Moscatilin inhibits vascular calcification by activating IL13RA2-dependent inhibition of STAT3 and attenuating the WNT3/ß-catenin signalling pathway.

INTRODUCTION: Vascular calcification, a devastating vascular complication accompanying atherosclerotic cardiovascular disease and chronic kidney disease, increases the incidence of adverse cardiovascular events and compromises the efficacy of vascular interventions. However, effective therapeutic drugs and treatments to delay or prevent vascular calcification are lacking. OBJECTIVES: This study was designed to test the therapeutic effects and mechanism of Moscatilin (also known as dendrophenol) from Dendrobium huoshanense (an eminent traditional Chinese medicine) in suppressing vascular calcification in vitro, ex vivo and in vivo. METHODS: Male C57BL/6J mice (25-week-old) were subjected to nicotine and vitamin D3 (VD3) treatment to induce vascular calcification. In vitro, we established the cellular model of osteogenesis of human aortic smooth muscle cells (HASMCs) under phosphate conditions. RESULTS: By utilizing an in-house drug screening strategy, we identified Moscatilin as a new naturally-occurring chemical entity to reduce HASMC calcium accumulation. The protective effects of Moscatilin against vascular calcification were verified in cultured HASMCs. Unbiased transcriptional profiling analysis and cellular thermal shift assay suggested that Moscatilin suppresses vascular calcification via binding to interleukin 13 receptor subunit A2 (IL13RA2) and augmenting its expression. Furthermore, IL13RA2 was reduced during HASMC osteogenesis, thus promoting the secretion of inflammatory factors via STAT3. We further validated the participation of Moscatilin-inhibited vascular calcification by the classical WNT/ß-catenin pathway, among which WNT3 played a key role in this process. Moscatilin mitigated the crosstalk between WNT3/ß-catenin and IL13RA2/STAT3 to reduce osteogenic differentiation of HASMCs. CONCLUSION: This study supports the potential of Moscatilin as a new naturally-occurring candidate drug for treating vascular calcification via regulating the IL13RA2/STAT3 and WNT3/ß-catenin signalling pathways.

The pterostilbene-dihydropyrazole derivative Ptd-1 ameliorates vascular calcification by regulating inflammation.

Vascular calcification is an independent risk factor for cardiovascular disease. However, there is still a lack of adequate treatment. This study aimed to examine the potential of (E)-1-(5-(2-(4-fluorobenzyloxy)Styryl)-4,6-dimethoxyphenyl)-3-methyl-4,5-dihydro-1H-pyrazole-1-yl) ethyl ketone (Ptd-1) to alleviate vascular calcification. ApoE-deficient mice were fed a high-fat diet for 12/16 weeks to induce intimal calcification, and wild-type mice were induced with a combination of nicotine and vitamin D3 to induce medial calcification. Human aortic smooth muscle cells (HASMCs) and aortic osteogenic differentiation were induced in vitro with phosphate. In the mouse model of atherosclerosis, Ptd-1 significantly ameliorated the progression of atherosclerosis and intimal calcification, and there were significant reductions in lipid deposition and calcium salt deposition in the aorta and aortic root. In addition, Ptd-1 significantly improved medial calcification in vivo and osteogenic differentiation in vitro. Mechanistically, Ptd-1 reduced the levels of the inflammatory factors IL-1ß, TNFα and IL-6 in vivo and in vitro. Furthermore, we demonstrated that Ptd-1 could attenuate the expression of p-ERK1/2 and ß-catenin, and that the levels of inflammatory factors were elevated in the presence of ERK1/2 and ß-catenin agonists. Interestingly, we determined that activation of the ERK1/2 pathway promoted ß-catenin expression, which further regulated the IL-6/STAT3 signaling pathway. Ptd-1 blocked ERK1/2 signaling, leading to decreased expression of inflammatory factors, which in turn improved vascular calcification. Taken together, our study reveals that Ptd-1 ameliorates vascular calcification by regulating the production of inflammatory factors, providing new ideas for the treatment of vascular calcification.

Erastin induces ferroptosis in cervical cancer cells via Nrf2/HO-1 signaling pathway.

