A revision of the genus Eurymesosa Breuning, 1938 (Cerambycidae, Lamiinae, Mesosini).

A taxonomic revision and redescription of the genus Eurymesosa Breuning, 1938 are presented, including a key to species. Three of the five currently accepted species are considered valid: Eurymesosaventralis (Pascoe, 1865), Eurymesosaallapsa (Pascoe, 1866) and Eurymesosaziranzhiyi Yamasako & Lin, 2016. Three junior synonyms are proposed for E.ventralis: Eurymesosaalbostictica Breuning, 1962, syn. nov., Eurymesosaaffinis Breuning, 1970, syn. nov., and Eurymesosamultinigromaculata Breuning, 1974, syn. nov. Additionally, E.allapsa (Pascoe, 1866) is resurrected from synonyms of E.ventralis. Females of E.allapsa and E.ziranzhiyi Yamasako & Lin, 2016 are described for the first time.

A revision of some species of Souvanna Breuning, 1963, Mispila Pascoe, 1864, and Athylia Pascoe, 1864 (Coleoptera, Cerambycidae, Lamiinae).

Alidussignatus Pic, 1926 is transferred from Mispila to Souvanna, and Souvannasignata (Pic, 1926), comb. nov. is proposed. The lectotype of Alidussignatus is designated. The following synonyms are proposed: Souvannasignata = Athylia (s. str.) quadristigma (Gressitt, 1940), syn. nov. = Souvannaphoumai Breuning, 1963, syn. nov. = Mispila (Dryusa) coomani Breuning, 1968, syn. nov., Mispila (s. str.) tenuevittata (Pic, 1930) = Mispila (s. str.) assamensis Breuning, 1938, syn. nov. The gender of the holotype of Alidusmultilineatus Pic, 1925 is determined. New distributional records for Souvannasignata, Mispilacurvilinea Pascoe, 1869, M.subtonkinea Breuning, 1968 and M.tenuevittata are provided.

Comparison of Pharmacokinetics and Tissue Distribution Characteristics of Three Diterpenoid Esters in Crude and Prepared Semen Euphorbiae.

BACKGROUND: Semen Euphorbiae (SE) and Semen Euphorbiae Pulveratum (SEP) have a long history of medicinal use. SEP is the processed product of SE; both ancient and modern studies have shown that SEP has a lower toxicity compared to SE. To clarify the influence of processing on the pharmacological properties of SE and SEP, a study was carried out to compare the pharmacokinetics and distribution characteristics of three active compounds after oral administration of SE and SEP extracts. METHODS: A UPLC-MS/MS method was established to simultaneously determine the contents of Euphorbia factors L1, L2, and L3 in rat plasma and mouse tissues after an oral administration of crude and processed SE with approximately the same dosage. Plasma and heart, liver, spleen, lung, kidney, and colon tissue samples were treated with ethyl acetate and separated by gradient elution on a C18 column with a mobile phase of 0.1% formic acid and methanol. RESULTS: The established method had good selectivity, linear range, accuracy, precision, stability, matrix effect, and extraction recovery. The area under the concentration time curve, time to maximum concentration, maximum concentration, half-life of elimination, and mean retention time of plasma samples in SEP-treated group decreased, and the clearance in SEP-treated group increased. Moreover, the active component concentrations in colon, liver, and kidney tissues were more followed by those in the heart, lungs, and spleen. CONCLUSION: These results indicate that the processing could influence the pharmacokinetics and tissue distribution of Euphorbia factors L1, L2, and L3 after oral administration of crude and processed SE. The data obtained may lay a foundation for the clinical use of SE and for further study on the processing mechanism of SE.

A remarkable new species of Teledapus Pascoe, 1871 from China (Coleoptera: Cerambycidae: Lepturinae: Teledapini).

Teledapus linyejiei sp. nov. is described from Yunnan, China and its adult habitus, hind wings and terminalia are described and illustrated.

Prenatal exposure to koumine results in cognitive deficits and increased anxiety-like behavior in mice offspring.

