The present study aimed to investigate the protective effects exerted by astragaloside‑IV (AIV) on retinal pigment epithelial (RPE) cells of rats with diabetes mellitus (DM), and to explore the underlying molecular mechanisms. For this purpose, a rat model of DM was established by injecting rats with an intraperitoneal injection of streptozotocin. AIV was then intragastrically administered. An electroretinogram (ERG) was used to assess retinopathy and TUNEL staining was used to detect the level of apoptosis of RPE cells. Western blot analysis was used to determine protein expression in RPE cells in vitro and in vivo. AIV was found to be able to significantly increase body weight and decrease blood glucose levels in rats with DM in a dose‑dependent manner. Compared with the rats with DM, the rat rod cell response a wave, b wave, maximum response b wave, photopic (photo)‑ERG b wave and oscillatory potential (OP) p4 wave latency significantly decreased and the amplitude of OP Os1 wave increased significantly in the rats with DM treated with AIV for 11 weeks. In addition, AIV significantly decreased the apoptotic levels of RPE cells from rats with DM and significantly decreased the protein expression levels of Bax/Bcl‑2, Fas/FasL, active caspase‑3, active caspase‑8, active caspase‑9, homeobox B3 (HOXB3), p‑phosphoinositide 3‑kinase (PI3K)/PI3K, p‑AKT/AKT and p‑p70S6K1/p70S6K1, whereas it significantly increased miR‑128 expression in the RPE cells from rats with DM. In vitro, AIV significantly inhibited the high glucose (HG)‑induced apoptosis of RPE cells by increasing miR‑128 expression and Bcl‑2 and FasL protein expression in vivo. On the whole, the findings of the present study demonstrate that AIV treatment protects RPE cells of diabetic rats from apoptosis, and that these effects may be associated with the upregulation of miR‑128 expression.

Acute lung injury (ALI) as a serious diseases with high mortality and is considered a threat to human health and life. A number of studies have focused on the treatment and prevention of lung injury. However, the molecular mechanisms responsible for the development of lung injury are not yet fully understood, and this has impeded the development of effective drugs and treatment strategies. Hence, in the present study, mice with lipopolysaccharide (LPS)‑induced ALI were used as a model to investigate the crosstalk between the CX3CL1-CX3CR1 axis and the nuclear factor (NF)-κB signaling pathway in the process of lung injury. CX3CL1-knockout (CX3CL1-KO or CX3CL1-/-) mice were used to examine the role of the CX3CL1-CX3CR1 axis in LPS-induced lung injury. We used baicalin, a natural product, to investigate its anti-inflammatory effects and its protective effects against lung injury. Western blot analysis, reverse transcription-quantitavie PCR (RT-qPCR), immunohistochemistry, enzyme-linked immunosorbent assay (ELISA) and the analysis of biochemical indicators were used to determine the key signaling pathway involved in the development of lung injury. The results indicated that, on the one hand, baicalin exerted potent anti-inflammatory effects by inhibiting the activation of the CX3CL1-CX3CR1 axis and NF-κB, thus preventing the the crosstalk between the CX3CL1‑CX3CR1 axis and NF-κB pathway. In addition, the phosphorylation of AKT, which was significantly induced by LPS-induced ALI through the CX3CL1-CX3CR1 axis, was inhibited by treatment with baicalin. On the other hand, we further investigated the role of the CX3CL1-CX3CR1 axis in lung injury. We determined the diffrences in the expression levels of CX3CR1 between wild-type (WT) and CX3CL1-/- mice in order to establish its association with lung injury. Our results indicated that CX3CL1 may be the central and major indicator in the process of lung injury, which mediates the CX3CR1 receptor to activate AKT and further promote NF-κB activation. These findings demonstrate that the crosstalk between the CX3CL1-CX3CR1 axis and NF-κB signaling pathway plays a direct role in LPS-induced lung injury. The inhibition of the activation of the CX3CL1-CX3CR1 axis may thus suppress the development of ALI. In addition, baicalin inhibited the crosstalk between the CX3CL1-CX3CR1 axis and NF-κB pathway in mice with LPS-induced ALI. Thus, treatment with baicalin may be a potential therapeutic strategy for ALI.

Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular injury and initial fibrosis severity has been suggested as an important prognostic factor of NASH. Silymarin was reported to improve carbon tetrachloride-induced liver fibrosis and reduce the activation of hepatic stellate cells (HSC). We investigated whether silymarin could suppress the activation of HSCs in NASH induced by methionine- and choline-deficient (MCD) diet fed to insulin-resistant rats. NASH was induced by feeding MCD diet to obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Non-diabetic Long-Evans Tokushima Otsuka (LETO) rats were fed with standard chow and served as the control. OLETF rats were fed on either standard laboratory chow, or MCD diet or MCD diet mixed with silymarin. Histological analysis of the liver showed improved non-alcoholic fatty liver disease (NAFLD) activity score in silymarin-fed MCD-induced NASH. Silymarin reduced the activation of HSCs, evaluated by counting α-smooth muscle actin (SMA)-positive cells and measuring α-SMA mRNA expression in the liver lysates as well as in HSCs isolated from the experimental animals. Although silymarin decreased α(1)-procollagen mRNA expression in isolated HSCs, the anti-fibrogenic effect of silymarin was not prominent so as to show significant difference under histological analysis. Silymarin increased the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased tumor necrosis factor (TNF)-α mRNA expression in the liver. Our study suggested that the possible protective effect of silymarin in diet induced NASH by suppressing the activation of HSCs and disturbing the role of the inflammatory cytokine TNF-α.

Epidemiological studies have shown that exposure to ethanol during pregnancy can result in an increased risk for depression in offspring. A 'brain‑derived neurotrophic factor (BDNF) hypothesis' has been proposed to help explain the pathogenic mechanism of depression. This study was designed to verify the enhanced susceptibility to depression in prenatal ethanol exposure (PEE) offspring rats and explore possible intrauterine programming mechanisms related to the BDNF signaling pathway. Pregnant rats were intragastrically administrated ethanol (4 g/kg/day) from gestational day 11 until term delivery. All offspring rats were given a high‑fat diet after weaning. Then the behavior tests, including sucrose preference test and open field test, were performed to adult offspring rats. The histomorphology of hippocampus was examined, and the expression of genes related to the BDNF signaling pathway was detected in the hippocampus of PEE offspring. The PEE female adult offspring rats showed depression‑like behavior, with obvious morphological injury in hippocampus. Additionally, the mRNA expression levels of glucocorticoid receptor (GR) and BDNF pathway‑associated genes were changed in hippocampus. Multigene RT‑qPCR also revealed that the mRNA expression levels for BDNF pathway‑associated genes and synaptic plasticity genes were decreased in the hippocampus of fetal offspring rats in the PEE group. The underlying mechanism involves an increased GR expression that constantly suppresses the BDNF signaling pathway, and aggravates the functional insult to the hippocampus, resulting in an increased susceptibility to depression among PEE female adult offspring rats. Results of the present study provide theoretical and experimental evidence that can be used for the early prevention and treatment of depression.

Hepatitis B virus X protein (HBx) is a multifunctional protein, and it activates multiple signal transduction pathways in multiple types of cells and regulates the process of cell apoptosis. In the present study, we mainly investigated the correlation between HBx and renal tubular epithelial cell apoptosis in hepatitis B virus-associated glomerulonephritis (HBVGN) and the possible signaling mechanism. Cell apoptosis in nephridial tissues of patients with HBVGN were determined by the TUNEL method. HBx, p-STAT3 and STAT3 levels in nephridial tissues were determined by immunohistochemical assay, and a correlation analysis between HBx expression levels and apoptosis index in nephridial tissues was conducted. The activation of the JAK2/STAT3 signaling pathway in HK-2 cells and the expression of the apoptosis-related proteins Bax and Bcl-2 were determined by western blot analysis following transfection with the HBx eukaryotic expression vector. Cellular proliferation activity was determined by the CCK‑8 method, and cell apoptosis was determined with HO33342 staining using transmission electron microscopy and Annexin V/PI double staining flow cytometry. The results revealed that the apoptosis index in nephridial tissues of patients with HBVGN was significantly higher when compared to that of the control group, and p-STAT3 expression levels in HBVGN nephridial tissues were significantly increased. In the control group, no HBx expression was observed in the nephridial tissues, whereas HBx expression was found in the nephridial tissues of 86% of the patients with HBVGN. The HBx expression levels had a linear correlation with the apoptosis index in the nephridial tissues. After target gene HBx infection, expression levels of both p-JAK2 and p-STAT3 in human proximal HK-2 cells were significantly increased, and the Bax/Bcl-2 ratio was also significantly increased. At the same time, cellular proliferation of HK-2 cells was significantly inhibited, and the rate of apoptosis was increased. After incubation with AG490, the JAK2/STAT3 signaling pathway was partially blocked, which caused a decrease in the Bax/Bcl-2 ratio and reduced cell apoptosis caused by HBx. In conclusion, HBx upregulates the Bax/Bcl-2 ratio by activating the JAK2/STAT3 signaling pathway to cause renal tubular epithelial cell apoptosis, and it is possibly involved in the pathogenic mechanism of nephridial tissue damage caused by HBV.

