PXR Activation Relieves Deoxynivalenol-Induced Liver Oxidative Stress Via Malat1 LncRNA m6A Demethylation.

Deoxynivalenol (DON) is a prevalent toxin causing severe liver damage through hepatocellular oxidative stress. However, the underlying mechanisms and effective therapeutic approaches remain unknown. Here, the unique role of the xenobiotic metabolism factor pregnane X receptor (PXR) in mediating DON-induced hepatocellular oxidative stress is investigated. Treatment with the PXR agonist 3-indole-propionic acid (IPA) alleviates DON-induced oxidative stress and liver injury both in vitro and in vivo. Mechanistically, it is discovered for the first time that PXR agonist IPA directly transactivates the m6A demethylase FTO expression, leading to site-specific demethylation and decreased abundance of YTHDC1-bound Malat1 lncRNA at single-nucleotide resolution. The diminished m6A modification of Malat1 lncRNA reduces its stability and augments antioxidant pathways governed by NRF2, consequently mitigating DON-induced liver injury. Furthermore, Malat1 knockout mice exhibit decreased DON-induced liver injury, emphasizing the role of Malat1 lncRNA in oxidative stress. Collectively, the findings establish that PXR-mediated m6A-dependent Malat1 lncRNA expression determines hepatocyte oxidative stress via m6A demethylase FTO, providing valuable insights into the potential mechanisms underlying DON-induced liver injury and offers potential therapeutic strategies for its treatment.

Characterization of the biological and transcriptomic signatures of natural killer cells derived from cord blood and peripheral blood.

Longitudinal studies have indicated the pivotal role of natural killer cells (NKs) in the elimination of certain infections and malignancies. Currently, perinatal blood (PB) and cord blood (CB) have been considered with promising prospective for autogenous and allogeneic NKs transplantation, yet the similarities and differences at the biological and molecular levels are largely obscure. We isolated mononuclear cells (MNCs) from PB and CB, and compared the biological phenotypes of resident NKs by flow cytometry and cell counting. Then, we turned to our well-established "3ILs" strategy and co-culture for NK cell activation and cytotoxicity analyses, respectively. Finally, with the aid of transcriptomic analyses, we further dissected the signatures of PB-NKs and CB-NKs. CB-NKs revealed superiority in cellular vitality over PB-NKs, together with variations in subpopulations. CB-NKs showed higher cytotoxicity over PB-NKs against K562 cells. Furthermore, we found both NKs revealed multifaceted conservations and differences in gene expression profiling and genetic variations, together with gene subsets and signaling pathway. Collectively, both NKs revealed multifaceted similarities and diverse variations at the cellular and transcriptomic levels. Our findings would benefit the further exploration of the biological and transcriptomic properties of CB-NKs and PB-NKs, together with the development of NK cell-based cytotherapy.

Melatonin Ameliorates Apoptosis of A549 Cells Exposed to Chicken House PM2.5: A Novel Insight in Poultry Production.

The particulate matter 2.5 (PM2.5) from the chicken production system can cause lung injury and reduce productivity through prolonged breath as it attaches large amounts of harmful substances and microbes. Melatonin has acted to regulate physiological and metabolic disorders and improve growth performance during poultry production. This research would investigate the apoptosis caused by chicken house PM2.5 on lung pulmonary epithelial cells and the protective action of melatonin. Here, the basal epithelial cells of human lung adenocarcinoma (A549 cells) were subjected to PM2.5 from the broiler breeding house to investigate the apoptosis induced by PM2.5 as well as the alleviation of melatonin. The apoptosis was aggravated by PM2.5 (12.5 and 25 µg/mL) substantially, and the expression of Bcl-2, Bad, Bax, PERK, and CHOP increased dramatically after PM2.5 treatment. Additionally, the up-regulation of cleaved caspase-9 and cleaved caspase-3 as well as endoplasmic reticulum stress (ERS)-related proteins, including ATF6 and CHOP, was observed due to PM2.5 exposure. It is worth noting that melatonin could support A549 cells' survival, in which reduced expression of Bax, Bad, cleaved caspase-3, and cleaved caspase-9 appeared. Concurrently, the level of malondialdehyde (MDA) was down-regulated and enhanced the intracellular content of total superoxide dismutase (T-SOD) and catalase (CAT) after treatment by PM2.5 together with melatonin. Collectively, our study underlined that melatonin exerted an anti-apoptotic action on A549 cells by strengthening their antioxidant capacity.