Koumine (KM) is a major alkaloid monomer in the traditional Chinese medicine herb Gelsemium elegans Benth that has exhibited therapeutic potential in clinical applications. However, the pharmacological toxicological mechanism of this drug has not been fully explored. The purpose of this study was to evaluate the impacts of KM administration at a therapeutic dose in offspring. On gestational day 0, mice were injected with KM once daily for 4 consecutive days. Male and female offspring were subjected to behavioral tests and neuropathological analyses from postnatal day 60. Prenatal KM exposure resulted in cognitive and memory impairments in the Morris water maze, Y-maze test, and novel object recognition test. The open field test and elevated plus maze test indicated that prenatal KM exposure induced anxiety-like behavior in offspring. Electrophysiological experiments demonstrated that KM exposure inhibited hippocampal long-term potentiation. Immunostaining for neurogenesis markers DCX and BrdU demonstrated that KM suppressed adult neurogenesis in the subgranular zone of the dentate gyrus. In addition, prenatal KM exposure induced a significant reduction in dendritic spine density in hippocampal neurons. Synaptic formation-related proteins were decreased in the KM group based on western blot. No sex differences in the effects of KM were observed. Collectively, our results indicate that prenatal KA exposure has detrimental neural effects on offspring. This study provides a preliminary preclinical toxicological assessment of the safety of KM use during pregnancy.

Notes on the genus Paracyriothasastes Breuning, 1978 (Coleoptera: Cerambycidae: Lamiinae: Lamiini).

The monotypic genus Paracyriothasastes Breuning, 1978 was established for Cereopsius marmoreus Pascoe, 1857 from Malaysia. Uraechoides Breuning, 1981 was established for Uraechoides vivesi Breuning, 1981 also from Malaysia, and is currently composed of the type species and U. taomeiae Hayashi, Nara Yu, 1995, the latter from China (Taiwan) (Tavakilian Chevillotte 2020).

A review of the genus Paragnia Gahan, 1893 (Coleoptera: Cerambycidae: Lamiinae: Lamiini).

A taxonomic review of the genus Paragnia Gahan, 1893 is presented. The genus is redescribed, Paragnia tiani sp. nov., from Vietnam, is described; and Paragnia fulvomaculata Gahan, 1893 is redescribed, reporting its intraspecific variation, and recorded it from Vietnam for the first time.

Description of Paraclytus xiongi sp. nov. from Yunnan, China (Coleoptera: Cerambycidae: Cerambycinae: Anaglyptini).

Paraclytus xiongi sp. nov. is described from Yunnan, China. Habitus of adults, hind wings, male terminalia and intraspecific variation of Paraclytus xiongi sp. nov. are illustrated. The differences between Paraclytus xiongi sp. nov. and related species are provided.

Hepatocytes paradoxically affect intrahepatic IFN-γ production in autoimmune hepatitis due to Gal-9 expression and TLR2/4 ligand release.

Hepatocytes are the targets in autoimmune hepatitis (AIH) that results in T cell-dependent liver injury. However, hepatocytes may also affect the hepatic T cells in AIH, but the underlying mechanisms are not fully understood. Here we report that hepatocytes could secrete galectin-9 (Gal-9) to suppress the intrahepatic production of Th1 cytokine IFN-γ and restrict AIH development, but hepatocyte damage resulted in opposite effects due to release of TLR2/4 ligands that promoted the intrahepatic production of IL-1ß, IL-6, and IL-12. Through Tim-3, Gal-9 could efficiently suppress the intrahepatic T cell activation despite presence of TLR2/4 ligands, thus attenuating Th1 response in AIH. Intriguingly, intrahepatic IL-6/IL-12 suppressed the effect of TGF-ß on Treg cells. Therefore, in AIH, Gal-9 promoted Foxp3 expression and function of hepatic Treg cells through TL1A signaling, although Treg function was still impaired, compared with that in naive state. Due to its promoting effect on Treg function, together with its effect on T effector cells in a Tim-3-independent way, Gal-9 could attenuate intrahepatic IFN-γ production by hindering the increase of hepatic CD4+CD43+ T cells resulting from extrahepatic T cell activation. TLR2/4 ligands attenuated the effects of Gal-9 on Treg cells and CD4+CD43+ T cells by increasing intrahepatic IL-6 and IL-12. Blocking TLR2/4 ligands could efficiently suppress intrahepatic IFN-γ production, liver injury, and hepatic fibrosis. These findings suggest that hepatocytes paradoxically affect Th1 response in AIH due to Gal-9 expression and TLR2/4 ligands release, and that targeting TLR2/4 signaling may provide an important approach in the therapeutic strategy for AIH.

TGF-ß1 and TNF-α synergistically induce epithelial to mesenchymal transition of breast cancer cells by enhancing TAK1 activation.