The aim of the present study was to explore the possible mechanisms by which hypertonic saline (HS) effectively ameliorates cerebral oedema via the vascular endothelial growth factor receptor 2 (VEGFR2)‑mediated endothelial nitric oxide synthase (eNOS) pathway of endothelial cells in rats. A middle cerebral artery occlusion (MCAO) model in Sprague‑Dawley rats and an oxygen‑glucose deprivation (OGD) model in cells were used in the present study. Evans blue (EB) staining and a horseradish peroxidase flux assay were performed to evaluate the protective effect of 10% HS on the blood‑brain barrier (BBB). The expression levels of vascular endothelial growth factor (VEGF), VEGFR2, zonula occludens 1 (ZO1) and occludin were quantified. The results demonstrated that 10% HS effectively reduced EB extravasation in the peri‑ischaemic brain tissue. At 24 h after MCAO, the protein expression levels of VEGF and VEGFR2 in the peri‑ischaemic brain tissue were downregulated following treatment with 10% HS. In vitro experiments demonstrated that the permeability of a monolayer endothelial cell barrier was decreased significantly following HS treatment. In addition, VEGF and VEGFR2 protein expression levels were increased in endothelial cells under hypoxic conditions, but that effect was suppressed by HS treatment. Furthermore, HS inhibited the downregulation of ZO1 and occludin effectively, possibly through the VEGFR2/phospholipase C γ1 (PLCγ1)/eNOS signalling pathway. In conclusion, 10% HS may alleviate cerebral oedema through reducing ischaemia‑induced BBB permeability, as a consequence of inhibiting VEGFR2/PLCγ1/eNOS‑mediated downregulation of ZO1 and occludin.

B7-H3, a member of the B7-family molecules, plays an important role in adaptive immune responses. In addition, B7-H3 is also expressed in several types of human cancers and is correlated with the poor outcome of cancer patients. However, its exact role in cancer is not known. In the present study, we compared B7-H3 expression in normal pancreas and pancreatic cancer tissue specimens, and determined the effects of low B7-H3 expression on the human pancreatic cancer cell line Patu8988 using lentivirus-mediated RNA interference. B7-H3 expression in pancreatic specimens was determined by enzyme-linked immunosorbent assay (ELISA). A Patu8988 cell line with low B7-H3 expression was established by lentivirus-mediated RNA interference to investigate the effect of B7-H3 on cell proliferation, migration and invasion in vitro. By establishing subcutaneous transplantation tumor and orthotopic transplantation pancreatic cancer mouse models, the effect of B7-H3 on cell proliferation, migration and invasion was studied in vivo. B7-H3 in tissue samples was significantly higher in the pancreatic cancer group than in the normal pancreas group (mean ± SD, 193.6±9.352 vs. 87.74±7.433 ng/g; P<0.0001). B7-H3 knockdown by RNA interference decreased cell migration and Transwell invasion up to 50% in vitro. No apparent impact was observed on cell proliferation in vitro. In the subcutaneous transplantation tumor mouse model, the tumor growth rate was reduced by the knockdown of B7-H3. In the orthotopic transplantation pancreatic cancer mouse model, the effect of inhibiting metastasis by knocking down B7-H3 was assessed in terms of the average postmortem abdominal visceral metastatic tumor weight. This demonstrated that inhibition of B7-H3 expression reduced pancreatic cancer metastasis in vivo. In conclusion, B7-H3 is aberrantly expressed in pancreatic cancer. In addition to modulating tumor immunity, B7-H3 may have a novel role in regulating pancreatic tumor progression.