Poly-ß-hydroxybutyrate alleviated diarrhea and colitis via Lactobacillus johnsonii biofilm-mediated maturation of sulfomucin.

Maintainance of sulfomucin is a key end point in the treatment of diarrhea and inflammatory bowel disease (IBD). However, the mechanisms underlying the microbial sense to sulfomucin are poorly understood, and to date, there are no therapies targeting the secretion and maturation of sulfomucin in IBD. Herein, we biosynthesized poly-ß-hydroxybutyrate (PHB) and found that PHB could alleviate inflammation caused by diarrhea and colitis by enhancing the differentiation of sulfomucin. Microbiota transplantation and clearance together demonstrate that PHB promoting sulfomucin is mediated by Lactobacillus johnsonii (L. johnsonii). Further studies revealed that PHB provides a favorable niche for L. johnsonii biofilm formation to resist disturbance and support its growth. L. johnsonii-biofilm alleviates colitis by regulating fucose residues to promote goblet cell differentiation and subsequent sulfomucin maturation. Importantly, PHB alleviates colitis by enhancing sulfomucin secretion and maturation in a L. johnsonii-dependent manner. PHB represents a class of guardians, acting as a safe probiotic-biofilm delivery system that significantly promotes probiotic proliferation. Altogether, this study adds weight to the possible role of probiotics and functional materials in the treatment of intestinal inflammation. The application of PHB and biofilm self-coating L. johnsonii carries high translational potential and may be of clinical relevance.

Sensation of dietary nutrients by gut taste receptors and its mechanisms.

Nutrients sensing is crucial for fundamental metabolism and physiological functions, and it is also an essential component for maintaining body homeostasis. Traditionally, basic taste receptors exist in oral cavity to sense sour, sweet, bitter, umami, salty and et al. Recent studies indicate that gut can sense the composition of nutrients by activating relevant taste receptors, thereby exerting specific direct or indirect effects. Gut taste receptors, also named as intestinal nutrition receptors, including at least bitter, sweet and umami receptors, have been considered to be activated by certain nutrients and participate in important intestinal physiological activities such as eating behavior, intestinal motility, nutrient absorption and metabolism. Additionally, gut taste receptors can regulate appetite and body weight, as well as maintain homeostasis via targeting hormone secretion or regulating the gut microbiota. On the other hand, malfunction of gut taste receptors may lead to digestive disorders, and then result in obesity, type 2 diabetes and gastrointestinal diseases. At present, researchers have confirmed that the brain-gut axis may play indispensable roles in these diseases via the secretion of brain-gut peptides, but the mechanism is still not clear. In this review, we summarize the current observation of knowledge in gut taste systems in order to shed light on revealing their important nutritional functions and promoting clinical implications.

Effects of maternal T-2 toxin exposure on microorganisms and intestinal barrier function in young mice.

T-2 toxin belongs to the trichothecenes group A compound, mainly produced by Fusarium fungi. It has been shown that T-2 toxin could cross the placental barrier and breast milk, thus endangering the health of offspring. The present study aimed to explore the effects of maternal T-2 toxin exposure on the integrity of the intestinal barrier and the intestinal microflora of young mice. From late pregnancy (GD 14) to lactation (LD 21), pregnant mice were given T-2 toxin daily at 0, 0.005, or 0.05 mg T-2 toxin/kg BW. Postnatal day 21 (PND21), PND28, and PND56 young mice were chosen as objects to detect the influences of maternal T-2 toxin exposure to mice on the offspring. The results showed that maternal exposure to T-2 toxin disturbed the balance of the intestinal microbial flora of the young mice. Villous adhesions and fusion of ileum were observed in T-2-treated groups. In addition, supplementation of T-2 toxin significantly decreased the gene expressions of Claudin 1, Occludin, Tjp1, Il10, Il6, and Tnf in PND 21. However, in PND 28, the expressions of Tnf were significantly increased. The expressions of Claudin 1, Occludin, Tjp1, Il10, Il6 and Tnf were significantly increased after T-2 toxin treatment in PND 56. These results suggested that maternal exposure to T-2 toxin has negative influences on the intestine of young mice, which may be due to the alterations of microbial composition.