TGF-ß1 is a main inducer of epithelial to mesenchymal transition (EMT). However, many breast cancer cells are not sensitive to the EMT induction by TGF-ß1 alone. So far, the mechanisms underlying the induction of TGF-ß1-insensitive breast cancer cells remains unclear. Here we report that TNF-α can induce EMT and invasiveness of breast cancer cells which are insensitive to TGF-ß1. Intriguingly, TGF-ß1 could cooperate with TNF-α to promote the EMT and invasiveness of breast cancer cells. The prolonged co-stimulation with TGF-ß1 and TNF-α could enhance the sustained activation of Smad2/3, p38 MAPK, ERK, JNK and NF-κB pathways by enhancing the activation of TAK1, which was mediated by the gradually up-regulated TßRs. Except for JNK, all of these pathways were required for the effects of TGF-ß1 and TNF-α. Importantly, the activation of p38 MAPK and ERK pathways resulted in a positive feed-back effect on TAK1 activation by up-regulating the expression of TßRs, favoring the activation of multiple signaling pathways. Moreover, SLUG was up-regulated and required for the TGF-ß1/TNF-α-induced EMT and invasiveness. In addition, SLUG could also enhance the activation of signaling pathways by promoting TßRII expression. These findings suggest that the up-regulation of TßRs contributes to the sustained activation of TAK1 induced by TGF-ß1/TNF-α and the following activation of multiple signaling pathways, resulting in EMT and invasiveness of breast cancer cells.

TLR2/4 ligand-amplified liver inflammation promotes initiation of autoimmune hepatitis due to sustained IL-6/IL-12/IL-4/IL-25 expression.

Autoimmune hepatitis (AIH), a serious autoimmune liver disease, can be a lifelong illness, leading to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). So far the mechanisms for disease initiation are largely unknown. Here we report that the amplified non-AIH liver inflammation could promote the initiation of AIH due to the sustained increase of IL-6, IL-12, IL-4, and IL-25 in the liver. The liver injury resulting from virus (adenovirus) or chemicals (CCl4) could induce an amplified (stronger/long-lasting) hepatic inflammation by releasing the ligands for TLR2/TLR4. The amplified inflammation resulted in the increase of multiple cytokines and chemokines in the liver. Among them, the sustained increase of IL-6/IL-12 resulted in the activation of STAT3 and STAT4 in hepatic CD4+CD25+ Treg cells, thus suppressing Foxp3 gene expression to reduce the suppressive function of Treg cells in the liver, but not those in the spleen. The increase of IL-12 and the impairment of Treg function promoted Th1 response in presence of self-mimicking antigen (human CYP2D6). Intriguingly, the amplified inflammation resulted in the increase of IL-4 and IL-25 in the liver. The moderate increase of IL-4 was sufficient for cooperating with IL-25 to initiate Th2 response, but inefficient in suppressing Th1 response, favoring the initiation of autoimmune response. Consequently, either adenovirus/CYP2D6 or CCl4/CYP2D6 could induce the autoimmune response and AIH in the mice, leading to hepatic fibrosis. The findings in this study suggest that the amplified non-AIH inflammation in the liver could be a driving force for the initiation of autoimmune response and AIH.

IL-35 induces N2 phenotype of neutrophils to promote tumor growth.

IL-35 is an immunosuppressive cytokine and exerts regulatory effects on T cells, B cells, macrophages and dendritic cells. Neutrophils are important innate immune cells that play key roles in tumor development. The effect of IL-35 on neutrophils remains unknown. Here, we report that IL-35 can induce N2 neutrophil polarization (protumor phenotype) by increasing G-CSF and IL-6 production, and promote neutrophil infiltration into tumor microenvironment. The sustained expression of IL-35 could promote chronic inflammation to augment the proangiogenic and immunosuppressive function of neutrophils. IL-35 stimulated macrophages to secrete proinflammatory cytokines IL-1ß and IL-6. IL-1ß stimulated γδ T cells to produce IL-17, which in turn increased the production of G-CSF. By increasing the expression of G-CSF and IL-6, IL-35 could up-regulate the expression of MMP-9 and Bv8, and down-regulate TRAIL expression in neutrophils, thus augmenting the proangiogenic function of neutrophils. Moreover, G-CSF/IL-6 induced the enhanced activation of STAT3 and ERK pathways in neutrophils, thus increasing the expression of iNOS to suppress T cell activation. Our findings suggest that IL-35 can promote tumor progression by functioning as an up-stream cytokine to promote cancer-associated inflammation and control neutrophil polarization. Targeting IL-35 might be an important approach for designing new strategy of tumor therapy.

Circulating tumor cells promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation.