OBJECTIVE: Our research aims to assess the influence of erastin, a ferroptosis-inducing agent, on cervical cancer cells. INTRODUCTION: Cervical cancer is a prevalent malignancy in females. Dysregulation of ferroptosis, a form of cell demise reliant on iron, is implicated in several cancers. METHODS: The effect of erastin on HeLa and SiHa was detected by transwell assay, scratch test, and colony formation assay, while cell apoptosis was detected using flow cytometry. Cellular reactive oxygen species (ROS) generation was detected using the dichloro-dihydro-fluorescein diacetate assay. Sequencing analysis identified differentially expressed genes (DEGs), and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Enrichment analyses were employed to identify the target gene. Subsequently, the utilization of small interfering RNA (siRNA) was employed to suppress the targeted gene expression in HeLa cells, thereby effectively mitigating the impact of erastin on various cellular processes including invasion, colony formation, migration, and ROS generation. RESULTS: The findings indicate that erastin attenuates the viability of both HeLa cells (IC50 = 30.88 µM) and SiHa cells (IC50 = 29.40 µM). Treatment with erastin at 10 µM inhibits the invasion, colony formation, and migration of both HeLa and SiHa cells within 24 h. Ferrostatin-1 (1 µM) notably alleviates the inhibitory effects of erastin of HeLa and SiHa cells. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream target, heme oxygenase-1 (HO-1), was found in erastin-treated cells compared to the control group. When knocked down HO-1 in HeLa cells, effectively counteracting the effects of erastin on the invasion, colony formation, migration, and ROS production in HeLa cells. CONCLUSION: Our research demonstrates that erastin induces ferroptosis and the accumulation of ROS in cervical cancer cells by activating the Nrf2/HO-1 pathway, significantly reducing cell proliferation and motility. These findings propose a potential molecular mechanism of erastin-mediated cervical cancer development.

Application effect of gastrointestinal bundle nursing on the protection of gastrointestinal function in patients with gastric cancer.

Evidence-based nursing practice was used to formulate the enhanced recovery surgery bundle nursing strategy and apply it to patients with gastric cancer, to explore its safety, effectiveness and feasibility in perioperative gastrointestinal function protection in patients with gastric cancer. Selected the clinical medical records of 100 gastric cancer patients treated in our hospital from June 2019 to June 2021 as the research objects, and divided them into the control group and the observation group with 50 cases in each group according to the random number table. Among them, the control group was given routine nursing measures for nursing intervention, and the observation group was given gastrointestinal enhanced recovery surgery cluster nursing on the basis of the control group. The differences in stress response, gastrointestinal function protection, negative emotions and pain scores of gastric cancer patients before and after nursing were compared between the 2 groups. The postoperative bowel sounds recovery time, first anal exhaust, and first defecation time in the observation group were lower than those in the control group, and the differences were statistically significant (P < .05). Before nursing, there was no significant difference in the scores of stress response changes between the 2 groups (P > .05). After nursing, heart rate (HR), mean arterial pressure (MAP), norepinephrine (NE), and epinephrine (E2) in the observation group were lower than those in the control group, and the difference was statistically significant (P < .05). The pain scores of the 2 groups were significantly improved at different time points, and the observation group was significantly less than the control group, and the difference was statistically significant (P < .05). Gastrointestinal enhanced recovery surgery bundle nursing can effectively improve the gastrointestinal function of patients with gastric cancer, improve the emotional response and stress response of patients, and has certain reference value for the nursing of patients with gastric cancer.

Nogo-B inhibition restricts ulcerative colitis via inhibiting p68/miR-155 signaling pathway.

BACKGROUND & AIMS: Ulcerative colitis (UC) is a main type of inflammatory bowel diseases which spreads globally during the westernization of lifestyle over the past few decades. However, the cause of UC is still not fully understood. We aimed to disclose the role of Nogo-B in the development of UC. METHODS: Nogo-deficiency (Nogo-/-) and wild-type male mice were treated with dextran sodium sulfate (DSS) to conduct a UC model, followed by determination of colon and serum inflammatory cytokines level. RAW264.7, THP1 and NCM460 cells were used to determine macrophage inflammation as well as proliferation and migration of NCM460 cells under Nogo-B or miR-155 intervention. RESULTS: Nogo deficiency significantly reduced DSS-induced weight loss, colon length and weight reduction, and inflammatory cells accumulation in the intestinal villus, while increased the expression of tight junctions (TJs) proteins (Zonula occludens-1, Occludin) and adherent junctions (AJs) proteins (E-cadherin, α-catenin), implying that Nogo deficiency attenuated DSS-induced UC. Mechanistically, Nogo-B deficiency reduced TNFα, IL-1ß and IL-6 levels in the colon, serum, RAW264.7 cells and THP1-derived macrophages. Furthermore, we identified that Nogo-B inhibition can reduce the maturation of miR-155, which is essential for Nogo-B-affected inflammatory cytokines expression. Interestingly, we determined that Nogo-B and p68 can interact with each other to promote the expression and activation of Nogo-B and p68, thus facilitating miR-155 maturation to induce macrophage inflammation. Blocking p68 inhibited Nogo-B, miR-155, TNFα, IL-1ß and IL-6 expression. Moreover, the culture medium collected from Nogo-B overexpressed macrophages can inhibit enterocytes NCM460 cells proliferation and migration. CONCLUSION: We disclose that Nogo deficiency reduced DSS-induced UC via inhibiting p68-miR-155-activated inflammation. Our results indicate that Nogo-B inhibition serves as a new potential therapeutic candidate for the prevention and treatment of UC.