In a previous study by our group, we demonstrated that electroacupuncture (EA) activates the class I phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. There is considerable evidence that the downstream mammalian target of rapamycin complex 1 (mTORC1) plays an important role in autophagy following ischemic stroke. The aim of the present study was to determine whether EA exerts a neuroprotective effect through mTORC1-mediated autophagy following ischemia/reperfusion injury. Our results revealed that EA at the LI11 and ST36 acupoints attenuated motor dysfunction, improved neurological deficit outcomes and decreased the infarct volumes. The number of autophagosomes, autolysosomes and lysosomes was decreased following treatment with EA. Simultaneously, the levels of the autophagosome membrane maker, microtubule-associated protein 1 light chain 3 beta (LC3B)Ⅱ/Ⅰ, Unc-51-like kinase 1 (ULK1), autophagy related gene 13 Atg13) and Beclin1 (ser14) were decreased, whereas mTORC1 expression was increased in the peri-infarct cortex. These results suggest that EA protects against ischemic stroke through the inhibition of autophagosome formation and autophagy, which is mediated through the mTORC1-ULK complex-Beclin1 pathway.

Acute kidney injury (AKI) is often accompanied by inflammation. Echinacea polysaccharide (EP) is an active ingredient that has been demonstrated to possess anti‑oxidative, anti‑inflammatory, antimicrobial and immunomodulatory functions. However, the role of EP in AKI has not been examined. The present study investigated the effects of EP on lipopolysaccharide (LPS)‑induced AKI. Western blotting, immunohistochemistry and immunofluorescence analyses were performed to detect protein expression levels. Administration of EP significantly attenuated LPS‑induced renal tissue injury, along with a decrease in blood urea nitrogen and creatinine levels. EP decreased the levels of inducible nitric oxide synthase and cyclo‑oxygenase‑2 in LPS‑treated mice. Furthermore, LPS‑induced inflammation was inhibited by EP in renal tissues and HBZY‑1 cells, as demonstrated by the downregulation of tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6, nitric oxide and prostaglandin E2 levels. Similarly, EP administration decreased oxidative stress (OS) via decreasing reactive oxygen species, malondialdehyde and oxidized glutathione levels, and increasing superoxide dismutase, catalase, glutathione reductase and reduced glutathione activity. Notably, EP induced a marked decrease in the expression levels of phospho‑extracellular signal‑regulated protein kinase (p‑ERK), phospho‑c‑Jun N‑terminal kinase (p‑JNK) and p‑p38 in vivo and in vitro. In addition, in LPS‑treated HBZY‑1 cells, EP enhanced cell viability and inhibited nuclear translocation of p‑ERK, p‑JNK and p‑p38. Overall, the present findings demonstrated that EP alleviated LPS‑induced AKI via the suppression of inflammation, OS and the mitogen‑activated protein kinase signaling pathway, providing insight into potential avenues for the treatment of AKI.

Gentianella acuta (G. acuta) is one of the most commonly used herbs in Chinese Mongolian medicine for the treatment of heart disease. Previously, it was found that G. acuta ameliorated cardiac function and inhibited isoproterenol (ISO)‑induced myocardial fibrosis in rats. In this study, the underlying anti‑fibrotic mechanism of G. acuta was further elucidated. Histopathological changes in the heart were observed by hematoxylin‑eosin, Masson trichrome and wheat germ agglutinin staining. Relevant molecular events were investigated using immunohistochemistry and western blotting. The results revealed that G. acuta caused improvements in myocardial injury and fibrosis. G. acuta also inhibited collagens I and III and α‑smooth muscle actin production in heart tissue. G. acuta downregulated the expression of transforming growth factor β1 (TGF‑β1) and notably inhibited the levels of phosphorylation of TGF‑β receptors I and II. Furthermore, G. acuta caused downregulation of the intracellular mothers against decapentaplegic homolog (Smads)2 and 4 expression and inhibited Smads2 and 3 phosphorylation. The results further demonstrated that the mechanism underlying anti‑myocardial fibrosis effects of G. acuta was based upon the suppression of the TGF‑β1/Smads signaling pathway. Therefore, G. acuta may be a potential therapeutic agent for ameliorating myocardial fibrosis.

