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Myocardial ischemia–reperfusion injury (MIRI) is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction. It has been shown that cocaine and amphetamine‐regulated transcript (CART) can ameliorate cerebral ischemia–reperfusion (I/R) injury, but the effect of CART on MIRI has not been studied yet. Here, we revealed that CART protected the heart during I/R process by inhibiting apoptosis and excessive autophagy, indicating that CART would be a potential drug candidate for the treatment of MIRI. Further analysis showed that CART upregulated the activation of phospho‐AKT, leading to downregulation of lactate dehydrogenase (LDH) release, apoptosis, oxidative stress and excessive autophagy after I/R, which was inhibited by PI3K inhibitor, LY294002. Collectively, CART attenuated MIRI through inhibition of cardiomyocytes apoptosis and excessive autophagy, and the protective effect was dependent on PI3K/AKT signalling pathway. [ABSTRACT FROM AUTHOR]

Background: Rosmarinic acid (RosA) is a natural phenolic compound that possesses a wide-range of pharmacological properties. However, the effects of RosA on influenza A virus-mediated acute lung injury remain unknown. In this study, we aimed to explore whether RosA could protect against H1N1 virus-mediated lung injury and elucidate the underlying mechanisms. Methods: Mice were intragastrically administered with RosA for 2 days before intranasal inoculation of the H1N1 virus (5LD50) for the establishment of an acute lung injury model. At day 7 post-infection (p.i.), gross anatomic lung pathology, lung histopathologic, and lung index (lung weight/body weight) were examined. Luminex assay, multiple immunofluorescence and flow cytometry were performed to detect the levels of pro-inflammatory cytokines and apoptosis, respectively. Western blotting and plasmid transfection with hematopoietic-type PGD2 synthase (h-PGDS) overexpression were conducted to elucidate the mechanisms. Results: RosA effectively attenuated H1N1 virus-triggered deterioration of gross anatomical morphology, worsened lung histopathology, and elevated lung index. Excessive pro-inflammatory reactions, aberrant alveolar epithelial cell apoptosis, and cytotoxic CD8+ T lung recruitment in the lung tissues induced by H1N1 virus infection were observed to be reduced by RosA treatment. In vitro experiments demonstrated that RosA treatment dose-dependently suppressed the increased levels of pro-inflammatory mediators and apoptosis through inhibition of nuclear factor kappa B (NF-κB) and P38 MAPK signaling pathways in H1N1 virus-infected A549 cells, which was accompanied by promoting activation of the h-PGDS-PGD2-HO-1 signal axis. Furthermore, we strikingly found that h-PGDS inhibition significantly abrogated the inhibitory effects of RosA on H1N1 virus-mediated activation of NF-κB and P38 MAPK signaling pathways, resulting in diminishing the suppressive effects on the increased levels of pro-inflammatory cytokines and chemokines as well as apoptosis. Finally, suppressing h-PGDS prominently abolished the protective effects of RosA on H1N1 virus-mediated severe pneumonia and lung injury. Conclusions: Taken together, our study demonstrates that RosA is a promising compound to alleviate H1N1 virus-induced severe lung injury through prompting the h-PGDS-PGD2-HO-1 signal axis. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis is a common systemic bone disease that leads to bone fragility and increases the risk of fracture. However, the pathogenesis of osteoporosis is considered to be highly complex. The exosomes can regulate the communication between cells. The specific mechanism of information transmission between osteoblasts and endothelial cells is worthy of further study. Methods: Exosomes were isolated and verified from senescent osteoblasts. The source and properties of exosomes were determined by TEM, particle size analysis and western blot. We established the co-culture model of endothelial cells and senescent osteoblasts. We used qRT-PCR to identify differentially expressed miRNAs. The functional changes of vascular endothelial cells were verified by cell transfection. β-Galactosidase cell senescence assay, Hoechst cell apoptosis assay, Ki67 cell proliferation assay and Transwell migration assay were used to verify cell senescence, apoptosis, proliferation, and migration. The potential target gene of miRNA was detected by bio-informatics pathway and double luciferase report. Results: We discovered that senescent osteoblasts could promote the senescence and apoptosis of vascular endothelial cells and inhibit their proliferation and migration. miR-214-3p was upregulated in senescent osteoblast-derived exosomes. miR-214-3p could effectively promote senescence and apoptosis of endothelial cells and inhibit proliferation and migration ability. L1CAM is a miR-214-3p direct target gene determined by bio-informatics and double luciferase report. Conclusions: In conclusion, senescent osteoblast-derived exosomes can accelerate endothelial cell senescence through miR-214-3p/L1CAM pathway. Our experiments reveal the role of exosomes in the skeletal microenvironment. [ABSTRACT FROM AUTHOR]

Objective. The aim of the study was to explore the potential mechanism of Zanthoxylum bungeanum in the treatment of diabetes mellitus (DM) using network pharmacology. Methods. The DrugBank database and TCMSP platform were used to search for the main chemical components and their targets of Zanthoxylum bungeanum, and the genes related to diabetes mellitus were obtained from the genecards database. Import the data into the Venny 2.1.0 platform for intersection analysis to obtain the Zanthoxylum bungeanum-DM-gene dataset. The protein-protein interaction (PPI) analysis of Zanthoxylum bungeanum-DM gene was performed using the String data platform, and the visualization and network topology analysis were performed using Cytoscape 3.8.2. The KEGG pathway enrichment and biological process of GO enrichment analysis were carried out using the David platform. The active ingredients and key targets of Zanthoxylum bungeanum were molecularly docked to verify their biological activities by using Discovery Studio 2019 software. Zanthoxylum bungeanum was extracted and isolated by ethanol and dichloromethane. HepG2 cells were cultured, and cell viability assay was utilized to choose the suitable concentration of Zanthoxylum bungeanum extract (ZBE). The western blot assay was used for measuring the expression of AKT1, IL6, HSP90AA1, FOS, and JUN proteins in HepG2 cells. Results. A total of 5 main compounds, 339 targets, and 16656 disease genes were obtained and retrieved, respectively. A total of 187 common genes were screened, and 20 core genes were finally obtained after further screening. The antidiabetic active ingredients of Zanthoxylum bungeanum are kokusaginin, skimmianin, diosmetin, beta-sitosterol, and quercetin, respectively. The main targets for its antidiabetic effect are AKT1, IL6, HSP90AA1, FOS, and JUN, respectively. GO enrichment analysis revealed that the biological process of Zanthoxylum bungeanum and DM is related to a positive regulation of gene expression, positive regulation of transcription, positive regulation of transcription from RNA polymerase II promoter, response to drug, positive regulation of apoptotic process, and positive regulation of cell proliferation, etc. KEGG enrichment analysis revealed that common biological pathways mainly including the phospholipase D signaling pathway, MAPK signaling pathway, beta-alanine metabolism, estrogen signaling pathway, PPAR signaling pathway, and TNF signaling pathway. Molecular docking results showed that AKT1 with beta-sitosterol and quercetin, IL-6 with diosmetin and skimmianin, HSP90AA1 with diosmetin and quercetin, FOS with beta-sitosterol and quercetin, and JUN with beta-sitosterol and diosmetin have relatively strong binding activity, respectively. Experiment verification results showed that DM could be significantly improved by downregulating the expression of AKT1, IL6, HSP90AA1, FOS, and JUN proteins after being treated at concentrations of 20 μmol/L and 40 μmol/L of ZBE. Conclusion. The active components of Zanthoxylum bungeanum mainly including kokusaginin, skimmianin, diosmetin, beta-sitosterol, and quercetin. The therapeutic effect of Zanthoxylum bungeanum on DM may be achieved by downregulating core target genes including AKT1, IL6, HSP90AA1, FOS, and JUN, respectively. Zanthoxylum bungeanum is an effective drug in treatment of DM related to the above targets. [ABSTRACT FROM AUTHOR]

