Intercropping Okra and Castor Bean Reduces Recruitment of Oriental Fruit Moth, Grapholita molesta (Lepidoptera: Tortricidae) in a Pear Orchard.

Intercrops can lower pest densities by increasing plant diversity, altering chemical communication in the arthropod community, and integrating well with other IPM tactics. We used two years of field observations and Y-tube olfactometer assays to explore the effects of intercropping a pear orchard with okra and castor bean on the cosmopolitan fruit-boring pest Grapholita molesta (Lepidoptera: Tortricidae). Intercropping okra reduced G. molesta trap catches in the pear orchard in both years, and intercropping with castor bean reduced them in the second year. Hydrocarbons, phenols, and ketones predominated in the GC-MS assay of okra volatiles, whereas castor bean volatiles were rich in aldehydes, ketones, and esters. Five of the commercially available volatiles released by these plants exhibited repellency to G. molesta in olfactometer trials, especially cinnamaldehyde, dibutyl phthalate, and thymol; the former compound also exhibited attraction to the egg parasitoid Trichogamma dendrolimi (Hymenoptera: Trichogrammatidae). In addition to their repellent properties, okra and castor bean may enhance integrated control of G. molesta in orchards by hosting prey that support populations of generalist predators that either provide biological pest control services within the orchard ecosystem or generate non-consumptive effects that contribute to pest deterence. Among the plant volatiles evaluated, cinnamaldehyde has the best potential for deployment in orchards to repel G. molesta without disrupting augmentative releases of T. dendrolimi.

LAIR1 drives glioma progression by nuclear focal adhesion kinase dependent expressions of cyclin D1 and immunosuppressive chemokines/cytokines.

Leukocyte-associated immunoglobulin-like receptor-1 (LAIR1), an immune receptor containing immunoreceptor tyrosine-based inhibiory motifs (ITIMs), has emerged as an attractive target for cancer therapy. However, the intrinsic function of LAIR1 in gliomas remains unclear. In this study, the poor prognosis of glioma patients and the malignant proliferation of glioma cells in vitro and in vivo were found to be closely correlated with LAIR1. LAIR1 facilitates focal adhesion kinase (FAK) nuclear localization, resulting in increased transcription of cyclin D1 and chemokines/cytokines (CCL5, TGFß2, and IL33). LAIR1 specifically supports in the immunosuppressive glioma microenvironment via CCL5-mediated microglia/macrophage polarization. SHP2Q510E (PTP domain mutant) or FAKNLM (non-nuclear localizing mutant) significantly reversed the LAIR1-induced growth enhancement in glioma cells. In addition, LAIR1Y251/281F (ITIMs mutant) and SHP2Q510E mutants significantly reduced FAK nuclear localization, as well as CCL5 and cyclin D1 expression. Further experiments revealed that the ITIMs of LAIR1 recruited SH2-containing phosphatase 2 (SHP2), which then interacted with FAK and induced FAK nuclear localization. This study uncovered a critical role for intrinsic LAIR1 in facilitating glioma malignant progression and demonstrated a requirement for LAIR1 and SHP2 to enhance FAK nuclear localization.

Function of Cytochrome P450s and Gut Microbiome in Biopesticide Adaptation of Grapholita molesta on Different Host Diets.

Insects that feed on various host plants possess diverse xenobiotic adaptations; however, the underlying mechanisms are poorly understood. In the present study, we used Grapholita molesta, which shifts feeding sites from peach shoots to apple fruits, as a model to explore the effects of shifts in host plant diet on the profiles of cytochrome P450s and the gut bacteria microbiome, as well as their effects on biopesticide adaptation. We found that the sensitivity of the fruit-feeding G. molesta to emamectin benzoate biopesticide was significantly lower than that of the shoot-feeding larvae. We also found that the P450 enzyme activity and the expression of nine cytochrome P450s were enhanced in G. molesta fed on Fuji apples compared to those fed on peach shoots. The survival rates of G. molesta exposed to emamectin benzoate significantly decreased as each of three of four emamectin benzoate-inducted cytochrome P450 genes were silenced. Furthermore, we discovered the gut bacteria dynamics of G. molesta changed with the host shift and the structure of the gut bacteria microbiome was determined by the final diet ingested; additionally, the dysbiosis of the gut microbiota induced by antibiotics could significantly increase the sensitivity to emamectin benzoate. Taken together, our results suggest that the expression of P450s and the composition of the gut bacteria microbiome promote adaptation to emamectin benzoate in G. molesta, providing new insights into the molecular mechanisms underlying xenobiotic adaptation in this notorious pest.