Diabetes, as a serious metobolic disorder, poses global threat to human health. It is estimated that over 50 million individuals are already affected by diabetes. Currently, diabetes-related osteoporosis has been a research hotspot due to its high incidence rate in older individuals. Osteoprotegerin, as an important protein for the prevention of osteoporosis, has been proven to be key to the suppression of osteoporosis. Hence, the loss of function of osteoprotegerin may promote the development of osteoporosis. Bergapten, as a natural anti-inflammatory and anti-tumor agent isolated from bergamot essential oil, other citrus essential oils, and grapefruit juice, has been proven to have the ability to attenuate a number of metabolic disorders. In view of these findings, in this study, we used a high-fat diet to construct a mouse model of diabetes-related osteoporosis and a mouse model of diabetes-related osteoporosis using osteoprotegerin knockout mice. Enzyme-linked immunosorbent assay (ELISA), qPCR, western blot analysis, immunohistochemical assay, H&E staining, Oil Red O staining, Masson's staining and other biochemical analyses were used to evaluate the related signaling pathways involved in the development of diabetes-related osteoporosis. We also examined the role of osteoprotegerin in the activation of these pathways and in the development of osteoporosis, as well as the protective effects of bergapten against diabetes-related osteoporosis and on the activation of related signaling pathways. Our results revealed that in diabetes-related osteoporosis, the phosphoinositide 3-kinase (PI3K)/AKT, c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) signaling pathways were activated and the expression levels of related indicators were increased. At the same time, osteoprotegerin knockout further promoted the activation of these pathways. By contrast, bergapten exerted effects similar to those of osteoprotegerin. Bergapten exhibited the ability to significantly inhibit RANKL-RANK signaling transduction, and to suppress the activation of the PI3K/AKT, JNK/MAPK and NF-κB signaling pathways, thus protecting trabecular structure and decreasing osteoclastogenic differentiation.

Sepsis-induced acute kidney injury (AKI) represents a major cause of mortality in intensive care units. Sivelestat, a selective inhibitor of neutrophil elastase (NE), can attenuate sepsis-related acute lung injury. However, whether sivelestat can preserve kidney function during sepsis remains unclear. In this study, we thus examined the effects of sivelestat on sepsis-related AKI. Cecal ligation and puncture (CLP) was performed to induce multiple bacterial infection in male Sprague-Dawley rats, and subsequently, 50 or 100 mg/kg sivelestat were administered by intraperitoneal injection immediately after the surgical procedure. In the untreated rats with sepsis, the mean arterial pressure (MAP) and glomerular filtration rate (GFR) were decreased, whereas serum blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels were increased. We found that sivelestat promoted the survival of the rats with sepsis, restored the impairment of MAP and GFR, and inhibited the increased BUN and NGAL levels; specifically, the higher dose was more effective. In addition, sivelestat suppressed the CLP-induced macrophage infiltration, the overproduction of pro-inflammatory mediators (tumor necrosis factor‑α, interleukin-1β, high-mobility group box 1 and inducible nitric oxide synthase) and serine/threonine kinase (Akt) pathway activation in the rats. Collectively, our data suggest that the inhibition of NE activity with the inhibitor, sivelestat, is beneficial in ameliorating sepsis-related kidney injury.