Confusoside (CF), a major chemical compound in the leaves of Anneslea fragrans Wall., is a dihydrochalcone glycoside with excellent antioxidant and anti-inflammatory effects. However, the hepatoprotective effect of CF has not been described. This study aimed to explore the hepatoprotective effect of CF against acetaminophen (APAP)-induced hepatic injury in HepG2 cells. First, the potential hepatoprotective effect mechanisms of CF were predicted by network pharmacology and were thought to involve reducing inflammation and inhibiting apoptosis. Target proteins (phosphatidylinositol3-kinase (PI3K) and caspase-3 (CASP3)) were found via molecular docking analysis. To verify the predicted results, an analysis of biological indicators was performed using commercial kits and Western blotting. The results showed that CF significantly decreased the levels of liver injury biomarkers (ALT, AST, and LDH), strongly inhibited the production of inflammatory cytokines (IL-1β, IL-6, and TNF-α) and the NO level via inhibiting the activation of the NF-κB signaling pathway, and markedly regulated the expression levels of Bcl2, Bax, and cleaved-CASP3/9 proteins by activating the PI3K-CASP3 apoptosis pathway. The results demonstrated that CF has a therapeutic effect on APAP-induced liver injury by inhibiting intracellular inflammation and cell apoptosis, indicating that CF may be used as a potential reagent for the prevention and treatment of APAP-induced liver injury. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI), resulting in damage of the normal structure and function of the spinal cord, would do great harm to patients, physically and psychologically. The mechanism of SCI is very complex. At present, lots of studies have reported that autophagy was involved in the secondary injury process of SCI, and several researchers also found that calcium ions (Ca2+) played an important role in SCI by regulating necrosis, autophagy, or apoptosis. However, to our best of knowledge, no studies have linked the spinal cord mechanical injury, intracellular Ca2+, and autophagy in series. In this study, we have established an in vitro model of SCI using neural cells from fetal rats to explore the relationship among them, and found that mechanical injury could promote the intracellular Ca2+ concentration, and the increased Ca2+ level activated autophagy through the CaMKKβ/AMPK/mTOR pathway. Additionally, we found that apoptosis was also involved in this pathway. Thus, our study provides new insights into the specific mechanisms of SCI and may open up new avenues for the treatment of SCI. [ABSTRACT FROM AUTHOR]

Sheng Mai Yin (SMY) has therapeutic effects on myocardial infarction (MI), heart failure (HF), diabetic cardiomyopathy (DCM), and myocarditis. To study whether SMY can relieve pyroptosis and play a protective role in diabetic cardiomyopathy, a molecular docking technique was used to predict the possible mechanism of SMY against DCM. Then, a DCM rat model was induced by intraperitoneal injection of streptozotocin (STZ), divided into 5 groups: the DM group (model), SMY-L group (2.7 mL/kg SMY), SMY-M group (5.4 mL/kg SMY), SMY-H group (10.8 mL/kg SMY), and Met group (120 mg/kg metformin). Rats in the CTL group (control) and DM group were given normal saline. After 8 weeks, the levels of blood glucose, lipids, and myocardial enzymes were detected according to the kit instructions. Cardiac function was detected by echocardiography. HE and Masson were used to observing the pathological changes, collagen deposition, and collagen volume fraction (CVF). The apoptosis rate of cardiomyocytes was determined by Tunel. The IL-1β level was determined by ELISA and RT-PCR. The expressions of NLRP3, caspase-1, and GSDMD were measured using RT-PCR and Western blotting. The docking results suggested that SMY may act on NLRP3 and its downstream signal pathway. The in vivo results showed that SMY could reduce blood glucose and lipid levels, improve heart function, improve histopathological changes and myocardial enzymes, and alleviate cardiomyocyte apoptosis and myocardial fibrosis. SMY inhibited the mRNA and protein expressions of NLRP3, ASC, Caspase-1, and GSDMD and IL-1β production. SMY can reduce DCM by regulating the NLRP3/caspase-1 signaling pathway, providing a new research direction for the treatment of DCM. [ABSTRACT FROM AUTHOR]

Methylglyoxal (MGO), a cytotoxic byproduct of glycolysis, causes neuro oxidative damage and apoptosis, and plays key roles in diabetic encephalopathy (DE). The goal of this research was to evaluate the roles of lutein attenuated MGO‐induced damage in PC12 cells as well as the underlying mechanisms. The findings of this study showed that lutein has a significant impact on reducing the generation of reactive oxygen species (ROS) and oxidative stress in MGO‐induced PC12 cells, which may be attributed to the increased antioxidant enzymes activity and the decreased MDA levels. Moreover, treatment with lutein also alleviated cell apoptosis and mitochondrial damage. Real‐time PCR and western blot analysis showed that lutein enhanced the Bcl‐2:Bax ratio, inhibited the expression of caspase‐3 and caspase‐9, and increased the protein level of phosphorylated Akt. The network pharmacology and molecular docking prediction results suggested that the phosphoinositide 3‐kinase/protein kinase B (PI3K/Akt) signaling pathway was a potential mechanism of lutein in DE treatment. Furthermore, LY294002, a specific PI3K inhibitor, partially abolished the protective effect of lutein. These results presented that lutein attenuated oxidative damage and apoptosis triggered by MGO in PC12 cells via the PI3K/Akt signaling pathway. Practical applications: Lutein is a common carotenoid dispersed in fruits and vegetables. This article confirmed a protective effect of lutein on oxidative damage and apoptosis in PC12 cells after MGO damage. These results indicated that lutein could potentially be developed as a nutraceutical or functional food in the prevention of diabetic‐related neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a multisystemic and placental inflammatory disease that causes maternal and infant health issues. As one of the active components in peony root extract, paeonol (Pae) exerts anti‐apoptosis and anti‐inflammatory effects. Nonetheless, the protective role of Pae in PE has not yet been characterized. A mouse model of PE was constructed through tail vein injection of 1 mg/d phosphatidylserine/dioleoyl‐phosphatidycholine suspension. The levels of inflammatory cytokines in the placenta were examined via enzyme‐linked immunosorbent assay (ELISA). The mRNA levels of inflammatory cytokines (TNF‐α, IL‐6, IFN‐γ, and IL‐4) and apoptosis markers (Bax, Bcl‐2, and caspase‐3) were tested using quantitative reverse transcription‐polymerase chain reaction (qRT–PCR). Western blot analysis was performed to detect the protein levels of apoptosis markers and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway‐related molecules. Here, Pae repressed the inflammatory response in the placenta of PE‐like mouse models, as demonstrated by the decreased concentrations and mRNA levels of TNF‐α, IL‐6, and IFN‐γ and the increased concentrations and mRNA levels of IL‐4. Apoptosis in the placentas of PE‐like mouse models was attenuated by Pae, as manifested by the downregulated mRNA and protein levels of Bax and cleaved‐caspase‐3 and the upregulated Bcl‐2. Administration of Pae inhibited the phosphorylation of JAK2 and STAT3 in the placental tissues of PE mice. The JAK2/STAT3 pathway agonist (SC‐39100) reversed Pae treatment‐mediated suppression of placental inflammation and apoptosis in PE mice. Overall, Pae inhibits the JAK2/STAT3 signaling pathway to attenuate placental inflammation and apoptosis in PE mice. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is a global health problem. Previous studies revealed that it involves acute myocardial infarction and ischemia-reperfusion (I/R) injury. The mechanism of myocardial I/R injury is complex. But recognizing its mechanisms will bring important clinical significance. Lupeol is widely found in Chinese medicinal herbs and has been shown to have a variety of bio-activities. However, the pharmacological action of lupeol in the progress of myocardial ischemia-reperfusion injury (MIRI) is unclear. This study used a rat myocardial I/R model and the morphological changes in myocardium were determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. The expression levels of IL-10, IL-1 β , TNF- α , and IL-6 were assessed by quantitative real-time PCR (qRT-PCR) and ELISA. The expression levels of MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH) level and inflammatory cytokines were quantified using ELISA. The cellular apoptotic rate was determined by TUNEL staining. The findings showed that lupeol significantly decreased myocardial infarction after I/R and ameliorated I/R-induced myocardial inflammation, apoptosis, and oxidative stress. Furthermore, our results suggested that lupeol protected against MIRI-induced myocardial infarction through modulation of NF- κ B and Nrf2 signaling pathways. In summary, this study first clarified the cardioprotective effects of lupeol against I/R-induced myocardial infarction in rats, which could be due to its anti-oxidant, anti-inflammatory, and anti-apoptotic activities. Our study also highlighted a mechanism of NF- κ B and Nrf2 signaling, through which lupeol could be a promising agent in protecting against I/R-induced myocardial infarction. [ABSTRACT FROM AUTHOR]