A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China.

OBJECTIVE: Recent therapeutic advances have greatly enhanced the survival rates of patients with neuroblastoma (NB). However, the outcomes of neuroblastoma patients in China, particularly those with high-risk (HR) NB, remain limited. METHOD: We retrospectively analyzed the clinical data and outcomes of NB patients who were treated at a tertiary pediatric cancer facility in China between January 2013 and October 2021. RESULTS: A total of 117 NB patients were recruited. Patients with very low-risk (VLR), low-risk (LR), intermediate-risk (IR), and HR-NB patients made up 4%, 27%, 15%, and 54% of total patient population, respectively. Patients diagnosed between 2013 and 2018 were treated according to the protocol of Sun Yat-Sen University Cancer Center and those diagnosed between 2019 and 2021 were treated according to the COG ANBL0531 or ANBL0532 protocol with or without autologous stem cell transplantation (ASCT). The 5-year EFS and OS of all risk groups of patients were 67.29% and 77.90%, respectively. EFS and OS were significantly decreased in patients with higher risk classifications (EFS: VLR/LR vs IR vs HR: 97.22% vs 67.28% vs 51.83%; ***P = .001; OS: VLR/LR vs IR vs HR: 97.06% vs 94.12% vs 64.38%; *P = .046). In HR-NB patients treated according to the COG protocol between 2019 and 2021, the 3-year OS of patients who received tandem ASCT was significantly greater than those who did not receive ASCT (93.33% % vs 47.41%; *P = .046; log-rank test). EFS was not significantly different between patients with and without ASCT (72.16% vs 60.32%). CONCLUSION: Our findings show that patients with lower risk classification have a positive prognosis for survival. The prognosis of patients with HR-NB remains in need of improvement. ASCT may enhance OS in HR-NB patients; however, protocol adjustment may be necessary to increase EFS in these patients.

Retracted: WNT974 Inhibits Proliferation, Induces Apoptosis, and Enhances Chemosensitivity to Doxorubicin in Lymphoma Cells by Inhibiting Wnt/b-Catenin Signaling.

This publication has been retracted by the Editor due to the identification of non-original figure images and manuscript content that raise concerns regarding the credibility and originality of the study and the manuscript. Reference: Senmin Chen, Xiuli Yuan, Huanli Xu, Meng Yi, Sixi Liu, Feiqiu Wen. WNT974 Inhibits Proliferation, Induces Apoptosis, and Enhances Chemosensitivity to Doxorubicin in Lymphoma Cells by Inhibiting Wnt/b-Catenin Signaling. Med Sci Monit, 2020; 26: e923799. DOI: 10.12659/MSM.923799.

Targeting NQO1/GPX4-mediated ferroptosis by plumbagin suppresses in vitro and in vivo glioma growth.

BACKGROUND: Ferroptosis has attracted increasing interest in cancer therapy. Emerging evidences suggest that naturally occurring naphthoquinones exhibit potent anti-glioma effects via various mechanisms. METHODS: The anti-glioma effects of plumbagin were evaluated by in vitro and in vivo experiments. Anti-glioma mechanism of plumbagin was studied by proteomics, flow cytometry, MDA assay, western blot, and RT-PCR. Gene knockdown/overexpression, molecular docking, PharmMappper database, and coimmunoprecipitation were used to study the targets of plumbagin. RESULTS: Plumbagin showed higher blood-brain barrier penetration ability than that of lapachol and shikonin and elicited significant growth inhibitory effects in vitro and in vivo. Ferroptosis was the main mechanism of plumbagin-induced cell death. Mechanistically, plumbagin significantly downregulated the protein and mRNA levels of xCT and decreased GPX4 protein levels. NAD(P)H quinone dehydrogenase 1 (NQO1) was revealed as a plumbagin predictive target using PharmMappper database and molecular docking. Plumbagin enhanced NQO1 activity and decreased xCT expression, resulting in NQO1-dependent cell death. It also induced GPX4 degradation via the lysosome pathway and caused GPX4-dependent cell death. CONCLUSIONS: Plumbagin inhibited in vitro and in vivo glioma growth via targeting NQO1/GPX4-mediated ferroptosis, which might be developed as a novel ferroptosis inducer or anti-glioma candidate.