Bacillus subtilis M6 improves intestinal barrier, antioxidant capacity and gut microbial composition in AA broiler.

Bacillus subtilis can secret a variety of substances to improve human and animal gut health via inhibiting the proliferation of pathogenic bacteria. In this study, a fast-growing and stress-resistant strain of Bacillus subtilis M6 (B. subtilis M6) were isolated, which showed a strong antibacterial activity to E. coli K88, S. typhimurium ATCC14028, and S. aureus ATCC25923 in vitro. In vivo studies showed that B. subtilis M6 can significantly improve the average daily gain (ADG) using an AA broiler model. Dietary B. subtilis M6 improved the intestinal morphology. The villus height of jejunum and ileum were significantly increased. The concentration of malondialdehyde (MDA) in the ileal mucosa was significantly reduced in B. subtilis M6 treatment group, which suggested the oxidative stress of the ileum was significantly relieved. Though the ß diversity of treatments was not significantly, B. subtilis M6 improved the composition of intestinal microbes, especially at the level of caecum genus, the dominant genus was changed from Ruminococcus to Akkermansia, which indicated the change of intestinal carbohydrate nutrition. In conclusion, these data indicate that the B. subtilis M6 shows a probiotic potential to improve intestinal health via altering gut microbiota.

Tibetan Pig-Derived Probiotic Lactobacillus amylovorus SLZX20-1 Improved Intestinal Function via Producing Enzymes and Regulating Intestinal Microflora.

The interaction between exogenous microorganisms and the host has received great attention, and finding new probiotics is always the way to improve the health of humans and animals. Lactobacillus amylovorus (L. amylovorus) is a kind of Lactobacillus that can efficiently utilize starch, as a food and feed additive, it has been widely used for mildew prevention and antibacterial, bacteriostasis, and enzyme production. Herein, a strain of L. amylovorus was isolated from the feces of Tibetan weaned piglets, named L. amylovorus SLZX20-1. Physiological and biochemical experiments in vitro confirmed that it had a fast growth rate and could produce a variety of enzymes, including α-galactosidase, ß-galactosidase, α-glucosidase, ß-glucosidase, and ferulic acid esterase. In addition, L. amylovorus SLZX20-1 exerted antibiotic effects on the growth of Salmonella typhimurium (S. typhimurium) SL1344, Citrobacter rodentium (C. rodentium) DBS100, Salmonella pullorum (S. pullorum) CVCC1791, Staphylococcus aureus (S. aureus) CVCC1882, Escherichia coli (E. coli) O157, E. coli K88, E. coli K99, and E. coli 987P, which are closely related to acid productivity, such as lactic acid and acetic acid. In vitro co-culture, L. amylovorus SLZX20-1 has shown the strong adhesion ability to intestinal porcine epithelial cells (IPEC-J2 cells) and activated IPEC-J2 cells with high expression of host defense peptides (HDPs), such as NK-Lysin, PEP2C, and PBD-1. In vivo experiment, via intragastric administration, L. amylovorus SLZX20-1 significantly improved the feed intake of mice, declined the crypt depth of jejunum and ileum, L. amylovorus SLZX20-1 changed the composition of intestinal microbes, especially at the level of colonic genus, the dominant genus was changed from Lactobacillus to S24-7, which indicated the change of intestinal carbohydrate nutrition. In conclusion, L. amylovorus SLZX20-1 showed strong probiotic characteristics, which met with the standard of probiotics and is worth further exploring its impacts on host health and its potential as a candidate strain of probiotics.

Formulation, Characterization, Antioxidant, Cytotoxicity, and Anti-acute Leukemia Effects of Fe Nanoparticles.