Purpose: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus and is characterized by myocardial hypertrophy and myocardial fibrosis. Pyrroloquinoline quinone (PQQ), a natural nutrient, exerts strong protection against various myocardial diseases. Pyroptosis, a type of inflammation-related programmed cell death, is vital to the development of DCM. However, the protective effects of PQQ against DCM and the associated mechanisms are not clear. This study aimed to investigate whether PQQ protected against DCM and to determine the underlying molecular mechanism. Methods: Diabetes was induced in mice by intraperitoneal injection of streptozotocin, after which the mice were administered PQQ orally (10, 20, or 40 mg/kg body weight/day) for 12 weeks. AC16 human myocardial cells were divided into the following groups and treated accordingly: control (5.5 mmol/L glucose), high glucose (35 mmol/L glucose), and HG + PQQ groups (1 and 10 nmol/L PQQ). Cells were treated for 24 h. Results: PQQ reduced myocardial hypertrophy and the area of myocardial fibrosis, which was accompanied by an increase in antioxidant function and a decrease in inflammatory cytokine levels. Moreover, myocardial hypertrophy—(ANP and BNP), myocardial fibrosis—(collagen I and TGF-β1), and pyroptosis-related protein levels decreased in the PQQ treatment groups. Furthermore, PQQ abolished mitochondrial dysfunction and the activation of NF-κB/IκB, and decreased NLRP3 inflammation-mediated pyroptosis in AC16 cells under high-glucose conditions. Conclusion: PQQ improved DCM in diabetic mice by inhibiting NF-κB/NLRP3 inflammasome-mediated cell pyroptosis. Long-term dietary supplementation with PQQ may be greatly beneficial for the treatment of DCM. Diagram of the underlying mechanism of the effects of PQQ on DCM. PQQ inhibits ROS generation and NF-κB activation, which stimulates activation of the NLRP3 inflammasome and regulates the expression of caspase-1, IL-1β, and IL-18. The up-regulated inflammatory cytokines trigger myocardial hypertrophy and cardiac fibrosis and promote the pathological process of DCM. [ABSTRACT FROM AUTHOR]

Background. Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. We sought to investigate the effect of cilengitide on the neovascularization of abdominal aortic plaques in rabbits and explore its underlying antiangiogenic mechanism on human umbilical vein endothelial cells (HUVECs). Materials and Methods. For the in vivo experiment, the abdominal aortic plaque model of rabbits was established and injected with different doses of cilengitide or saline for 14 consecutive days. Conventional ultrasound (CUS) and contrast-enhanced ultrasound (CEUS) were applied to measure the vascular structure and blood flow parameters. CD31 immunofluorescence staining was performed for examining neovascularization. Relative expressions of vascular endothelial growth factor (VEGF) and integrin of the plaque were determined. For in vitro experiments, HUVECs were tested for proliferation, migration, apoptosis, and tube formation in the presence of different doses of cilengitide. Relative expressions of VEGF, integrin, and Ras/ERK/AKT signaling pathways were determined for the exploration of underlying mechanism. Results. CEUS showed modestly increased size and eccentricity index (EI) of plaques in the control group. Different degrees of reduced size and EI of plaques were observed in two cilengitide treatment groups. The expressions of VEGF and integrin in the plaque were inhibited after 14 days of cilengitide treatment. The neovascularization and apoptosis of the abdominal aorta were also significantly alleviated by cilengitide treatment. For in vitro experiments, cilengitide treatment was found to inhibit the proliferation, migration, and tube formation of HUVECs. However, cilengitide did not induce the apoptosis of HUVECs. A higher dose of cilengitide inhibited the mRNA expression of VEGF-A, β3, and β5, but not αV. Lastly, cilengitide treatment significantly inhibited the Ras/ERK/AKT pathway in the HUVECs. Conclusions. This study showed that cilengitide effectively inhibited the growth of plaque size by inhibiting the angiogenesis of the abdominal aortic plaques and blocking the VEGF-mediated angiogenic effect on HUVECs. [ABSTRACT FROM AUTHOR]

The pathogenesis of osteoporosis is considered extremely intricate. Osteoblast differentiation and angiogenesis can greatly affect bone development and formation, given their coupling role in these processes. Exosome-mediated miRNA regulates cellular senescence, proliferation, and differentiation. However, whether senescent osteoblasts can regulate the senescence of vascular endothelial cell by miRNA through exosomal pathway remains unclear. In this study, senescent osteoblasts could regulate endothelial cell function, promote cell senescence and apoptosis, and decrease cell proliferation via exosomal pathway. miR-139-5p showed high expression in senescent osteoblasts and their exosomes. After senescent osteoblast-derived exosome treatment, miR-139-5p was also upregulated in endothelial cells. Furthermore, transfection of miR-139-5p mimic promoted the senescence and apoptosis of vascular endothelial cells and inhibited their proliferation and migration, whereas transfection of miR-139-5p inhibitor rescued the effect of D-galactose. Using double luciferase assay, TBX1 was confirmed to be a direct target gene of miR-139-5p. In conclusion, senescent osteoblast-derived exosome-mediated miR-139-5p regulated endothelial cell function via exosomal pathway. Our study revealed the role of osteoblast-derived exosomes in the bone environment during aging, providing a clue for inventing a new target therapy. [ABSTRACT FROM AUTHOR]