[Effects of landscape complexity and local management on bee pollinator diversity in apple orchards in Changping District, Beijing, China.] / åŒ—äº¬æ˜Œå¹³åŒºæ™¯è§‚å¤æ‚åº¦å’Œå±€åœ°ç®¡ç†å¯¹è‹¹æžœå›­ä¼ ç²‰èœ‚å¤šæ ·æ€§çš„å½±å“.

Pollinators provide important ecosystem services for crop production and food security. With the development of agricultural economy and the increasing intensity of land-use, a large number of natural or semi-natural habitats have been converted to croplands. Landscape homogenization and intensive management lead to the decline of wild bee diversity and threaten the sustainable agricultural production. In this study, we investigated the effects of landscape complexity (proportion of semi-natural habitats), local management practices (local flowering plant diversity and soil total nitrogen), and their interactions on diversity of bee pollinators in apple orchard in Changping District, Beijing. A total of 8642 bee individuals were captured, including 5125 honey bees and 3517 wild bees from 5 families, 14 genera, and 49 species. The optimal landscape scale for the response of bee diversity to landscape complexity and local management intensity was 500 m. Within 500 m radius of the site, the abundance of overall bees and wild bees significantly increased with increasing proportion of semi-natural habitats. The landscape complexity interacting with local flowering plant diversity significantly affected the richness of overall bee and wild bee. When the proportion of semi-natural habitats surrounding the apple orchards was low (≤29.9%), we found a positive effect of flowering plant diversity on the richness of overall bee and wild bee, whereas a reversed trend was found when the proportion of semi-natural habitats surrounding the apple orchards was high (>29.9%). In addition, the abundance of honey bees significantly increased with the increase of local flowering plant diversity and soil total nitrogen. The soil total nitrogen interacting with local flowering plant diversity significantly affected the honey bee abundance. At low levels of soil total nitrogen (≤1.9 g·kg-1), there was a positive effect of flowering plant diversity on honey bee abundance; whereas this trend was reversed at high levels of soil total nitrogen (>1.9 g·kg-1). Increasing the proportion of semi-natural habitats in agricultural landscape was beneficial to the increase of wild bee abundance, and flowering plant diversity could promote bee diversity but depending on landscape scale (proportion of semi-natural habitats) and local scale (nitrogen application). Therefore, multi-scale factors should be considered to develop conservation strategies to maintain the diversity of wild bees in agricultural landscape. Maintaining a higher proportion of cultivated land as much as possible is still a long-term requirement for production, while maintaining intermediate landscape complexity, increasing the diversity of flowering plants on the ground, and reducing the application of nitrogen fertilizer would be effective ways to promote the diversity of pollinating bees in apple orchards.

circKL inhibits the growth and metastasis of kidney cancer by sponging miR­182­5p and upregulating FBXW7.

Circular RNAs (circRNAs) are a type of non­coding RNA with important roles in the regulation of various biological processes involved in malignant progression. However, the potential molecular mechanisms and roles of circRNAs in kidney cancer have remained to be fully elucidated. In a previous study by our group, high­throughput microarray sequencing data were analyzed to determine the differentially expressed circRNAs in kidney cancer. In this analysis, a novel circRNA (hsa_circ_0100312, named circKL) was identified as a frequently downregulated circRNA in kidney cancer cells and tissues by reverse transcription­quantitative PCR. In the present study, Cell Counting Kit­8, colony formation, Transwell, wound­healing and mouse xenograft assays as well as a lung metastasis experiment were performed to confirm the functions of circKL. The experiments confirmed that circKL overexpression significantly inhibited the proliferation, migration, tumor growth and metastasis of kidney cancer both in vitro and in vivo. The potential molecular mechanisms of circKL were investigated by performing dual­luciferase and RNA immunoprecipitation assays. Western blot assays confirmed that overexpression of circKL significantly increased the protein level of F­box and WD repeat domain containing 7 (FBXW7). All results suggested that circKL suppressed the growth and migration of kidney cancer by sponging microRNA (miR)­182­5p and upregulating FBXW7 expression. Overall, the circKL/miR­182­5p/FBXW7 axis was indicated to have a key role in the growth and metastasis of kidney cancer and may be targeted as a novel therapeutic strategy.