In this study, iron nanoparticles were prepared and synthesized in aqueous medium using Cinnamomum verum as stabilizing and reducing agents. We determined the anti-acute leukemia potentials of FeNPs against acute T cell leukemia and acute lymphoblastic leukemia cell lines. FeNPs inhibited half of the DPPH molecules in the concentration of 139 µg/mL. MTT assay was used on J.RT3-T3.5 (Acute T cell leukemia cell line), Jurkat, Clone E6-1 (Acute T cell leukemia cell line), MOLT-3 (Acute lymphoblastic leukemia cell line), TALL-104 (Acute lymphoblastic leukemia cell line), and HUVEC (Normal cell line) for analyzing of cytotoxicity and anti-acute leukemia effects of FeNPs. These nanoparticles had high cell death and anti-acute leukemia effects against J.RT3-T3.5, Jurkat, Clone E6-1, MOLT-3, and TALL-104 cell lines. Among the above cell lines, the best result of anti-acute leukemia properties of composite was gained in the cell line of Jurkat, Clone E6-1. All result showed the iron nanoparticles may be used as a chemotherapeutic treatment drug of leukemia in humans.

Mogroside V exerts anti-inflammatory effects on fine particulate matter-induced inflammation in porcine alveolar macrophages.

Mogroside V is the main bioactive component of Siraitia grosvenorii (Swingle), and has a potential anti-inflammatory function. However, the effect of mogroside V on fine particulate matter (PM2.5)-induced inflammation has not been reported. In the present study, the biological effect of mogroside V on inflammation was investigated in PM2.5- treated porcine alveolar macrophages (3D4/21). The results showed that mogroside V significantly inhibited PM2.5-induced nitric oxide (NO) production and rescued the arginase activity inhibited by PM2.5. In the presence of mogroside V, the upregulation of IL-18, TNF-α and COX-2 by PM2.5 in 3D4/21 cells was inhibited. Mogroside V attenuated PM2.5-induced phosphorylation of NF-κB p65 and the expression of NLRP3. Mogroside V reduced intracellular ROS levels induced by PM2.5. In the transcriptomic analysis, inflammation-related genes in 3D4/21 cells were not significantly affected after treatment with mogroside V. These results indicated that mogroside V can alleviate the inflammatory response of porcine alveolar macrophages induced by PM2.5 from pig house and that mogroside V may play the role through the antioxidant function of eliminating ROS. Mogroside V has a clear anti-inflammatory function in the presence of inflammation.

Dynamic variations in serum amino acid and the related gene expression in liver, ovary, and oviduct of pigeon during one egg-laying cycle.

The present study was carried to investigate dynamic variations in serum amino acid (AA) contents and the relative mRNA abundance of the AA transporters and AA synthesis-related enzymes in liver, ovary and oviduct of pigeons during one egg-laying cycle (ELC). In experiment 1, seventy laying pigeons (American Silver King) were randomly divided into 14 groups by different days of one ELC (DELC) and arranged as a 2 × 7 factorial design, which included 2 ages (6-mo-old or 12-mo-old) and 7 DELCs. For experiment 2, 35 six-mo-old laying pigeons (American Silver King) were randomly divided into 7 groups by different DELCs and immediately treated with a 12-h fasting. Dynamic variations in serum AAs were detected during one ELC, characterized by high levels of Lys, Met, Leu, Phe, Tyr, Asp, Ser, Glu, Ala, and TAA on day 1 (D1) of one ELC (P < 0.05). Fasting caused obvious decreases in serum levels of Leu, Ile, Val, Phe, Tyr, and TAA from day 2 (D2) to day 7 (D7) (P < 0.05). Relative organ weights of ovary and oviduct increased to the peak values on day 13 (D13) (P < 0.05). Serum calcium decreased to the lowest level on day 4 (D4) (P < 0.05) and serum total triglyceride was kept in a high level on D1, D7, day 10 (D10), and D13 (P < 0.05). Relative mRNA expression of the AA synthesis genes and the AA transport genes exhibited different variation patterns in liver, ovary and oviduct, but Pearson correlation test showed the percentage of positive r values with significant differences were much higher in oviduct than those in liver or ovary. In conclusion, dynamic variations of serum AAs during one ELC were positively related with the expression of the AA transport genes and AA synthesis genes in oviduct, suggesting the upregulated serum AAs might be necessary to meet the AAs requirement for egg white formation in pigeon.

Vapor phase polymerized conducting polymer/MXene textiles for wearable electronics.