Context • Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer-related deaths in the world. The current treatments include surgery and chemotherapy, either alone or in combination with radiotherapy, but the prognosis for patients with GC is usually poor. A safe and effective chemopreventive treatment for this malignant disease is urgently needed. Objective • The study intended to investigate the effects and underlying mechanisms of plumbagin, a quinonoid constituent that is derived from the roots of the medicinal plant Plumbago zeylanica, which exhibits potent anticancer properties against a number of cancers. Design • The in vitro study used the human GC cell line SGC-7901. Setting • All experiments were conducted at the Hubei University of Chinese Medicine and Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China). Intervention • SGC-7901 cells were cultured in 30-mm dishes and treated with plumbagin at concentrations of 0, 5, 10, to 20 μmol/L. The cells were incubated with 10 μmol/L plumbagin for different amounts of time (0, 2, 4, 8, 12, and 24 h) in contact with the cancer cells. Outcome Measures • The cell viability was examined using a cell counting kit-8 viability assay, and the cell proliferation rate was determined using a 5-ethynyl-2'-deoxyuridine incorporation assay. The cell cycle distribution was assessed by flow cytometry using propidium iodide staining, and Western blotting was used to assess the expression of BAX, BCL-2, and caspase-3 and to identify any downregulation in the activation of transcription 3 (STAT3), protein kinase B (Akt), and extracellular signal-regulated kinase (ERK1/2). Results • The plumbagin concentrations of 5-20 mmol/L reduced the viability of the GC cells in a dependent manner. Plumbagin suppressed the expression of BAX, BCL-2, pro-caspase-3, and cleaved-caspase-3. It also restrained the expression and phosphorylation of STAT3 and decreased the phosphorylation of Akt1 but did not change the total protein or phosphorylation levels of ERK1/2. Conclusions • Plumbagin inhibits cell apoptosis in human GC cells, and that effect may be related with its ability to suppress phosphorylation of STAT3 and Akt. Given those 2 effects, plumbagin may be a promising agent in the treatment of gastric cancer. [ABSTRACT FROM AUTHOR]

Shenlian extract (SL), extracted from Salvia miltiorrhiza Bunge and Andrographis paniculata (Burm. f.) Nees, has been proved to be effective in the prevention and treatment of atherosclerosis. Recently, we have partially elucidated the mechanisms involved in the therapeutic effects of SL on myocardial ischemia (MI). However, the underlying mechanisms remain largely unclear. This study aims to explore the potential molecular mechanism of SL on MI on the basis of network pharmacology. First, the main active ingredients of SL were screened in the Traditional Chinese Medicine Integrated Database, and the MI-associated targets were collected from the DisGeNET database. Then, we used compound–target and target–pathway networks to uncover the therapeutic mechanisms of SL. On the basis of network pharmacology analysis results, we assessed the effects of SL in MI rat model and oxygen glucose deprivation model of H9c2 cells and validated the possible molecular mechanisms of SL on myocardial injury in vivo and in vitro. The network pharmacology results showed that 37 potential targets were recognized, including TNF-α, Bcl-2, STAT3, PI3K and MMP2. These results revealed that the possible targets of SL were involved in the regulation of inflammation and apoptosis signaling pathway. Then, in vivo experiments indicated that SL significantly reduced the myocardial infarction size of MI rats. Serum CK-MB, cTnT, CK, LDH, and AST levels were significantly decreased by SL (P < 0.05 or P < 0.01). In vitro , SL significantly increased H9c2 cell viability. The levels of inflammation factors including TNF-α and MMP2 were significantly decreased by SL (P < 0.05 or P < 0.01). TUNEL and Annexin V/propidium iodide assays indicated that SL could significantly decrease the cell apoptotic rate in vivo and in vitro (P < 0.05 or P < 0.01). The remarkable upregulation of anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax protein level further confirmed this result. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the PI3K–AKT and JAK2–STAT3 pathways were significantly enriched in SL. Compared with the model group, SL treatment significantly activated the PI3K–AKT and JAK2–STAT3 pathways in vivo and in vitro according to Western blot analyses. SL could protect the myocardium from MI injury. The underlying mechanism may be related to the reduction of inflammation and apoptosis by activating the PI3K/AKT and JAK2/STAT3 pathways. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) plays crucial roles in plant development and defence response. Reactive oxygen species (ROS) are produced during normal plant growth, and high ROS concentrations can change the antioxidant status of cells, leading to spontaneous cell death. In addition, ROS function as signalling molecules to improve plant stress tolerance, and they induce PCD under different conditions. This review describes the mechanisms underlying plant PCD, the key functions of mitochondria and chloroplasts in PCD, and the relationship between mitochondria and chloroplasts during PCD. Additionally, the review discusses the factors that regulate PCD. Most importantly, in this review, we summarise the sites of production of ROS and discuss the roles of ROS that not only trigger multiple signalling pathways leading to PCD but also participate in the execution of PCD, highlighting the importance of ROS in PCD. [ABSTRACT FROM AUTHOR]

O-Linked N-acetylglucosamine ( O-GlcNAc) modification of serines/threonines on cytoplasmic proteins is a significant signal regulating cellular processes such as cell cycle, cell development, and cell apoptosis. O-GlcNAcase (OGA) is responsible for the removal of O-GlcNAc, and it thus plays a critical role in O-GlcNAc metabolism. Interestingly, OGA can be cleaved by caspase-3 into two fragments during apoptosis, producing an N-terminal fragment (1-413 a.a.), termed nOGA. Here, using 4-MU-GlcNAc (4-methylumbelliferyl 2-acetamido-2-deoxy-β-D-glucopyranoside) as substrate, we found that the nOGA fragment retains high glycosidase activity. To probe the role of nOGA in apoptosis, it is essential to develop a potent and specific nOGA inhibitor. However, many reported inhibitors active at nanomolar concentrations (including PUGNAc, STZ, GlcNAc-statin, and NAG-thiazoline) against full-length OGA were not potent for nOGA. Next, we screened a small triazole-linked carbohydrate library and first identified compound 4 (4-pyridyl-1-(2′-deoxy-2′-acetamido-β-D-glucopyranosyl)-1,2,3-triazole) as a potent and competitive inhibitor for nOGA. This compound shows 15-fold selectivity for nOGA ( K = 48 μM) over the full-length OGA ( K = 725 μM) and 10-fold selectivity over human lysosomal β-hexosaminidase A&B (Hex A&B) ( K = 502 μM). These results reveal that compound 4 can be used as a potent and selective inhibitor for probing the role of nOGA in biological systems. [ABSTRACT FROM AUTHOR]