Circulating tumor cells (CTCs) have been studied well in the prognosis for malignant diseases as liquid biopsy, but their contribution to tumor metastasis is not clearly defined. Here we report that CTCs could promote the metastatic colonization of disseminated carcinoma cells by inducing systemic inflammation and neutrophil recruitment to pre-metastatic organs. Depletion of neutrophils in vivo could effectively abrogate the promoting effect of CTCs on tumor cell metastasis. In the presence of CTCs, the pro-tumor function of neutrophils was augmented, whereas the antitumor function of neutrophils was suppressed. Mechanically, CTC-derived ligands for TLR2 and TLR4 (TLR2/4) induced the systemic inflammation, thus increasing the production of proinflammatory cytokines such as G-CSF and IL-6 that could induce the conversion of neutrophil function from tumor-suppressing to tumor-promoting. Moreover, CTCs induced the production of endogenous TLR2/4 ligands such as S100A8, S100A9, and SAA3, which may amplify the stimulating effect that induces the expression of proinflammatory cytokines. The promoting effect of CTCs on tumor cell metastasis could be abrogated by suppressing inflammatory response with IL-37, an anti-inflammatory cytokine, or blocking CTC-derived ligands for TLR2/4. Identification of the metastatic axis of CTCs/systemic inflammation/neutrophils may provide potential targets for preventing tumor cell metastasis.

14,15-EET induces the infiltration and tumor-promoting function of neutrophils to trigger the growth of minimal dormant metastases.

Infiltrating neutrophils are known to promote in the development of tumor. However, it is unclear whether and how neutrophils are involved in triggering the growth of dormant metastases. Here we show that 14,15-epoxyeicosatrienoic acid (14,15-EET) can trigger the growth of dormant micrometastases by inducing neutrophilic infiltration and converting neutrophil function. 14,15-EET triggered neutrophil infiltration in metastatic lesions by activating STAT3 and JNK pathways to induce the expression of human IL-8 and murine CXCL15 in corresponding tumor cells. The continuous expression of hIL-8/mCXCL15 was maintained by the sustained and enhanced activation of JNK pathway. 14,15-EET up-regulated miR-155 expression by activating STAT3 and JNK pathways. miR-155 in turn down-regulated the expression of SHIP1 and DET1, thus augmenting the activation of JNK and c-Jun. Moreover, the function of neutrophils was converted from tumor-suppressing to tumor-promoting by 14,15-EET in vivo. By inducing the production of G-CSF/IL-6 in vivo, 14,15-EET induced the enhancement of STAT3 activation in neutrophils to increase MMP-9 expression and decrease TRAIL expression. Neutrophil-derived MMP-9 was required for 14,15-EET to induce angiogenesis during the growth of dormant micrometastases. Depleting neutrophils or inhibiting hIL-8/mCXCL15 up-regulation resulted in the failure of 14,15-EET to promote the development of micrometastases. These findings reveal a mechanism through which the infiltration and tumor-promoting function of neutrophils could be induced to trigger the growth of dormant metastases, which might be a driving force for the tumor recurrence based on dormant metastases.

Cyclin D1b splice variant promotes αvß3-mediated adhesion and invasive migration of breast cancer cells.

Cyclin D1b, a splice variant of the cell cycle regulator cyclin D1, holds oncogenic functions in human cancer. However, the mechanisms underlying cyclin D1b function remain poorly understood. Here we introduced wild-type cyclin D1a or cyclin D1b variant into non-metastatic MCF-7 cells. Our results show that ectopic expression of cyclin D1b promotes invasiveness of the cancer cells in a cyclin D1a independent manner. Specifically, cyclin D1b is found to modulate the expression of αvß3, which characterizes the metastatic phenotype, and enhance tumor cell invasive potential in cooperating with HoxD3. Notably, cyclin D1b promotes αvß3-mediated adhesion and invasive migration, which are associated with invasive potential of breast cancer cells. Further exploration indicates that cyclin D1b makes breast cancer cells more sensitive to toll-like receptor 4 ligand released from damaged tumor cells. These findings reveal a role of cyclin D1b as a possible mediator of αvß3 transcription to promote tumor metastasis.

Neutrophils with protumor potential could efficiently suppress tumor growth after cytokine priming and in presence of normal NK cells.