α-mangostin is a dietary xanthone which has been shown to have antioxidant, anti-allergic, antiviral, antibacterial, anti-inflammatory and anticancer effects in various types of human cancer cells. In the present study, we aimed to elucidate the molecular mechanisms responsible for the apoptosis-inducing effects of α-mangostin on YD-15 tongue mucoepidermoid carcinoma cells. The results from MTT assays revealed that cell proliferation significantly decreased in a dose-dependent manner in the cells treated with α-mangostin. DAPI staining illustrated that chromatin condensation in the cells treated with 15 µM α-mangostin was far greater than that in the untreated cells. Flow cytometric analysis indicated that α-mangostin suppressed YD-15 cell viability by inducing apoptosis and promoting cell cycle arrest in the sub-G1 phase. Western blot analysis of various signaling molecules revealed that α-mangostin targeted the extracellular signal‑regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) signaling pathways through the inhibition of ERK1/2 and p38 phosphorylation in a dose‑dependent manner. α-mangostin also increased the levels of Bax (pro-apoptotic), cleaved caspase-3, cleaved caspase-9 and cleaved-poly(ADP-ribose) polymerase (PARP), whereas the levels of the anti-apoptotic factors, Bcl-2 and c-myc, decreased in a dose-dependent manner. The anticancer effects of α-mangostin were also investigated in a tumor xenograft mouse model. The α-mangostin-treated nude mice bearing YD-15 tumor xenografts exhibited a significantly reduced tumor volume and tumor weight due to the potent promoting effects of α-mangostin on cancer cell apoptosis, as determined by TUNEL assay. Immunohistochemical analysis revealed that the level of cleaved caspase-3 increased, whereas the Ki-67, p-ERK1/2 and p-p38 levels decreased in the α-mangostin‑treated mice. Taken together, the findings of our study indicate that α-mangostin induces the apoptosis of YD-15 tongue carcinoma cells through the ERK1/2 and p38 MAPK signaling pathways.

The root of Cynanchum wilfordii (C. wilfordii) contains several biologically active compounds which have been used as traditional medicines in Asia. In the present study, we evaluated the anti-inflammatory effects of an ethanol root extract of C. wilfordii (CWE) on tumor necrosis factor (TNF)-α-stimulated human aortic smooth muscle cells (HASMCs). The inhibitory effects of CWE on vascular cell adhesion molecule (VCAM)-1 expression under an optimum extraction condition were examined. CWE suppressed the expression of VCAM-1 and ICAM-1 and the adhesion of THP-1 monocytes to the TNF-α-stimulated HASMCs. Consistent with the in vitro observations, CWE inhibited the aortic expression of ICAM-1 and VCAM-1 in atherogenic diet-fed mice. CWE also downregulated the expression of nuclear factor-κB (NF-κB p65) and its uclear translocation in the stimulated HASMCs. In order to identify the active components in CWE, we re-extracted CWE using several solvents, and found that the ethyl acetate fraction was the most effective in suppressing the expression of VCAM-1 and ICAM-1. Four major acetophenones were purified from the ethyl acetate fraction, and two components, p-hydroxyacetophenone and cynandione A, potently inhibited the expression of ICAM-1 and VCAM-1 in the stimulated HASMCs. We assessed and determined the amounts of these two active components from CWE, and our results suggested that the root of C. wilfordii and its two bioactive acetophenones may be used for the prevention and treatment of atherosclerosis and vascular inflammatory diseases.

Isosteviol sodium (STVNa), which is a derivate of the natural sweet‑tasting glycoside stevioside, has recently been developed and it has been determined that this compound exhibits neuro‑ and cardio‑protective properties. In the current study, whether STVNa interferes with the development of cardiac hypertrophy, which is induced by isoprenaline (Iso), was investigated in an experimental rat model. Rats were treated with a vehicle (0.9% NaCl; control), isoprenaline (Iso; 5 mg/kg) or Iso (5 mg/kg) with STVNa (4 mg/kg; Iso + STVNa). Cardiomyocytes were isolated using enzymatic dissociation and were treated with 5 µM Iso for 24 h and co‑treated with 5 µM STVNa. Brain natriuretic peptide (BNP) mRNA expression was determined using PCR analysis. Cell surface area, intracellular reactive oxygen species (ROS), mitochondrial transmembrane potential (ΔΨm), cytoplasmic Ca2+ and Ca2+ and contractile function were examined using a laser scanning confocal microscope. The current study demonstrated that STVNa inhibited Iso‑induced cardiac hypertrophy by inhibiting cardiomyocyte size. STVNa significantly reduced cell surface area and decreased BNP mRNA expression in ventricular cardiomyocyte Iso‑induced hypertrophy. STVNa was also revealed to restore ΔΨm and reduce ROS generation and intracellular Ca2+ concentration when compared with the Iso‑treated group. Additionally, STVNa preserved Ca2+ transients in hypertrophic cardiomyocytes. In conclusion, the present study demonstrated that STVNa protects against Iso‑induced myocardial hypertrophy by reducing oxidative stress, restoring ΔΨm and maintaining Ca2+ homeostasis.