Abstract: Development of early embryos is regulated by autocrine/paracrine factors. Analyzing the expression of polypeptide ligand–receptor pairs using DNA microarray datasets, we identified transcripts for artemin, a member of the GDNF (glial cell line-derived neurotrophic factor) family, its receptor GFRA3 (GDNF family receptor-alpha 3) and coreceptor RET. Here we report an autocrine/paracrine role of the artemin-GFRA3 signaling system in regulating early embryonic development and apoptosis. Possible involvement of the MAP kinase signaling pathway was also demonstrated. The genome-wide survey of ligand–receptor pairs and early embryo cultures provided a better understanding of autocrine/paracrine embryonic factors important for optimal blastocyst development. [Copyright &y& Elsevier]

Ethnopharmacological relevance Hedyotis diffusa is an ethno-medicine used for anti-cancer treatment in the clinic of traditional Chinese medicine (TCM). The total coumarins of Hedyotis diffusa (TCHD) was a selected extract with observed antiproliferative activity, which has not been tested in treatment of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Aim of the study This study aimed to evaluate the apoptosis-inducing effect of TCHD on human MDS cell line (SKM-1) and explore its action mechanism in association with caspase family and PI3K/Akt signaling pathway. Materials and methods The chemical constituents and total coumarins content of TCHD were determined by High Performance Liquid Chromatography-tandem mass spectrometry (HPLC-MS/MS) and UV–vis spectrophotometry, respectively. MTT assay, Hoechst 33258 staining, and Annexin V-FITC/PI double labeling were applied to evaluate TCHD's efficacy on SKM-1 cells. Western blot analysis was also used to clarify the action mechanism of TCHD on protein expression level. Results Two compounds, p -coumaric acid and E -6-O- p -coumaroyl scandoside methyl ester, were identified in TCHD, and its total coumarins content reached 87.4%. By MTT assay, apoptosis-inducing effect of TCHD on SKM-1 cells was found in a dose-dependent manner after 24–48 h treatment, with IC 50 values of 104.48 μg/ml and 100.66 μg/ml, respectively. Morphological and flow cytometry observation also confirmed such effect of TCHD. Western blot analysis clarified its action mechanism associating with the activation of caspases and inhibition of PI3K/Akt pathway proteins. Conclusions This is the first report regarding the apoptosis-inducing efficacy and mechanism of TCHD on SKM-1 cells, providing a promising candidate of TCM for MDS and AML therapy with fewer side effects. [ABSTRACT FROM AUTHOR]

• MGL significantly ameliorated CD-like colitis. • MGL protected the intestinal barrier through inhibiting IEC apoptosis. • The effect of MGL might be partly mediated via suppressing PI3K/AKT signalling pathway in IECs. Previous reports have shown that preventing excessive intestinal epithelial cell (IEC) apoptosis is a crucial approach for protecting the intestinal barrier in patients with Crohn's disease (CD). Magnolin (MGL) has various biological activities, including antiapoptotic activities, but its role in CD has largely not been determined. This study investigated how MGL impacts CD-like colitis and the underlying mechanism involved. Mice were treated with TNBS to establish a disease model, and these mice were used to assess the therapeutic effects of MGL on CD-like colitis. TNF-α-treated colon organoids were used to evaluate the impact of MGL on intestinal barrier function and IEC apoptosis. Enrichment analysis was performed to examine the potential pathways through which MGL inhibits IEC apoptosis. Finally, rescue experiments showed the mechanism by which MGL suppresses IEC apoptosis. The animal experiments demonstrated that MGL treatment alleviated the weight loss, colon shortening, elevated disease activity index (DAI) scores, increased colitis histological scores and upregulated inflammatory factor expression that were observed in model mice. MGL ameliorated intestinal barrier dysfunction and the loss of tight junction (TJ) proteins (ZO-1 and Claudin-1) by inhibiting IEC apoptosis in both TNBS-treated mice and TNF-α-treated colon organoids. MGL inhibited the PI3K/AKT signalling pathway, thus safeguarding the intestinal barrier and alleviating CD-like colitis in vivo and in vitro. MGL improves the intestinal barrier integrity and prevents CD-like colitis by inhibiting IEC apoptosis. The potential mechanism of its anti-apoptotic impact on IECs could be associated with the PI3K/AKT pathway, presenting novel approaches and avenues for the clinical management of CD. [ABSTRACT FROM AUTHOR]

Perioperative or postoperative adjuvant chemotherapy based on 5-fluorouracil (5-FU) is a common first-line adjuvant therapy for gastric cancer (GC). However, drug resistance and the side effects of 5-FU have reduced its efficacy. Among these side effects, gastrointestinal (GI) toxicity is one of the most common. Xianglian Pill (XLP) is a Chinese patent medicine that is commonly used for the treatment of diarrhoea. It can reduce inflammation and has a protective effect on the intestinal mucosa. Recent studies have shown that many components of XLP can inhibite tumor cell growth. However, the therapeutic effect of XLP in combination with 5-FU on GC is unclear. To investigate whether the combination of XLP and 5-FU can enhance anti-GC activity while reducing GI toxicity. XLP was administered orally during intraperitoneal injection of 5-FU in GC mice model. Mice were continuously monitored for diarrhea and xenograft tumor growth. After 2 weeks, the mice were sacrificed and serum was collected to determine interleukin-6 levels. Pathological changes, the expression of pro-inflammatory factors and p38 mitogen-activated protein kinase (MAPK) in GI tissue were determined by Western blot analysis. Pathological changes, apoptosis levels and p38 MAPK expression levels in xenograft tissues were also determined. The results showed that XLP could alleviate GI mucosal injury caused by 5-FU, alleviated diarrhea, and inhibited the expression of nuclear factor (NF)-κB and myeloid differentiation primary response-88. Besides, XLP could promote the 5-FU-induced apoptosis of GC cells and enhance the inhibitory effect of 5-FU on tumor xenografts. Further study showed that XLP administration could regulate the expression of p38 MAPK. XLP in combination with 5-FU could alleviate its GI side effects and enhance its inhibitory effect on xenograft tumor. Moreover, these effects were found to be related to the regulation of the p38 MAPK/NF-κB pathway. [Display omitted] • XLP combined with 5-FU could alleviate the diarrhea and reduce the inflammation of gastrointestinal mucosa in GC mice model. • XLP combined with 5-FU could inhibit the growth of xenogaft and promote tumor cell apoptosis in GC mice model. • Those effects were related to the regulation of p38MAPK/NF-κB signaling pathway by XLP. [ABSTRACT FROM AUTHOR]