Multifunctional electronic textiles hold great potential applications in the wearable electronics field. However, it remains challenging to seamlessly integrate the multiple functions on the textile substrates without sacrificing their intrinsic properties. Herein, we report a novel and facile vapor phase polymerization (VPP) and spray-coating strategy towards the construction of a laminated film containing a PEDOT film and Ti3C2Tx MXene sheets on the fiber surface. The fabricated PEDOT/MXene decorated cotton fabrics are integrated with excellent electrochemical performance, joule heating performance, good electromagnetic interference (EMI) shielding, and strain sensing performance. The resultant multifunctional textiles have a low sheet resistance of 3.6 Ω sq-1, and the assembled all-solid-state fabric supercapacitors exhibit an ultrahigh specific capacitance of 1000.2 mF cm-2, which exceeds the state-of-the-art MXene-based fabric supercapacitors. In addition, the PEDOT/MXene modified fabrics exhibit an exceptional joule heating performance of 193.1 °C at the applied voltage of 12 V, high EMI shielding effectiveness of 36.62 dB, and high sensitivity as strain sensors for human motion detection. This work provides a novel strategy for the structure design of multifunctional textiles and will lay the foundation for the development of multifunctional wearable electronics.

Maternal Exposure to T-2 Toxin Affects Puberty Genes and Delays Estrus Cycle in Mice Offspring.

Among foodborne toxicities, the T-2 toxin is the most toxic member of trichothecenes mycotoxins, which has been shown to impair the development and reproductive efficiency of animals. Pups are particularly more quickly prone to programming the effects of the maternal diet during the gestational and lactation periods. Few studies have reported the maternal toxic effect on the next generation. Dams were served the T-2 toxin at a dose of 0.005 and 0.05 mg/kg body weight/day and control group 0 mg/kg from gestation day 14 to lactation day 21. Female mice offspring were selected at the weaning age. Our observations indicate that age during the vaginal opening and di-estrus stage increased and the length of the estrus cycle, first di-estrus, and regular estrus cycling were delayed with prolonged di-estrus in the 0.05 mg/kg group compared to the 0.005 mg/kg and control group. Transcription level analysis showed that mice at a dose of 0.05 mg/kg exhibited a decrease in hypothalamic mRNA expression of Gnrh and Gnrhr, Lhb, and Fshb in the pituitary gland, with a significant decrease of Fshr and Lhr in the ovaries. Present findings report that postnatal exposure to the T-2 toxin delayed puberty age in female mice and induced oxidative stress, ovarian damage, and reduced vaginal epithelium wall majorly in the 0.05 mg/kg group, and showed fewer effects in the 0.005 mg/kg group.

Disruption of cytochrome P450 enzymes in the liver and small intestine in chicken embryos in ovo exposed to glyphosate.

Glyphosate is the active component of several commercial formulations as in Roundup®. The present study was investigated the toxic effects of pure glyphosate or Roundup® on the liver and small intestine of chick embryos. On day 6, a total of 180 fertile eggs injected with deionized water (control group), 10 mg pure glyphosate, or 10 mg of the active ingredient glyphosate in Roundup®/kg egg mass. The results showed an increase in relative weights of the liver in embryos that treated with Roundup®. Furthermore, oxidative stress was observed in the embryos treated with glyphosate or Roundup®, increased total superoxide dismutase, and content of malondialdehyde in the liver and intestine; moreover, decrease of glutathione peroxidase in the liver with increased in the intestine compared with the control. Besides, glutamic-pyruvic transaminase was increased in Roundup® group compared with other groups. Moreover, histopathological alterations in the liver and intestine tissues were observed in treated groups. Suppression of hepatic CYP1A2, CYP1A4, CYP1B1, and MDR1 mRNA expression after exposed to Roundup®. Furthermore, inhibition of CYP1A4 in the duodenum, CYP1A4, and MRP2 in the jejunum in embryos exposed to glyphosate or Roundup®. In addition, glyphosate treatment caused an increase of CYP3A5, CYP1C1, and IFNY mRNA expression in the jejunum and CYP1A2 expression in the ileum, while IFN-Y gene increase in embryos treated with Roundup®. In conclusion, in ovo exposure to glyphosate caused histopathological alterations and induced oxidative stress in the liver and small intestines. Moreover, the expression of cytochrome P450, MDR1, and MRP2 transporters was also modulated in the liver and small intestines for chick embryos.