Cartilage‑derived morphogenetic protein‑1 (CDMP1) is a polypeptide growth factor with specific cartilage inducibility, which is predominantly expressed in the developmental long bone cartilage core and in the pre‑cartilage matrix in the embryonic stage. The aim of the present study was to investigate the roles and the mechanisms of CDMP1 overexpression on the apoptosis of rat dorsal root ganglia (DRG) neurons that were induced by inflammatory cytokines. Cell counting Kit‑8 assay, flow cytometry and TdT‑mediated dUTP nick‑end labeling assay were performed to examine cell viability and apoptosis. ELISA, hematoxylin and eosin staining and immunohistochemistry assays were performed to examine the levels of several factors in DRG tissues. Western blot analysis and reverse transcription‑quantitative polymerase chain reaction assays were used to determine the mRNA and protein expression levels, respectively. The results demonstrated that CDMP1 expression was downregulated, while inflammatory cytokine expression was upregulated in DRG tissues derived from lumbar disc herniation (LDH) model rats. In addition, DRG cells from LDH rats exhibited increased apoptosis compared with control rats. CDMP1 overexpression enhanced the cell viability of inflammatory cytokine‑induced DRG cells, and suppressed the apoptosis of inflammatory cytokine‑induced DRG cells via regulating the expression levels of Caspase‑3/8/9, BCL2 apoptosis regulator, and BCL2 associated X. Furthermore, CDMP1 overexpression was demonstrated to affect the Wnt/β‑Catenin pathway in the inflammatory cytokine‑induced DRG cells. In conclusion, the present findings suggested that CDMP1 overexpression mediated inflammatory cytokine‑induced apoptosis via Wnt/β‑Catenin signaling in rat DRG cells.

Leukemia is a type of cancer which originates in blood‑forming tissues. MicroRNAs (miRNAs or miRs) have been shown to be involved leukemogenesis. In the present study, following the gain‑ and loss‑function of miR‑145 and ATP‑binding cassette sub‑family E member 1 (ABCE1) in K562 cells and K562 adriamycin‑resistant cells (K562/ADM cells), the levels of multidrug resistance protein 1 (MRP1) and P‑glycoprotein (P‑gp) were measured. The viability of the K562 cells and K562/ADM cells treated with various concentrations of ADM, and cell sensitivity to ADM were measured. The apoptosis of stem cells was detected. K562/ADM cells were transfected with miR‑145 mimic or with miR‑145 mimic together with ABCE1 overexpression plasmid to examine the effects of ABCE1 on the sensitivity of K562/ADM cells to ADM. The association between miR‑145 and ABCE1/MRP1 was then verified. The dose‑ and time‑dependent effects of ADM on the K562 cells and K562/ADM cells were examined. The K562/ADM cells exhibited a greater resistance to ADM, higher levels of MRP1 and P‑gp, and a lower miR‑145 expression. The K562/ADM cells and stem cells in which miR‑145 was overexpressed exhibited a suppressed cell proliferation, decreased MRP1 and P‑gp levels, and an increased apoptotic rate. However, K562 cells with a low expression of miR‑145 exhibited an increased cell proliferation, increased levels of MRP1 and P‑gp, and a suppressed apoptotic rate. Compared with the overexpression of miR‑145, the combination of miR‑145 and ABCE1 decreased the sensitivity of drug‑resistant K562/ADM cells to ADM. The above‑mentioned effects of miR‑145 were achieved by targeting ABCE1. Taken together, the findings of the present study demonstrate that the overexpression of miR‑145 promotes leukemic stem cell apoptosis and enhances the sensitivity of K562/ADM cells to ADM by inhibiting ABCE1.