HucMSC exosomes promoted imatinib-induced apoptosis in K562-R cells via a miR-145a-5p/USP6/GLS1 axis.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with increasing incidence worldwide. Growing evidence suggests that ubiquitin-specific proteases (USPs) play a role in cancer treatment. Dysregulation of miR-146a has been found in both adult and pediatric patients with acute leukemia. Knockdown of glutaminase-1 (GLS1) resulted in inhibition of tumor growth. However, the role of miR-146a-5p/USP6/GLS1 in leukemia and chemoresistance of leukemia cells remains to be elucidated. In the current study, USP6 level was increased in bone marrow aspiration specimens of patients with CML and associated with poor prognosis. USP6 was significantly upregulated in imatinib (IM)-resistant clinical samples compared with IM-sensitive samples. USP6 overexpression significantly inhibited IM-induced apoptosis of leukemia cells. Overexpressing USP6 significantly increased GLS1 ubiquitination to decrease GLS protein. A mechanism study indicated that USP6 regulation of IM resistance of CML cells was GLS1 dependent and regulated by miR-146a-5p. Administration of human umbilical cord mesenchymal stem cell (hucMSC) exosomes promoted IM-induced cell apoptosis through miR-145a-5p/USP6. Therefore, hucMSC exosomes promoted IM-induced apoptosis of K562-R cells by suppressing GLS1 ubiquitination to increase GLS protein via miR-146a-5p and its target GLS1. The findings highlight the importance of miR-146a-5p/USP6/GLS1 signaling in chemoresistance of leukemia and provide new insights into therapeutic strategies for chemoresistant leukemia.

Sinomenine ester derivative inhibits glioblastoma by inducing mitochondria-dependent apoptosis and autophagy by PI3K/AKT/mTOR and AMPK/mTOR pathway.

Glioblastoma multiforme (GBM) in the central nervous system is the most lethal advanced glioma and currently there is no effective treatment for it. Studies of sinomenine, an alkaloid from the Chinese medicinal plant, Sinomenium acutum, showed that it had inhibitory effects on several kinds of cancer. Here, we synthesized a sinomenine derivative, sino-wcj-33 (SW33), tested it for antitumor activity on GBM and explored the underlying mechanism. SW33 significantly inhibited proliferation and colony formation of GBM and reduced migration and invasion of U87 and U251 cells. It also arrested the cell cycle at G2/M phase and induced mitochondria-dependent apoptosis. Differential gene enrichment analysis and pathway validation showed that SW33 exerted anti-GBM effects by regulating PI3K/AKT and AMPK signaling pathways and significantly suppressed tumorigenicity with no obvious adverse effects on the body. SW33 also induced autophagy through the PI3K/AKT/mTOR and AMPK/mTOR pathways. Thus, SW33 appears to be a promising drug for treating GBM effectively and safely.

Glutaredoxins and thioredoxin peroxidase involved in defense of emamectin benzoate induced oxidative stress in Grapholita molesta.

Glutaredoxins (Grxs) and thioredoxin peroxidases (Tpxs) are major antioxidant enzyme families involved in regulating cellular redox homeostasis and in defense of enhanced oxidative stress through scavenging reactive oxygen species (ROS). However, the functions of these enzymes have not been reported in the oriental fruit moth, Grapholita molesta (Busck), a worldwide pest of stone and pome fruits. Here, we identified four new antioxidant genes, GmGrx, GmGrx3, GmGrx5, and GmTpx which were induced by exposure with emamectin benzoate, a commonly used biopesticide for G. molesta control. Other environmental factors (low and high temperatures, Escherichia coli and Metarhizium anisopliae) also significantly induced the expression of these genes. After GmGrx or GmTpx silenced by RNA interference (RNAi), the percentage of larval survival to emamectin benzoate were significantly decreased, demonstrating that GmGrx and GmTpx are involved in protecting G. molesta from stresses induced by emamectin benzoate. Furthermore, silenced GmGrx, GmGrx3, GmGrx5, or GmTpx significantly enhanced the enzymatic activities of superoxide dismutase (SOD) (except GmTpx) and peroxidase (POD), as well as the contents of hydrogen peroxide and metabolites ascorbate. Taken together, our results suggest that GmGrx, GmGrx3, GmGrx5, and GmTpx may play critical roles in antioxidant defense. Specially, GmGrx and GmTpx contribute to the defense of oxidative damage induced by exposure to emamectin benzoate through scavenging excessive ROS in G. molesta. Our findings provided a theoretical basis for understanding functions of insect glutaredoxin and peroxidase systems.