The roles of Nrf2 and autophagy in modulating inflammation mediated by TLR4 - NFκB in A549 cell exposed to layer house particulate matter 2.5 (PM2.5).

Particulate matter (PM) from layer house has adverse effect on people and chicken respiratory health, which can further influence animal performance and reduce production efficiency. However, little study focus on the respiratory inflammation induced by PM2.5 from layer house and the underlying mechanism also unclear. In this study, human adenocarcinoma alveolar basal epithelial cells (A549 cell) was subjected to the PM2.5 from layer house to evaluate the inflammation reaction caused by PM2.5 and explore the role of Nrf2 and autophagy in regulating the inflammation. Results showed that the viability of A549 cell decreased in a time - and concentration - dependent manner after PM2.5 treatment. TNFα, IL6, and IL8 increased significantly treated with PM2.5 at 12 h. RNA sequencing indicated differentially expressed genes were enriched in immune system process, oxidative stress (OS), endoplasmic reticulum stress (ERS), and autophagy. Further studies showed TLR4 - NFκB p65 signal pathway involved in the inflammation reaction caused by PM2.5. The overexpression of Nrf2 decreased the level of TNFα, IL6, IL8 markedly as well as the level of NFκB p65 and NFκB pp65. OS and ERS were also limited under overactivation of Nrf2 in PM2.5 treated cells. Autophagy induced by PM2.5 promoted the inflammation through increasing the level of NFκB p65 and NFκB pp65. Autophagy deficient strengthened the expression of Nrf2. Collectively, our study revealed Nrf2 prevents inflammation caused by layer house PM2.5 stimulation, however, autophagy exerts a promotive role in TLR4 - NFκB p65 mediating inflammation in A549 cell.

Maternal Exposure to T-2 Toxin Induces Changes in Antioxidant System and Testosterone Synthesis in the Testes of Mice Offspring.

T-2 toxin, the most toxic member of trichothecene mycotoxin, is widely distributed in cereals, and has been extensively studied, but few studies focus on the toxicity of maternal exposure to offspring. This study focused on the effects of maternal exposure to T-2 toxin (during gestation and lactation) on the testicular development of mice offspring. Dams were orally administered with T-2 toxin at 0, 0.005, or 0.05 mg/kg body weight from the late stage of gestation to the end of lactation. Testicular samples of the mice offspring were collected on the postnatal day 21, 28, and 56. The results showed significant decreases in body weight and testicular weight on the postnatal day 28. Moreover, significant inhibition of antioxidant system and testosterone synthesis was detected on the postnatal day 28. Furthermore, there were significant decreases in the gene expression levels of StAR and 3ß-HSD, which are involved in testosterone synthesis. In general, present results demonstrated that maternal exposure to T-2 toxin during gestation and lactation led to bad effects on the capacity of antioxidant system and inhibited testosterone synthesis in testes during pre-puberty with no significant effects on post-puberty.

4-Chlorobenzoyl berbamine, a novel berbamine derivative, induces apoptosis in multiple myeloma cells through the IL-6 signal transduction pathway and increases FOXO3a-Bim expression.

Multiple myeloma (MM) is an incurable hematopoietic malignancy, although many novel therapeutic agents have been explored. In the present study, we showed that 4-chlorobenzoyl berbamine (BBD9), a novel derivative of berbamine, inhibited the growth of 4 MM cell lines (U266, RPMI 8226, MM1.R and MM1.S). After a 24-h treatment with BBD9, the half maximal inhibitory concentration (IC(50)) values were 1.8, 2.3, 1.5 and 2.4 µg/ml, respectively, using MTT assays. In BBD9-treated U266 and RPMI 8226 cells, Annexin V (AV)-propidium iodide (PI) staining and FACS analysis demonstrated that apoptosis was involved in this inhibition. This was confirmed by western blot analysis indicating activation and cleavage of caspase-3, -8, -9 and PARP. BBD9 also induced G2/M phase cell cycle arrest in these cells. To investigate the mechanisms responsible for BBD9-induced apoptosis, U266 cells were incubated with 0, 1 or 2 µg/ml of BBD9 combined with 0 or 150 ng/ml of interleukin (IL)-6. MTT assays showed that IL-6 partially abrogated the BBD9-induced cell growth inhibition. Furthermore, BBD9 inhibited autocrine IL-6 production, and downregulated membrane IL-6 receptor (IL-6R) expression. Crucial proteins downstream of the IL-6 signaling pathway, including AKT and STAT3, were inactivated in BBD9-treated U266 cells, although exogenous IL-6 did not abrogate this effect. Forkhead transcription factor class 3a (FOXO3a), a nuclear transcription factor downstream from AKT, was upregulated in the nuclei of BBD9-treated U266 cells. Bim, the target gene of FOXO3a, was upregulated at both the protein and mRNA levels, as shown by western blot analysis and quantitative PCR. These results suggest that BBD9 induces apoptosis in MM cells through the inhibition of the IL-6 signaling pathway, leading to FOXO3a activation and upregulation of pro-apoptotic Bim.