Transcription factor 21 accelerates vascular calcification in mice by activating the IL-6/STAT3 signaling pathway and the interplay between VSMCs and ECs.

Vascular calcification is caused by the deposition of calcium salts in the intimal or tunica media layer of the aorta, which increases the risk of cardiovascular events and all-cause mortality. However, the mechanisms underlying vascular calcification are not fully clarified. Recently it has been shown that transcription factor 21 (TCF21) is highly expressed in human and mouse atherosclerotic plaques. In this study we investigated the role of TCF21 in vascular calcification and the underlying mechanisms. In carotid artery atherosclerotic plaques collected from 6 patients, we found that TCF21 expression was upregulated in calcific areas. We further demonstrated TCF21 expression was increased in an in vitro vascular smooth muscle cell (VSMC) osteogenesis model. TCF21 overexpression promoted osteogenic differentiation of VSMC, whereas TCF21 knockdown in VSMC attenuated the calcification. Similar results were observed in ex vivo mouse thoracic aorta rings. Previous reports showed that TCF21 bound to myocardin (MYOCD) to inhibit the transcriptional activity of serum response factor (SRF)-MYOCD complex. We found that SRF overexpression significantly attenuated TCF21-induced VSMC and aortic ring calcification. Overexpression of SRF, but not MYOCD, reversed TCF21-inhibited expression of contractile genes SMA and SM22. More importantly, under high inorganic phosphate (3 mM) condition, SRF overexpression reduced TCF21-induced expression of calcification-related genes (BMP2 and RUNX2) as well as vascular calcification. Moreover, TCF21 overexpression enhanced IL-6 expression and downstream STAT3 activation to facilitate vascular calcification. Both LPS and STAT3 could induce TCF21 expression, suggesting that the inflammation and TCF21 might form a positive feedback loop to amplify the activation of IL-6/STAT3 signaling pathway. On the other hand, TCF21 induced production of inflammatory cytokines IL-1ß and IL-6 in endothelial cells (ECs) to promote VSMC osteogenesis. In EC-specific TCF21 knockout (TCF21ECKO) mice, VD3 and nicotine-induced vascular calcification was significantly reduced. Our results suggest that TCF21 aggravates vascular calcification by activating IL-6/STAT3 signaling and interplay between VSMC and EC, which provides new insights into the pathogenesis of vascular calcification. TCF21 enhances vascular calcification by activating the IL-6-STAT3 signaling pathway. TCF21 inhibition may be a new potential therapeutic strategy for the prevention and treatment of vascular calcification.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Conditioned Medium Promotes Human Endometrial Cell Proliferation through Wnt/ß-Catenin Signaling.