The Complete Mitochondrial Genome of Lepidotrigona flavibasis (Hymenoptera: Meliponini) and High Gene Rearrangement in Lepidotrigona Mitogenomes.

We reported the sequence and characteristics of the complete mitochondrial genome of an ecologically important stingless bee, Lepidotrigona flavibasis (Hymenoptera: Meliponini), that has suffered serious population declines in recent years. A phylogenetic analysis based on complete mitogenomes indicated that L. flavibasis was first clustered with another Lepidotrigona species (L. terminata) and then joined with the other two Melipona (Hymenoptera: Meliponini) stingless bees (M. scutellaris and M. bicolor), forming a single clade of stingless bees. The stingless bee clade has a closer relationship with bumblebees (Bombus) (Hymenoptera: Apidae) than with honeybees (Apis) (Hymenoptera: Apidae). Extremely high gene rearrangements involving tRNAs, rRNAs, D-loop regions, and protein-coding genes were observed in the Lepidotrigona mitogenomes, suggesting an overactive evolutionary status in Lepidotrigona species. These mitogenomic organization variations could provide a good system with which to understand the evolutionary history of Meliponini.

Exogenous salicylic acid improves resistance of aphid-susceptible wheat to the grain aphid, Sitobion avenae (F.) (Hemiptera: Aphididae).

Salicylic acid (SA), a phytohormone, has been considered to be a key regulator mediating plant defence against pathogens. It is still vague how SA activates plant defence against herbivores such as chewing and sucking pests. Here, we used an aphid-susceptible wheat variety to investigate Sitobion avenae response to SA-induced wheat plants, and the effects of exogenous SA on some defence enzymes and phenolics in the plant immune system. In SA-treated wheat seedlings, intrinsic rate of natural increase (rm), fecundity and apterous rate of S. avenae were 0.25, 31.4 nymphs/female and 64.4%, respectively, and significantly lower than that in the controls (P < 0.05). Moreover, the increased activities of phenylalanine-ammonia-lyase, polyphenol oxidase (PPO) and peroxidase in the SA-induced seedlings obviously depended on the sampling time, whereas activities of catalase and 4-coumarate:CoA ligase were suppressed significantly at 24, 48 and 72 h in comparison with the control. Dynamic levels of p-coumaric acid at 96 h, caffeic acid at 24 and 72 h and chlorogenic acid at 24, 48 and 96 h in wheat plants were significantly upregulated by exogenous SA application. Nevertheless, only caffeic acid content was positively correlated with PPO activity in SA-treated wheat seedlings (P = 0.031). These findings indicate that exogenous SA significantly enhanced the defence of aphid-susceptible wheat variety against aphids by regulating the plant immune system, and may prove a potential application of SA in aphid control.

Case Report: Myeloid Sarcoma Development During Treatment for B Cell Lymphoblastic Lymphoma in a Boy with KRAS/NRAS Gene Mutations.

