Reveal the Potential Antitumor Effective Substances and Mechanism of Phellinus igniarius.

Phellinus igniarius (P. igniarius) is a medicinal fungus that is widely used in East Asia for the adjuvant treatment of cancer. To elucidate the antitumor effective substances and mechanism of P. igniarius, we designed an approach incorporating cytotoxicity screening, phytochemical analysis, network pharmacology construction, and cellular and molecular experiments. The dichloromethane extract of P. igniarius (DCMPI) was identified as the active portion in HT-29 cells. Nineteen constituents were identified, and 5 were quantified by UPLC-ESI-Q/TOF-MS. Eight ingredients were obtained in the network pharmacology study. In total, 473 putative targets associated with DCMPI and 350 putative targets related to colon cancer were derived from online databases and target prediction tools. Protein-protein interaction networks of drug and disease putative targets were constructed, and 84 candidate targets were identified based on topological features. Pathway enrichment analysis showed that the candidate targets were mostly related to reactive oxygen species (ROS) metabolic processes and intrinsic apoptotic pathways. Then, a cellular experiment was used to validate the drug-target mechanisms predicted by the system pharmacology analysis. Experimental results showed that DCMPI increased intracellular ROS levels and induced HT-29 cell apoptosis. Molecular biology experiments indicated that DCMPI not only increased Bax and Bad protein expression and promoted PARP and caspase-3/9 cleavage but also down-regulated Bcl-2 and Bcl-xl protein levels to induce apoptosis in HT-29 cells. In conclusion, our study provides knowledge on the chemical composition and antitumor mechanism of P. igniarius, which may be exploited as a promising therapeutic option for colon cancer.

Protective effect of dioscin against doxorubicin-induced cardiotoxicity via adjusting microRNA-140-5p-mediated myocardial oxidative stress.

Clinical application of doxorubicin (DOX) is limited because of its cardiotoxicity. Thus, exploration of effective lead compounds against DOX-induced cardiotoxicity is necessary. The aim of the present study was to investigate the effects and possible mechanisms of dioscin against DOX-induced cardiotoxicity. The in vitro model of DOX- treated H9C2 cells and the in vivo models of DOX-treated rats and mice were used in this study. The results showed that discoin markedly increased H9C2 cell viability, decreased the levels of CK, LDH, and improved histopathological and electrocardio- gram changes in rats and mice to protect DOX-induced cardiotoxicity. Furthermore, dioscin significantly inhibited myocardial oxidative insult through adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px in vitro and in vivo. Our data also indicated that dioscin activated Nrf2 and Sirt2 signaling pathways, and thereby affected the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a through decreasing miR-140-5p expression level. In addition, the level of intracellular ROS was significantly increased in H9C2 cells treated by DOX after miR-140-5p mimic transfection, as well as the down-regulated expression levels of Nrf2 and Sirt2, which were markedly reversed by dioscin. In conclusion, our data suggested that dioscin alleviated DOX-induced cardiotoxicity through modulating miR-140-5p-mediated myocardial oxidative stress. This natural product should be developed as a new candidate to alleviate cardiotoxicity caused by DOX in the future.