Purpose: Mesenchymal stem cells (MSCs) and their derivant are among the promising treatments for intrauterine adhesion (IUA); they have been reported to repair the endometrial injury by proliferating endometrial cells. However, the signal pathways involved are not clear. This study investigated the role of human umbilical cord mesenchymal stem cell-derived conditioned medium (hUCMSC-CM) in relieving IUA to find out whether Wnt/ß-catenin signaling was involved, and if so, to determine the possible ligands. Methods: After endometrial epithelial cells (EECs) were treated with hUCMSC-CM, their proliferation and migration were measured by the CCK8 assay and the scratch assay. The activation of Wnt/ß-catenin signaling was measured by Western blots, fluorescent staining, and T-cell factor/lymphoid enhancer factor (TCF/LEF) luciferase. A Wnt inhibitor (XAV393) was used to inhibit the proliferation effect of hUCMSC-CM in EECs. Wnt5a expression in hUCMSC was measured by Western blots and fluorescent staining, and Wnt5a in hUCMSC-CM was detected by enzyme-linked immunosorbent assay (ELISA), to further clarify the mechanism. Results: As shown by the CCK8 assay, hUCMSC-CM promoted proliferation and migration of EECs. The expression of ß-catenin, c-myc, and cyclin D1 increased in EECs after being treated with hUCMSC-CM. Moreover, hUCMSC-CM was found to promote ß-catenin delivery into nuclei by Western blot and fluorescent staining; meanwhile, the inhibitor (XAV393) could restrain this process and inhibit the effect of hUCMSC-CM on EEC proliferation. Wnt5a was detected in hUCMSCs and hUCMSC-CM, which might be a potential therapeutic target. Conclusion: This study demonstrated that hUCMSC-CM promoted human endometrial cell proliferation through Wnt/ß-catenin signaling, and Wnt5a might be a potential activator. This would be one of the activating signal pathways in the MSC-related treatment of IUA.

Risk factors for postpartum hemorrhage in patients with retained placenta: building a predict model.

OBJECTIVES: Among patients with placenta retention, the risk factors of massive blood loss remain unclear. In this study, a secondary data analysis was conducted to construct a predictive risk model for postpartum hemorrhage (PPH) in this particular population. METHODS: A prediction model based on the data of 13 hospitals in the UK, Uganda, and Pakistan, from December 2004, to May 2008 was built. A total of 516 patients and 14 potential risk factors were analyzed. The least absolute shrinkage and selection operator regression (LASSO) model was used to optimize feature selection for the PPH risk model. Multivariable logistic regression analysis was applied to build a prediction model incorporating the LASSO model. Discrimination and calibration were assessed using C-index and calibration plot. RESULTS: Among patients with placenta retention, the incidence of PPH was 62.98% (325/526). Risk factors in the model were country, number of past deliveries, previous manual removal of placenta, place of placenta delivery, and how the placenta was delivered. In these factors, patients in the low-income country (i.e., Uganda) (OR: 1.753, 95% CI=1.055-2.915), retained placentas delivered in the theater (OR: 2.028, 95% CI=1.016-4.050), and having placentas partially removed by controlled cord traction (cct), completely removed manually (OR: 4.722, 95% CI=1.280-17.417) were independent risk factors. The C-statistics was 0.702. CONCLUSIONS: By secondary data analysis, our study constructed a prediction model for PPH in patients with placenta retention, and identified the independent risk factors.

Prevalence characteristics of cervical human papillomavirus genotypes in Nanning, China: A 10-year survey of 77,756 women from one medical center.

OBJECTIVES: The prevalence of human papillomavirus (HPV) infection and HPV genotypes varies in different regions. However, there is little data on HPV prevalence and genotyping in Guangxi Province, South China. This study conducted a 10-year survey in a health center, to estimate the prevalence characteristics of HPV genotypes. METHODS: By using polymerase chain reaction (PCR) amplification and nucleic acid molecular hybridization, the HPV genotypes were detected from 77,756 females who were patients of the Department of Obstetrics and Gynecology and those who visited the Health Management Center for a physical examination between August 2011 and November 2020. The prevalence, genotypes, age-related HPV infections, as well as chronological change of HPV prevalence, and the HPV genotype distribution were analyzed. RESULTS: The overall prevalence of HPV infection was 21.14% (16,439/77,756). The HPV infection rate differed significantly between the patients of the Department of Obstetrics and Gynecology and the women who underwent a physical examination (22.98% vs. 9.88%, p < 0.05). The prevalence rates of high-risk HPV, low-risk HPV, mixed HPV (mixed high-risk, and low-risk HPV infection), and multiple HPV infections were 18.96% (14,739/77,756), 4.09% (3178/77,756), 1.90% (1478/77,756), and 4.94% (3838/77,756), respectively. The most prevalent genotypes were HPV 52, 16, and 58. The age-associated HPV prevalence showed bimodal curves, with the first peak at <25 years and the second peak at >56 years. CONCLUSIONS: This study provides baseline data on the HPV prevalence in the general female population of Nanning, Guangxi Province. Women <25 and >56 years old faced the greatest threat of HPV infection, and HPV 52, 16, and 58 were the most common genotypes.