Here, we report a rare case of a 12-year-old boy who was initially diagnosed with B cell lymphoblastic lymphoma (BLBL) and developed myeloid sarcoma (MS) eight months after chemotherapy. Next-generation sequencing (NGS) showed mutations of KRAS and NRAS genes in both the bone marrow and lymph node. He presented an abnormal karyotype of 46, XY, -9, der (16) t (9; 16) (q13; q12), +mar. He received chemotherapy according to the South China Children's Leukemia Group 2016 protocol. Complete remission was achieved by the 15th day post-treatment. Eight months later and immediately prior to the start of maintenance therapy, the patient developed fever, skin nodules in both upper arms, and enlargement of bilateral testes. Pathological analysis of skin and testicular biopsies suggested the diagnosis of myeloid sarcoma (MS). Again, NGS examination showed mutations of KRAS and NRAS genes. The patient underwent haploidentical hematopoietic stem cell transplantation but unfortunately did not survive. The interval of eight-month interval between the initial disease onset and MS brings into question whether MS developed as part of the initial onset of disease or as a secondary tumor in association with chemotherapy. Thus, understanding the pathogenesis of MS involving abnormalities of lymphoid progenitors may assist in the prediction of prognosis and development of novel target therapies.

Complete mitochondrial genome of the stingless bee Lepidotrigona terminata (Hymenoptera: Meliponinae) and phylogenetic analysis.

Lepidotrigona terminata (Smith, 1878) is a stingless bee that distributed in Eastern Asia. The complete mitogenome of L. terminata (GenBank accession number MN737481) is 15,431 bp in size, including 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a noncoding D-loop region. The D-loop region is located between ND4L and tRNAMet, different from the other two stingless bee mitogenomes previously reported. The base composition of the whole L. terminata mitogenome is 38.18% for A, 11.67% for G, 38.32% for T, and 11.83% for C, with a high AT bias of 76.50%. The present data could contribute to a detailed phylogeographic analysis of this valuable economic insect for further study in differentiating closely related species.

Exosomes-Coated miR-34a Displays Potent Antitumor Activity in Pancreatic Cancer Both in vitro and in vivo.

PURPOSE: MiR-34a, which acts as an important tumor suppressor gene, plays an important role in pancreatic cancer. However, the therapeutic application of miR-34a is limited by the lack of an effective delivery system. In the present study, we synthesize exosomes-coated miR-34a (exomiR-34a), and the anticancer effect of exomiR-34a was evaluated in pancreatic cancer. MATERIALS AND METHODS: An ultrasound approach was used to synthesize exomiR-34a, and its transfection efficiency was examined by confocal microscopy and flow cytometry. The level of miR-34a and its targeted gene Bcl-2 was detected by real-time quantitative PCR (qRT-PCR). MTT analysis was performed to determine the effect of exomiR-34a on the growth of pancreatic cancer cells. Annexin-V/PI double staining and Western blot analysis were carried out to determine the apoptosis of the pancreatic cancer cells. The xenograft nude mice model bearing human pancreatic cancer Panc28 cells was used to determine the antitumor effect of exomiR-34a in vivo. RESULTS: The exomiR-34a could cross the cell membrane efficiently, and downregulated the expression of the targeted gene Bcl-2. Treatment with exomiR-34a inhibited the growth of the pancreatic cancer cells significantly and the nanoparticles also induced apoptosis in cancer cells via affecting the expression of apoptotic-related genes. In vivo study using xenograft nude mice bearing Panc28 cancer cells revealed that exomiR-34a suppressed the growth of tumors significantly. CONCLUSION: ExomiR-34a can inhibit the growth of pancreatic cancer both in vitro and in vivo. Targeting miR-34a is a promising strategy for the treatment of pancreatic cancer. ExomiR-34a has the potential to be developed as a novel anticancer agent for the treatment of human pancreatic malignancy.

WNT974 Inhibits Proliferation, Induces Apoptosis, and Enhances Chemosensitivity to Doxorubicin in Lymphoma Cells by Inhibiting Wnt/ß-Catenin Signaling.