4-Chlorobenzoyl berbamine induces apoptosis and G2/M cell cycle arrest through the PI3K/Akt and NF-kappaB signal pathway in lymphoma cells.

Berbamine is an herbal compound derived from Berberis amurensis, which is used in Chinese traditional medicine. However, few studies have investigated this anti-tumor effect or the underlying mechanisms of berbamine on lymphoma cells. We investigate the effect, as well as the mechanism of action, of 4-chlorobenzoyl berbamine (BBD9) on Raji, L428, Namalwa and Jurkat lymphoma cells lines. Our findings show that BBD9 inhibits cell proliferation and induces cell apoptosis in lymphoma cell lines as well as G2/M cell cycle arrest through PI3K/Akt and NF-kappaB signaling pathways in a caspase-dependent manner. These results may provide new insights into the treatment of lymphoma.

Interleukin-6-independent expression of glucocorticoid receptor is upregulated by triptolide in multiple myeloma.

Glucocorticoids are widely used chemotherapeutic agents for multiple myeloma. Drug resistance to steroid therapies is associated with the downregulation or loss of glucocorticoid receptor expression in malignant plasma cells. In this study, we examined the constitutive expression of glucocorticoid receptor in dexamethasone-sensitive and dexamethasone-resistant multiple myeloma cell lines. We found that triptolide increased the amount of the phosphorylated glucocorticoid receptor and enhanced the growth inhibitory effect of dexamethasone. Notably, these effects could not be blocked by interleukin-6, one of the most important growth factors in multiple myeloma.

Casticin induces leukemic cell death through apoptosis and mitotic catastrophe.

Casticin, a component from Vitex rotundifolia, widely used as an anti-inflammatory agent in Chinese traditional medicine, was reported to have anti-tumor activities. This study aims to examine the anti-leukemic activity of casticin on leukemia cells and its molecular mechanism. Cell viability was measured by MTT method; apoptosis and cell cycle arrest were determined by flow cytometry, AV-PI assay, and DNA fragmentation assay. Western blot were performed to measure the protein expression level. The cell morphology alteration was detected with immunofluorescent analysis and DAPI nuclear staining. Our results showed that the proliferation of leukemia cells, including K562, Kasumi-1, and HL-60, were inhibited by casticin in a time- and dose-dependent manner. The IC50, determined after 48 h incubation, was 5.95 microM, 4.82 microM, and 15.56 microM for K562, HL-60, and Kasumi-1, respectively. The cell cycle analysis demonstrated casticin treatment resulted in a significant G2/M accumulation, concomitant with upregulation of P21waf1 and P27kip1. The percentage of cells in G2/M increased with time of exposure and reached to its climax (75.3%) at 12 h after casticin treatment, and subsequently declined to 27% at 48 h. We found that casticin treatment induced remarkable apoptosis, evidenced by increased percentage of AV-positive PI-negative cells as well as the cleavage of PARP and caspase 3. In addition, DNA fragmentation assay showed the typical apoptotic DNA ladder in casticin-treated K562 cells. Mitotic catastrophe and decreased polymeric tubulin can also be observed in casticin-treated K562 cells. In addition, we found that PI3K/AKT pathway was activated; Ly294002, a PI3K/AKT specific inhibitor, can enhance the anti-leukemic effect of casticin. Taken together, these results demonstrated that casticin induced leukemic cell death via apoptosis and mitotic catastrophe, and could synergize with PI3K/AKT inhibitor, suggesting that casticin could be a promising therapeutic agent against leukemia.