125I seeds can effectively inhibit the growth of a variety of cancer cells. It has been used in the treatment of a variety of cancers, and has achieved certain curative effect. However, to the best of our knowledge, no report has described the effects of 125I seeds on the biological functions of cholangiocarcinoma (CCA) and the mechanisms underlying the effects of the seeds on this cancer. In this study, we demonstrated that 125I seeds could inhibit the proliferation, migration and invasion of CCA cells, as well as promoting apoptosis and blocking the cell cycle in these cells. Moreover, 125I seeds inhibited the growth of CCA xenografts and promoted the apoptosis of CCA cells in vivo. Furthermore, transcriptome sequencing showed that 125I seeds could inhibit the growth of CCA by inhibiting the expression of AGR2 and regulating p38 MAPK pathway. Finally, this finding indicated that 125I seeds can inhibit proliferation and promote apoptosis in CCA cells by inhibiting the expression of AGR2 and DUSP1 and increasing the expression of p-p38 MAPK and p-p53. This study provides a new research direction for studies investigating the mechanisms underlying the effects of 125I seeds on CCA. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) is closely related to the development of several malignancies, such as B-cell lymphoma (B-CL), by the mechanism through which these malignancies develop remains largely unknown. We previously observed downregulation of the long noncoding RNA (lncRNA) IGFBP7-AS1 in response to EBV infection. However, the role of IGFBP7-AS1 in EBV-associated cancers has not been clarified. Here, we found that expression of IGFBP7-AS1, as well as its sense gene IGFBP7, is decreased in EBV-positive B-CL cells and clinical tissues. IGFBP7-AS1 stabilizes IGFBP7 mRNA by forming a duplex based on their overlapping regions. The tumour suppressor p53 transcriptionally activates IGFBP7-AS1 expression by binding to the promoter region of the lncRNA gene. The IGFBP7-AS1 expression is able to be rescued in EBV-positive cells in wild-type (wt) p53-dependent manner. IGFBP7-AS1 inhibits the proliferation and promotes the apoptosis of B-CL cells. Moreover, tumorigenic properties due to the depletion of IGFBP7-AS1 were restored by exogenous expression of IGFBP7 or wt-p53. Furthermore, the functional p53/IGFBP7-AS1/IGFBP7 axis facilitates apoptosis by suppressing the production and secretion of the NPPB signal peptide and further regulating the cGMP-PKG signalling pathway. This study demonstrates that EBV promotes tumorigenesis, particularly in B-CL progression, by downregulating the novel p53-responsive lncRNA IGFBP7-AS1. [ABSTRACT FROM AUTHOR]

Abstract: Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding lectin, has been reported to display remarkable anti-proliferative and apoptosis-inducing activities toward a variety of cancer cells; however, the precise molecular mechanisms by which PCL induces cancer cell death are still elusive. In the current study, we found that PCL could induce apoptosis and autophagy in murine fibrosarcoma L929 cells. Subsequently, we demonstrated that inhibition of Ras could promote L929 cell death, suggesting that Ras–Raf signaling pathway plays the key negative regulator in PCL-induced apoptosis. And, we showed that Ras-Raf signaling pathway was also involved in PCL-induced autophagy as the negative regulator. In addition, we found that class I phosphatidylinositol 3-kinase (PI3K)–Akt signaling pathway could play the negative regulator in PCL-induced apoptosis and autophagy. Taken together, these results demonstrate that PCL induces murine fibrosarcoma L929 cell apoptosis and autophagy via blocking Ras-Raf and PI3K–Akt signaling pathways. [ABSTRACT FROM AUTHOR]

Euphorbia fischeriana S. (E. fischeriana) is a classic Chinese herb with toxicity that is mainly used for cancer treatment and in insect repellent, anti-inflammatory and anti-edema applications (Liu et al., 2001). 12-Deoxyphorbol13-palmitate (DP), a tetracyclic diterpene monomer compound, was extracted from the roots of E. fischeriana by our research groups. Previous studies found that DP could inhibit the proliferation of leukemia cells in vitro. However, the underlying mechanism of DP in leukemia is unknown. Hence, DP's pharmacological effect on leukemia cells was investigated in this study. DP was obtained from the Natural Medicine Chemistry Laboratory of Qiqihaer Medical University. In vitro, K562 cells and HL60 cells were incubated with DP or DP combined with LY294002 at different concentrations. Cell proliferation and apoptosis were detected by the relevant experimental methods. In vivo, nude mouse xenograft models were established by injecting K562 cells. DP was intraperitoneally administered to observe the influence on the growth of transplanted tumors. Gene detection and immunoblot analysis were performed to validate the mechanisms. The cell counting kit-8 (CCK-8) assay proved that DP inhibited the growth of K562 and HL60 cells in a time- or dose-dependent manner. At 12 h, DP could induce apoptosis by Annexin V-FITC/propidium iodide (PI) dual labeling, loss of mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS), acridine orange/ethidium bromide (AO/EB) staining and transmission electron microscopy (TEM) observation in K562 or HL60 cells. Furthermore, in an assay of gene and protein expression, we found that DP could downregulate the gene and protein expression levels of Bcl-2, upregulate the gene and protein expression levels of Bax and Bim, and downregulate the protein expression levels of PI3k, p-Akt, and p-FoxO3a. Moreover, the effects of DP on proliferation and apoptosis in K562 cells were enhanced by LY294002. Then, we tested the antitumor effects of DP in vivo. Nude mouse xenograft models were established by subcutaneously injecting K562 cells. We found that tumor volume was significantly decreased in DP-treated xenograft nude mice. Morphologic changes, apoptosis degree, and related gene and protein expression levels in transplanted tumor tissue of DP-treated nude mice were assessed by different experimental methods. The in vivo and in vitro experimental results indicated that DP might inhibit the proliferation and induce the apoptosis of leukemia cells, which might be a result of suppressing the PI3k/Akt signaling pathways. The in vivo and in vitro experimental results indicated that DP might inhibit the proliferation and induce the apoptosis of leukemia cells, which might be a result of suppressing the PI3k/Akt signaling pathways. [Display omitted] [ABSTRACT FROM AUTHOR]

• IL-11 directly protects neuronal cells from oxidative damage caused by H 2 O 2 and reduces neuronal apoptosis. • Transcriptome analysis suggests that the JAK/STAT pathway may be involved in the antioxidant activity of IL-11. • Rescue experiments and animal models demonstrated that IL-11 prevented neuronal apoptosis caused by oxidative imbalance through activation of the JAK/STAT signaling pathway and promoted the recovery of motor function in SCI rats. Excess reactive oxygen species (ROS) generated by oxidative stress is a crucial factor affecting neuronal dysfunction after spinal cord injury (SCI). IL-11 has been reported to have antioxidative stress capacity. In the present study, we investigated the protective effect and mechanism of IL-11 against neuronal cell damage caused by oxidative imbalance. We established a H 2 O 2 -induced oxidative stress injury model in PC12 cells and observed the effects of IL-11 on cellular activity, morphology, oxidase and antioxidant enzymes, and ROS release. Furthermore, the effect of IL-11 on apoptosis of PC12 cells was assessed by flow cytometry, a TUNEL assay and Western blotting. Transcriptome analysis and rescue experiments revealed the mechanism by which IL-11 protects neurons from oxidative stress damage. For the in vivo investigation, an adenovirus-mediated IL-11 overexpression SCI rat model was constructed to validate the beneficial effect of IL-11 against SCI. IL-11 significantly improved the viability and enhanced the antioxidant activity of H 2 O 2 -treated PC12 cells while reducing ROS release. In addition, IL-11 reduced H 2 O 2 -induced PC12 cell apoptosis. Transcriptome analysis revealed that the JAK/STAT pathway may be related to the antioxidant activity of IL-11. Treatment with a JAK/STAT inhibitor (Stattic) exacerbated the oxidative damage induced by H 2 O 2 and attenuated the protective effects of IL-11. The results of in vivo studies showed that IL-11 prevented neuronal apoptosis due to oxidative imbalance and promoted the restoration of motor function in SCI rats by activating the JAK/STAT signaling pathway. IL-11 inhibited oxidative stress-induced neuronal apoptosis at least in part by activating the JAK/STAT signaling pathway and further promoted the recovery of motor function. These findings suggest that IL-11 may be an effective target for the treatment for SCI. [ABSTRACT FROM AUTHOR]