Correction: P62 regulates resveratrol-mediated Fas/Cav-1 complex formation and transition from autophagy to apoptosis.

[This corrects the article DOI: 10.18632/oncotarget.2733.].

Pharmacokinetics, tissue distribution, and safety evaluation of a ligustilide derivative (LIGc).

Ligustilide (LIG) is the main active ingredient of Angelica sinensis (Oliv.) Diels and has a neuroprotective effect against ischemic stroke. However, owing to its multi-conjugated unstable structure, the compound has poor drug-forming properties. Therefore, we synthesized highly stable colorless needle crystals (known as ligusticum cycloprolactam, LIGc) through the structural modification of LIG. After a stability experiment was conducted at room temperature for four months, no impurity peaks were found by HPLC-DAD analysis, which indicated that LIGc resolved the stability issues of LIG. LIGc was absorbed and eliminated rapidly after intravenous administration (Cmax = 6.42 ±â€¯1.65 mg/L at a dose of 20 mg/kg) and oral administration (Tmax = 0.5 h, Cmax = 9.89 ±â€¯1.62 mg/L at a dose of 90 mg/kg, t1/2z approximately 2.5 h). The absolute oral bioavailability (F) of LIGc was clearly higher than the F of LIG reported in the literature (F, 83.97 % versus 2.6 %). Linear dose-dependent pharmacokinetics were observed after oral administration, with a higher area under the curve (AUC0-t, 22.31 ±â€¯2.88 mg/L*h) observed at 90 mg/kg than that at 45 mg/kg (AUC0-t, 13.673 ±â€¯0.666 mg/L*h). Tissue distribution results indicated that LIGc easily crossed the blood-brain barrier (BBB) and was distributed widely to the main tissues and organs of rats. We also conducted a preliminary safety assessment of LIGc by means of an acute toxicity test in KM mice. All mice had excellent health status (ig, dosage of 5.0 g/kg), with no histopathological changes observed in the main organs.

Methamphetamine Inhibits Long-Term Memory Acquisition and Synaptic Plasticity by Evoking Endoplasmic Reticulum Stress.

Methamphetamine (MA), an illicit drug abused worldwide, leads to cognitive impairment and memory loss. However, the detailed mechanisms of MA-induced neurologic impairment are still unclear. The present study aimed to investigate the mechanisms of MA-induced inhibition of memory acquisition from the perspective of endoplasmic reticulum (ER) stress. ER stress, caused by the accumulation of wrongly folded proteins in the ER, is important for new protein synthesis, which further influence the formation of long-term memory. A subacute MA poisoning model of mice was established and several behavioral experiments were performed, including elevated plus maze, Morris water maze, electro-stimulus Y-maze, and novel object recognition tasks. The present results suggested that 4 days exposure to MA induced significant memory loss. Whereas, this damage to memory formation could be protected when mice were pre-treated with ER stress inhibitor, tauroursodeoxycholic acid (TUDCA). The results of Western blotting showed that subacute exposure to MA increased the expression levels of ER stress marker proteins, such as binding immunoglobulin protein, phosphorylated eukaryotic translation initiation factor 2α, cyclic AMP-dependent transcription factor (ATF)-4, ATF-6, and CCAAT-enhancer binding protein homologous protein. Meanwhile, the enhanced expression levels of these proteins were reversed by TUDCA, indicating that MA administration induced memory loss by evoking ER stress in the hippocampus. We also found that MA inhibited the induction of long-term potentiation (LTP) in the hippocampus. Nevertheless, LTP could be induced when mice were pre-treated with TUDCA. In conclusion, MA inhibited long-term memory acquisition and synaptic plasticity via ER stress.

miR-139-5p regulates proliferation, apoptosis, and cell cycle of uterine leiomyoma cells by targeting TPD52.