Chemoresistance to anticancer drugs is a major obstacle in the efforts to develop a successful treatment strategy for esophageal squamous carcinoma (ESCC). Thus, the exploration of new drugs and treatment strategies for combating resistance are of utmost importance. In this study, we investigated the antitumor drug resistance activity of Jesridonin, a new ent-kaurene diterpenoid, and its possible mechanisms of action using the resistant cancer cell line, EC109/Taxol. MTT assay revealed that Jesridonin had similar IC50 values against EC109 paclitaxel-sensitive cells and drug-resistant EC109/Taxol cells in vitro. In mice, Jesridonin effectively prevented the growth of EC109/Taxol tumor xenografts without exerting any significant toxicity. In addition, Jesridonin significantly inhibited the proliferation of EC109/Taxol cells, induced apoptosis and arrested the cell cycle at the G2/M phase. Furthermore, western blot analysis revealed that Jesridonin upregulated the expression of p53, p53 upregulated modulator of apoptosis (PUMA), cleaved-caspase-9 and cleaved-caspase-3 in EC109/Taxol cells, and downregulated the expression of procaspase-3, procaspase-9 and Bcl-2 in the EC109/Taxol cells in a concentration-dependent manner. Overall, our results demonstrate that Jesridonin may have potential for use in the treatment of paclitaxel-resistant ESCC. The data of the present study may lead to the development of novel treatment strategies for paclitaxel-resistant tumors.

Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced acute lung injury (ALI). High-mobility group box 1 (HMGB1), a nuclear DNA-binding protein, plays a key role in the development of ALI. The aim of this study was to investigate whether UTI attenuates ALI through the inhibition of HMGB1 expression and to elucidate the underlying molecular mechanisms. ALI was induced in male rats by the intratracheal instillation of LPS (5 mg/kg). UTI was administered intraperitoneally 30 min following exposure to LPS. A549 alveolar epithelial cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines. Western blot analysis was performed to detect the changes in the expression levels of Toll-like receptor 2/4 (TLR2/4) and the activation of nuclear factor-κB (NF-κB). The results revealed that UTI significantly protected the animals from LPS-induced ALI, as evidenced by the decrease in the lung wet to dry weight ratio, total cells, neutrophils, macrophages and myeloperoxidase activity, associated with reduced lung histological damage. We also found that UTI post-treatment markedly inhibited the release of HMGB1 and other pro-inflammatory cytokines. Furthermore, UTI significantly inhibited the LPS-induced increase in TLR2/4 protein expression and NF-κB activation in lung tissues. In vitro, UTI markedly inhibited the expression of TLR2/4 and the activation of NF-κB in LPS-stimulated A549 alveolar epithelial cells. The findings of our study indicate that UTI attenuates LPS-induced ALI through the inhibition of HMGB1 expression in rats. These benefits are associated with the inhibition of the activation of the TLR2/4-NF-κB pathway by UTI.

Intestinal ischemia/reperfusion (IIR) is a common pathological event associated with intestinal injury and apoptosis with high mortality. Nuclear factor (NF)-E2-related factor-2 (Nrf2) is a key transcription factor that interacts with NF-κB and has a vital anti-inflammatory effect. However, whether Nrf2 has a role in IIR-induced apoptosis and the possible underlining mechanisms, such as modulation of the inflammation regulation pathway, have remained to be fully elucidated. In the present study, IIR was identified to cause significant intestinal injury and apoptosis, with high expression levels of inflammatory cytokines, as well as the apoptotic proteins B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax) and caspase-3, while simultaneously decreasing the protein levels of Bcl-2. The effect was more pronounced after pretreatment of the animals with all-trans retinoic acid or brusatol, potent inhibitors of Nrf2. t-Butylhydroquinone, an Nrf2 activator, significantly attenuated IIR-induced intestinal injury and apoptosis, with inhibition of the overexpression of the inflammatory cytokines, Bax and caspase-3 protein and partial restoration of Bcl-2 protein expression. Taken together, these results indicated that increased Nrf2 expression reduced IIR-induced intestinal apoptosis and that the protective function of Nrf2 may be based on its anti-inflammatory effects through the inhibition of the NF-κB pathway.