Phylloporia ribis (Schumach:Fr.)Ryvarden is a genus of needle Phellinus medicinal fungi, parasitic on the living rhizomes of hawthorn and pear trees. As a traditional Chinese medicine, Phylloporia ribis was used in folklore for long-term illness, weakness and memory loss in old age. Previous studies have shown that polysaccharides from Phylloporia ribis (PRG) significantly promoted synaptic growth in PC12 cells in a dose-dependent manner, exhibiting "NGF"-like neurotrophic activity. Aβ 25-35 damage to PC12 cells produced neurotoxicity and decreased cell survival, and PRG reduced the apoptosis rate, suggesting that PRG has neuroprotective effects. The studies confirmed that PRG had the potential to be a neuroprotective agent, but its neuroprotective mechanism remained unclear. We aimed to elucidate the neuroprotective effects of PRG in an Aβ 25-35 -induced Alzheimer's disease (AD) model. Highly-differentiated PC12 cells were treated with Aβ 25-35 (AD model) and PRG, and were assessed for cellular apoptosis, inflammatory factors, oxidative stress, and kinase phosphorylation. The results showed that the PRG groups effectively inhibited the neurotoxicity, mainly manifested by inhibiting mitochondrial oxidative stress, attenuating neuroinflammatory responses, and improving mitochondrial energy metabolism, eventually resulting in higher cell survival. The expression of p-ERK, p-CREB and BDNF proteins was increased in the PRG groups compared to the model group, which confirmed that PRG reversed the inhibition of the ERK pathway. We provide evidence for neuroprotection conferred by PRG and its mechanism by inhibiting ERK1/2 hyper-phosphorylation, prevention of mitochondrial stress, and subsequent prevention of apoptosis. The study highlights PRG as a promising candidate with neuroprotective effects, the potential of which can be harnessed for identifying novel therapeutic targets. [Display omitted] [ABSTRACT FROM AUTHOR]

• Two injections of CFA can induce pain sensitivity and depression-like behavior in adult male SD rats. • CFA leads to pathological morphological changes and increased apoptosis in the hippocampal tissue of rats, as well as inhibition of the PI3K/Akt pathway. • Both electrical acupuncture and duloxetine can activate the PI3K/Akt signaling pathway, reduce hippocampal neuronal apoptosis, and improve pain and depression-like behavior. In chronic inflammatory pain (CIP) and depression, neuroapoptosis has been identified as a contributing factor. Electroacupuncture (EA) shows promise as an alternative therapy for this comorbidity. However, the underlying mechanism remains unclear. This study aimed to investigate the effects of EA on hippocampal neuronal apoptosis in rats with CIP and depression. Rats received plantar injections of complete Freund's adjuvant (CFA) on days 0 and 14. They were then divided into groups: sham operation, model, EA, and duloxetine. EA was administered at Hegu (LI4) and Taichong (LR3) from days 15 to 28, while the duloxetine group received duloxetine and distilled water daily (0.1 mg/ml). Pain behavior was assessed using the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. Depression-like behavior was evaluated through the sucrose preference test (SPT), open-field test (OFT), and forced swim test (FST). Hematoxylin and eosin (HE) staining was employed to assess pathological changes in the hippocampus. Nerve cell apoptosis was determined using TUNEL fluorescence staining. Western blot analysis was conducted to measure the protein expression of Bcl-2, Bax, p-PI3K/PI3K, and p-Akt/Akt. EA demonstrated significant pain intensity reduction and alleviation of pain-related depressive symptoms. Our findings from the HE staining confirmed that CIP induced by CFA led to morphological changes in the hippocampus, while EA effectively reversed these pathological alterations. Moreover, EA intervention remarkably reduced neuronal apoptosis and exhibited an upregulation of Bcl-2 protein expression accompanied by a decrease in Bax expression. Additionally, EA activated the PI3K/Akt signaling pathway. Overall, our study suggests that EA holds the potential to improve pain and depressive behaviors in rats with CIP and depression comorbidity, potentially mediated through the activation of the PI3K/Akt pathway, leading to a reduction in hippocampal neuronal apoptosis. [ABSTRACT FROM AUTHOR]

Background: Programmed cell death, including apoptosis, mitochondria-mediated necrosis, and necroptosis, is critically involved in ischemic cardiac injury, pathological cardiac remodeling, and heart failure progression. Whereas apoptosis and mitochondria-mediated necrosis signaling is well established, the regulatory mechanisms of necroptosis and its significance in the pathogenesis of heart failure remain elusive.Methods: We examined the role of tumor necrosis factor receptor-associated factor 2 (Traf2) in regulating myocardial necroptosis and remodeling using genetic mouse models. We also performed molecular and cellular biology studies to elucidate the mechanisms by which Traf2 regulates necroptosis signaling.Results: We identified a critical role for Traf2 in myocardial survival and homeostasis by suppressing necroptosis. Cardiac-specific deletion of Traf2 in mice triggered necroptotic cardiac cell death, pathological remodeling, and heart failure. Plasma tumor necrosis factor α level was significantly elevated in Traf2-deficient mice, and genetic ablation of TNFR1 largely abrogated pathological cardiac remodeling and dysfunction associated with Traf2 deletion. Mechanistically, Traf2 critically regulates receptor-interacting proteins 1 and 3 and mixed lineage kinase domain-like protein necroptotic signaling with the adaptor protein tumor necrosis factor receptor-associated protein with death domain as an upstream regulator and transforming growth factor β-activated kinase 1 as a downstream effector. It is important to note that genetic deletion of RIP3 largely rescued the cardiac phenotype triggered by Traf2 deletion, validating a critical role of necroptosis in regulating pathological remodeling and heart failure propensity.Conclusions: These results identify an important Traf2-mediated, NFκB-independent, prosurvival pathway in the heart by suppressing necroptotic signaling, which may serve as a new therapeutic target for pathological remodeling and heart failure. [ABSTRACT FROM AUTHOR]

The objective was to examine the protective effect of resveratrol (RSV) on myocardial ischemia/reperfusion (IR) injury and whether the mechanism was related to vascular endothelial growth factor B (VEGF-B) signaling pathway. Rat hearts were isolated for Langendorff perfusion test and H9c2 cells were used for in vitro assessments. RSV treatment significantly improved left ventricular function, inhibited CK-MB release, and reduced infarct size in comparison with IR group ex vivo . RSV treatment markedly decreased cell death and apoptosis of H9c2 cells during IR. We found that RSV was responsible for the up-regulation of VEGF-B mRNA and protein level, which caused the activation of Akt and the inhibition of GSK3β. Additionally, RSV prevented the generation of reactive oxygen species (ROS) by up-regulating the expression of MnSOD either in vitro or ex vivo . We also found that the inhibition of VEGF-B abolished the cardioprotective effect of RSV, increased apoptosis, and led to the down-regulation of phosphorylated Akt, GSK3β, and MnSOD in H9c2 cells. These results demonstrated that RSV was able to attenuate myocardial IR injury via promotion of VEGF-B/antioxidant signaling pathway. Therefore, the up-regulation of VEGF-B can be a promising modality for clinical myocardial IR injury therapy. [ABSTRACT FROM AUTHOR]