BACKGROUND: Uterine leiomyoma is one of the most common benign tumors in women. It dramatically decreases the quality of life in the affected women. However, there is a lack of effective treatment paradigms. Micro-RNAs are small noncoding RNA molecules that are extensively expressed in organisms, and they are interrelated with the occurrence and development of the tumor. miR-139-5p was found to be downregulated in various cancers, but its function and mechanism in uterine leiomyoma remain unknown. The aim of this study was to investigate the role of miR-139-5p and its target gene in uterine leiomyoma. METHODS: By using a bioinformatic assay, it was found that TPD52 was a potential target gene of miR-139-5p. Then, expressions of miR-139-5p and TPD52 in uterine leiomyoma and adjacent myometrium tissues were evaluated by quantitative real-time polymerase chain reaction and Western blot. Proliferation, apoptosis, and cell cycle of uterine leiomyoma cells transfected by miR-139-5p mimics or TPD52 siRNA were determined. RESULTS: It was observed that the expression of miR-139-5p in uterine leiomyoma tissues was significantly lower (P<0.001) than that in the adjacent myometrium tissues. Overexpression of miR-139-5p inhibited the growth of uterine leiomyoma cells and induced apoptosis and G1 phase arrest. Dual-luciferase reporter assay and Western blot validated that TPD52 is the target gene of miR-139-5p. Furthermore, downregulation of TPD52 by siRNA in uterine leiomyoma cells inhibited cell proliferation and induced cell apoptosis and G1 phase arrest. CONCLUSION: Data suggested that miR-139-5p inhibited the proliferation of uterine leiomyoma cells and induced cell apoptosis and G1 phase arrest by targeting TPD52.

miR-10b Inhibits Apoptosis and Promotes Proliferation and Invasion of Endometrial Cancer Cells via Targeting HOXB3.

MicroRNAs are small RNA that are tightly interrelated with the initiation, development, and metastasis of cancers. Studies have shown that miR-10b is increased in various cancers. However, the underlying mechanisms of miR-10b in the occurrence and metastasis of endometrial cancer are poorly understood. To investigate its roles and correlations with Homeobox box 3 (HOXB3) in endometrial cancer, cancer tissues and adjacent normal endometrium tissues from 20 patients with endometrial cancer were studied. miR-10b expression was significantly up-regulated (p < 0.01) in endometrial cancer tissue, whereas HOXB3 was lowly expressed. The silence of miR-10b resulted in significantly enhanced cell apoptosis, and remarkably reduced cell proliferation, migration, and invasion (p < 0.05). Moreover, the protein levels of HOXB3 were increased in KLE cells with silenced miR-10b, and dual-luciferase reporter assay suggested that miR-10b could directly target HOXB3. Furthermore, overexpression of HOXB3 promoted cell apoptosis but inhibited cell proliferation, migration, and invasion (p < 0.01). To conclude, miR-10b might control cell apoptosis, proliferation, migration, and invasion in endometrial cancer via regulation of HOXB3 expression.

P62 regulates resveratrol-mediated Fas/Cav-1 complex formation and transition from autophagy to apoptosis.

Resveratrol is a potential polyphenol drug used in cancer treatment. We examined the relationship between autophagy and apoptosis in RSV-treated non-small lung adenocarcinoma A549 cells. Resveratrol treatment increased autophagy and autophagy-mediated degradation of P62. Immunocytochemistry revealed P62 co-localized with Fas/Cav-1 complexes, known to induce apoptosis. However, siRNA-mediated P62 downregulation enhanced formation of Fas/Cav-1 complexes, suggesting that P62 inhibited Fas/Cav-1 complex formation. Fas/Cav-1 complexes triggered caspase-8 activation and cleavage of Beclin-1, releasing a C-terminal Beclin-1 peptide that translocated to the mitochondria and initiate apoptosis. Inhibition of autophagy by siRNA-mediated repression of Beclin-1 also blocked RSV-induced apoptosis, showing a dependence of apoptosis on autophagy. P62 knockdown by siRNA accelerated the activation of caspase-8 and initiate apoptosis, while Cav-1 knockdown inhibited apoptosis, but increased autophagy. Inhibition of autophagy by 3-MA prevented both P62 degradation and induction of apoptosis, whereas inhibition of apoptosis by z-IETD-FMK or z-DEVD-FMK enhanced both P62 induction and autophagic cell death. In conclusion, P62 links resveratrol-induced autophagy to apoptosis. P62 blocks apoptosis by inhibiting Fas/Cav-1 complex formation, but RSV-induced autophagic degradation of P62 enables formation of Fas/Cav-1 complexes which then activate caspase-8-mediated Beclin-1 cleavage, resulting in translocation of the Beclin-1 C-terminal fragment to the mitochondria to initiate apoptosis.

Resveratrol-induced apoptosis is enhanced by inhibition of autophagy in esophageal squamous cell carcinoma.