In tumor-bearing state, the function of neutrophils is converted from tumor-suppressing to tumor-promoting. Here we report that priming with IFN-γ and TNF-α could convert the potential of neutrophils from tumor-promoting to tumor-suppressing. The neutrophils with protumor potential have not lost their responsiveness to IFN-γ and TNF-α. After priming with IFN-γ and TNF-α, the potential of the neutrophils to express Bv8 and Mmp9 genes was reduced. Conversely, the tumor-promotional neutrophils recovered the expression of Rab27a and Trail, resumed the activation levels of PI3K and p38 MAPK pathways in response to stimuli, and expressed higher levels of IL-18 and NK-activating ligands such as RAE-1, MULT-1, and H60. Therefore, the anti-tumor function of the neutrophils was augmented, including the cytotoxicity to tumor cells, the capability of degranulation, and the capacity to activate NK cells. Since the function of NK cells is impaired in tumor-bearing state, the administration of normal NK cells could significantly augment the efficiency of tumor therapy based on neutrophil priming. These findings highlight the reversibility of neutrophil function in tumor-bearing state, and suggest that neutrophil priming by IFN-γ/TNF-α might be a potential approach to eliminate residual tumor cells in comprehensive strategy for tumor therapy.

Adeno-associated virus-mediated expression of recombinant CBD-HepII polypeptide of human fibronectin inhibits metastasis of breast cancer.

CH50, a recombinant CBD-HepII polypeptide of human fibronectin, was shown to suppress tumor metastasis in murine hepatocarcinoma and melanoma models. However, the effect of CH50 on human cancer cells is still not clear. Here we evaluated the efficiency of CH50 delivered by recombinant adeno-associated virus (rAAV) vector for breast cancer treatment. Infection of the two human breast cancer cell line MDA-MB-231 and MDA-MB-468 with a rAAV2 vector encoding CH50 resulted in secretion of soluble CH50. In vitro rAAV-CH50 transduction inhibited adhesion to ECM molecules, and transwell migration and invasion of breast cancer cells induced by fibronectin. In both breast cancer cells, rAAV-CH50 targeted αVß3 signaling, namely inhibited the expression of αVß3, the activation of FAK, the upregulation of cdc2, and the production and activation of MMP-9 by ECM molecules stimulation. rAAV-mediated tail vein transfusion and stable expression of CH50 in the liver resulted in the long-term presence of CH50 in sera of nude mice. Sustained CH50 expression mediated by rAAV vector suppressed the growth and spontaneous metastasis of orthotopic breast cancer xenograft, experimental metastasis of circulating breast cancer cells, and improved the long-term survival of breast tumor-bearing mice. These findings suggest for the first time that rAAV-CH50 gene therapy may present a novel and promising strategy for treatment against metastatic breast cancer.

TLR4 ligand/H2O2 enhances TGF-ß1 signaling to induce metastatic potential of non-invasive breast cancer cells by activating non-Smad pathways.

TGF-ß1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-ß1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-ß1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-ß1 alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4 ligand (LPS) and H2O2 cooperated with TGF-ß1 to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-κB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-ß1 signaling by down-regulating Nm23-H1 expression and up-regulating the expression of TßRI and TßRII, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-ß1 signaling induced higher expression of SNAI2, which also promoted TßRII expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-ß1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF-ß1/H2O2/LPS. The metastatic potential induced by TGF-ß1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice. The findings in this study suggested that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, and that targeting one of stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy.

IL-6 cooperates with G-CSF to induce protumor function of neutrophils in bone marrow by enhancing STAT3 activation.

Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting. In this article, we report that the conversion of murine neutrophil function occurs in bone marrow, and that IL-6 cooperation with G-CSF is required for this conversion. IL-6 cooperated with G-CSF to modulate neutrophils in bone marrow, altering the activation potential of signaling pathways in neutrophils, especially that of STAT3. Costimulation with G-CSF and IL-6 induced a higher level of phospho-STAT3 in neutrophils, which was further increased by upregulation of STAT3 expression in neutrophils owing to downregulation of IFN-ß expression in bone marrow macrophages by IL-6. Augmented STAT3 activation was crucial for upregulating the expression of Mmp9 and Bv8 genes and downregulating the expression of Trail and Rab27a genes in neutrophils. Moreover, G-CSF/IL-6-modulated neutrophils could not efficiently release azurophilic granules because of downregulation of Rab27a and inefficient activation of PI3K and p38 MAPK pathways. Because of premodulation by G-CSF and IL-6, neutrophils in response to complex stimuli in tumor released much less myeloperoxidase, neutrophil elastase, and TRAIL, but showed much higher expression of Mmp9 and Bv8 genes. Taken together, these results demonstrate that G-CSF and IL-6, despite their well-known physiological functions, could modulate the activation potential of signaling pathways in neutrophils, resulting in the production or release of the above-mentioned factors in a way that favors tumor angiogenesis and tumor growth.