Areca Thirteen Pill, also called Gao You-13 (GY-13), is a traditional Mongolian herbal formula and has been extensively used to treat depression in Mongolian areas, which belongs to Heyi disease in Mongolian medicine. Major depressive disorder is a serious psychiatric disease, only one-third of individuals with depression are responsive to current antidepressants in clinic. Growing attention has been attracted by traditional herbal medicines in fighting depression because they are considered safer alternatives to pharmacotherapy. To reveal the mechanism of GY-13 in the treatment of depression. The rat depression model was established by chronic unpredictable mild stress (CUMS), and primary hippocampal neurons were used to construct a glutamate-induced excitotoxicity model. The antidepressant effect of GY-13 was then assessed by performing sucrose preference tests, open field tests, and body weight measurements on rats. The expression of cAMP and PKA, mRNA levels of brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB), and hippocampal neuronal apoptosis were measured. The results indicate that GY-13 significantly improves depression-like behavior, rescues decreased cAMP， PKA, recovers the mRNA levels of CREB and BDNF, and increases the proliferative activity of hippocampus. In addition, blockade of PKA reverses the effects of GY-13 treatment on CREB mRNA, BDNF mRNA levels. In vitro, GY-13 treatment increased hippocampal proliferative activity and attenuated Glu-induced apoptosis of hippocampal neurons as well as reduced CREB mRNA and BDNF mRNA expression levels. Our research demonstrated that GY-13 treatment exerted a potent antidepressant action via activation of cAMP/CREB/BDNF signaling pathway, promoting proliferation, and suppressing apoptosis. This research provides molecular biological ground for developing GY-13 into a potent alternative for the intervention of depression. [Display omitted] [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is a common digestive tract malignant tumor that its morbidity and mortality seriously affect human health. At present, Dachengqi Decoction (DCQ), a traditional Chinese medicine formula, has been clinically used as an adjuvant therapy for CRC. However, pharmacodynamic substance basis and therapeutic mechanism are still unclear. The main constituents absorbed in the blood and possible active targets after DCQ administration were explored based on the analysis method of "into serum components, action target and key pathway", which may provide reference for the study of the pharmacodynamic material basis and action mechanism of Dachengqi Decoction in the treatment of CRC. Based on the serum pharmacochemistry of traditional Chinese medicine (TCM), the prescription prototype ingredients of DCQ in mice serum samples were identified by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry technology (UPLC-Q-TOF-MSE). Taking the prototype ingredients absorbed into serum as the research object, the possible targets and key pathways of DCQ in vivo were demonstrated by network pharmacology. Finally, using molecular docking verified the binding activity of prototype components and potential action targets. A total of 46 prototype components of DCQ were identified in mice serum, most of which were derived from flavonoids and anthraquinones in Citrus aurantium L. and Rheum palmatum L. Network pharmacology prediction results indicated that the drug prototype components entering the serum may mainly regulate targets including mitogen-activated protein kinase (MAPK), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), etc. and main pathways such as (phosphatidylinositol 3-kinase/protein kinase B) PI3K-AKT signaling pathway, advanced glycation end products-receptor for AGE (AGE-RAGE) signaling pathway and IL-17 signaling pathway, etc. Molecular docking showed that the prototype active components had strong binding activity to VEGF, Harvey rat sarcoma viral oncogene homolog (HRAS) and MAPK1. This study elucidated that most of the direct acting substances of DCQ in vivo were flavonoids and anthraquinones, which may play a role in regulating cell reproduction and apoptosis and inhibiting inflammation, providing a reference for the research of pharmacodynamic material basis and mechanism of DCQ in the treatment of CRC. [Display omitted] • 46 prototype chemical components of DCQ were identified in serum. • The main active ingredients were anthraquinones and flavonoids. • The active components mainly regulated immune system and tumor cells. • The active components and potential key targets showed strongly binding activity. [ABSTRACT FROM AUTHOR]

TGF-β/Smad2/3 signal pathway is regarded as a central regulator in various tumors, but its roles in brain cancer therapy remain unknown. In this study, we identify that the TGF-β/Smad2/3 signal pathway is activated in human brain glioma cells; inhibitor (SB203580) and siRNA against Smad2/3 quickly inhibited the phosphorylation of Smad2 and 3, expression of its major downstream gene, Ki-67, arrested cells in the G2/M phase and induced apoptosis of cells. The findings suggest that TGF-β/Smad2/3 pathway plays a key role in U251 cell growth and metastasis, which suggests its potential role in the molecular therapy of brain cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The present study was designed to investigate the inhibitory effects of fluorofenidone on Ang II-induced apoptosis in renal tubular cells and the related signaling pathway. Methods: Rat proximal tubular epithelial cells (NRK-52E) were used to examine the anti-apoptosis effects of fluorofenidone. Cell proliferation was assessed by methyl thiazolyl tetrazolium assay. Apoptosis was examined by AO/EB staining and TUNEL assay. The expression of Fas/FasL pathway members, including Fas, FasL, Bax, Bcl-2, Caspase-8, and Caspase-3 was detected by real-time RT-PCR and/or Western blot, respectively. The activity of Caspase-8 and Caspase-3 was detected by spectrophotometry. Results: Fluorofenidone didn''t affect the proliferation of NRK-52E cells, but significantly inhibited the apoptosis of NRK-52E cells induced by Ang II. Fluorofenidone significantly reduced Ang II-induced increases in Fas, FasL, Bax, Caspase-8 and Caspase-3 at the mRNA level. Consistent with these observations, fluorofenidone also prevented Ang II-mediated up-regulation of FasL and Bax at the protein level. Additionally, Ang II-induced activation of Caspase-8 and Caspase-3 as well as Ang II-initiated downregulation of Bcl-2 at both mRNA and protein levels was all prevented by fluorofenidone. Conclusions: Fluorofenidone can inhibit Ang II-induced apoptosis of renal tubular cells through blockage of the Fas/FasL pathway. [Copyright &y& Elsevier]

Goal of this study was to investigate the pro-apoptotic properties of RRR-gamma-tocopherol (gammaT) in human breast cancer cells. gammaT was shown to induce cancer cells but not normal cells to undergo apoptosis, sensitize cancer cells to Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL)-induced apoptosis, and increase death receptor 5 (DR5) mRNA, protein and cell surface expression. Knockdown of DR5 attenuated gammaT-induced apoptosis. Investigations of post-receptor signaling showed: caspase-8, Bid and Bax activation, increases in mitochondria permeability, cytochrome c release and caspase-9 activation. Thus, gammaT is a potent pro-apoptotic agent for human breast cancer cells inducing apoptosis via activation of DR5-mediated apoptotic pathway. [ABSTRACT FROM AUTHOR]