The anti-cancer activity of resveratrol in human esophageal squamous cell carcinoma (ESCC) was investigated focusing on the role of autophagy and its effects on apoptotic cell death. We demonstrated that resveratrol inhibits ESCC cell growth in a dose-dependent manner by inducing cell cycle arrest at the sub-G1 phase and resulting in subsequent apoptosis. Mechanistically, resveratrol-induced autophagy in the ESCC cells is AMPK/mTOR pathway independent. Since both pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells, this provided a novel strategy in potentiating the anti-cancer effects of resveratrol and other chemotherapeutic reagents in ESCC cancer treatment.

Indole-3-carbinol enhances the resolution of rat liver fibrosis and stimulates hepatic stellate cell apoptosis by blocking the inhibitor of κB kinase α/inhibitor of κB-α/nuclear factor-κB pathway.

Hepatic stellate cells (HSC) play a pivotal role in liver fibrosis, and the clearance of activated HSC by apoptosis is associated with the resolution of liver fibrosis. The development of strategies that promote this process in a selective way is therefore important. We evaluated the effects of indole-3-carbinol (I3C), a nutritional component derived from vegetables from the Brassica family, on liver fibrosis and HSC apoptosis. The in vivo therapeutic effects of I3C were monitored in three rat models of liver fibrosis induced by porcine serum, bile duct ligation, or multiple hepatotoxic factors, and its proapoptotic effect and molecular mechanism were studied in vitro in HSC-T6, a rat HSC line. The results showed that I3C treatment significantly reduced the number of activated HSC in the livers of rats with liver fibrosis. In histopathology, I3C reduced hepatocyte degeneration and necrosis, accelerated collagen degradation, and promoted the reversal of liver fibrosis. I3C prescribed to HSC-T6 resulted in morphologic alterations typical of apoptosis and DNA cleavage to a nucleosomal ladder. Moreover, I3C significantly increased the HSC-T6 apoptosis rate and the expression ratio of Bax to Bcl-2. High-throughput protein array analysis indicated that the tumor necrosis factor-α/nuclear factor-κB (NF-κB) signal pathway participated in I3C-induced HSC-T6 apoptosis. Western blot and electrophoretic mobility-shift assay confirmed that I3C inhibited the phosphorylation of inhibitor of κB kinase α and inhibitor of κB-α and NF-κB DNA binding activity. In conclusion, I3C could promote the reverse process of liver fibrosis in vivo and induce apoptosis of activated HSC in vitro, which indicates the use of I3C as a potential therapeutic agent in liver fibrosis treatment.

Sesquiterpenoids from Valeriana tangutica.

A new guaiane-type sesquiterpenoid ethoxyvalerianol (1) and one known sesquiterpenoid valeranone (2) together with selina-4,7(11)-diene (3) and selinene (4), which were obtained from (+)-maaliol (5) by decyclization and dehydration, were isolated from Valeriana tangutica. Their structures were elucidated by 1D- and 2D-NMR spectroscopic data and HR-ESI-MS analysis.

Cytotoxic diarylheptanoids from the pericarps of walnuts (Juglans regia).

Two new diarylheptanoids, juglanin A (1) and B (2), together with 15 known compounds, were isolated from the extract of the seed husks of walnuts (Juglans regia L.). The structures of 1 and 2 were elucidated by various spectroscopic methods including intensive 2D-NMR techniques, HR-ESI-MS, and X-ray single-crystal diffraction analysis, and the cytotoxic activities of 1, 2, and 10 against human hepatoma (Hep G2) cells was reported.

[Study on chemical constiuents from Ligularia intermedia of shanxi].

OBJECTIVE: To study the chemical constituents of Ligularia intermedia of Shanxi. METHOD: The compounds were isolated by column chromatography on silica gel and preparative TLC. The structures were identified by IR, MS, 1D/2DNMR spectral data and X-ray single crystal diffraction and other methods1. RESULT: Nine compound were isolated and identified as 8beta-hydroxyeremophil-7(11)-ene-12, 8alpha(4beta, 6alpha)-diolide (1), 8beta-methoxyeremophil-7(11)-ene-12, 8alpha(4beta, 6alpha)-diolide (2), petasin (3), isopetasin (4), liguhodgsonal (5), ligudentatol (6), ligujapone (7), lupeol (8) and lupeol palmitate (9). CONCLUSION: Compounds 2, 3, 4, 6, 7 and 9 were isolated from the plant for the first time.