BACKGROUND Upregulation of the Wnt/ß-catenin pathway has been demonstrated to promote tumor proliferation and chemoresistance in lymphoma. Our objective was to evaluate the effect of the Wnt/ß-catenin pathway inhibitor WNT974 in lymphoma cells. MATERIAL AND METHODS Human lymphoma cell lines HUT-78 and BJAB were treated with or without 1 µM WNT974±0.15 µg/L doxorubicin (Dox). Cell viability and proliferation were evaluated by CCK-8 and colony formation assay. Expression of proliferating cell nuclear antigen (PCNA), KI67, and apoptotic-related proteins including Bcl-2, Bax, cleaved-caspase3, and cleaved-caspase9, together with Wnt pathway proteins Wnt, ß-catenin, Axin2, and c-Myc, were detected by Western blot analysis. Flow cytometry was used to calculate the ratio of apoptotic cells. RESULTS In HUT-78 and BJAB cells, 1 µM WNT974 significantly reduced viability and colony formation. The expression of 2 markers of tumor cell proliferation, protein PCNA and KI67, was also reduced by WNT974. Treatment with 1 µM WNT974 for 48 h increased the rate of cell apoptosis, inhibited the expression of anti-apoptotic protein Bcl-2, and enhanced pro-apoptotic proteins Bax, cleaved-caspase3, and cleaved-caspase9 expression in both cell lines. After treatment with WNT974 plus Dox, cell viability was markedly decreased compared with Dox treatment alone. Mechanistically, WNT974 prevented the expression of Wnt, Axin2, ß-catenin, and its target gene c-Myc. CONCLUSIONS WNT974 effectively treats lymphoma by inhibiting cell proliferation, inducing cell apoptosis, and enhancing chemosensitivity to Dox, and these effects are dependent on blocking Wnt/ß-catenin signaling.

Exosomes-coated bcl-2 siRNA inhibits the growth of digestive system tumors both in vitro and in vivo.

BACKGROUND: The therapeutic application of small interfering RNA is limited by the lack of an effective delivery system to tumors. In the present study, an efficient approach to deliver siRNA to cancer cells using exosome system was developed. MATERIALS & METHODS: Exosomes were isolated from bovine milk and exosomes-coated bcl-2 siRNA (exosiBcl-2) was synthesized using ultrasonic approach. The anticancer effect of exsosiBcl-2 was studied by Confocal microscopy, flow cytometry, scratch wound healing and Transwell experiments, RT-qPCR and Western blot approaches, etc. Xenograft nude mice tumor model was performed to check the antitumor activity of exosiBcl-2 in vivo. RESULTS: ExosiBcl-2 can cross the cell membrane efficiently and inhibit the growth of cancer cells. ExosiBcl-2 treatment led to apoptosis and dramatic inhibition of migration and invasion of cancer cells via downregulating metastatic related genes. In vivo study revealed that exosiBcl-2 inhibited the tumor growth significantly in nude mice. CONCLUSION: ExosiBcl-2 has potential to be developed as a novel anticancer agent.

Antitumor Effects and the Compatibility Mechanisms of Herb Pair Scleromitrion diffusum (Willd.) R. J. Wang-Sculellaria barbata D. Don.

Herb pair Scleromitrion diffusum (Willd.) R. J. Wang (HD) and Scutellaria barbata D. Don (SB) has been most frequently used for cancer treatment in traditional Chinese medicine. This study aimed to explore the in vitro and in vivo antitumor effects of HD-SB extract and to elucidate the underlying compatibility mechanisms. HD, SB, and HD-SB extracts were prepared, and the components were detected by ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry method. The in vitro antitumor effects of various concentrations of these extract were detected on several tumor cell lines using MTS assay. The in vivo antitumor effects were evaluated in Panc28 cells-bearing nude mice model. The compatibility mechanisms of herb pair HD-SB were evaluated based on the systems pharmacology strategy and then validated by cellular experiments. HD-SB extract was demonstrated to inhibit the proliferation of the cancer cell lines dose dependently by MTS assay. In vivo antitumor effects of HD-SB were much more potent than either of the two single herbs in Panc28 xenograft mice model. A total 29 active ingredients involved in antitumor effects were selected from HD and SB, and the "herb-composition-target-disease" network was constructed. Then, 58 cancer-related targets and 66 KEGG pathways were identified, and PTGS2-, HSP90-, EGFR-, MMP2-, PPARγ-, and GSTP-mediated pathways were predicted to be the antitumor mechanisms of HD-SB. The cellular experiments showed that HD-SB significantly induced cancer cell apoptosis, decreased p-EGFR, HSP90 and bcl-2 expressions, and increased PPARγ, bax, cleaved caspase 3, cleaved PARP, p-AKT, and p-PI3K expressions compared with HD or SB treatment. Our study showed that HD-SB inhibited tumor growth both in vitro and in vivo, which might be related with apoptosis induction via the EGFR/PPARγ/PI3K/AKT pathway.