Deregulation of Toll-like receptor 4 (TLR4) is closely associated with the progression of various types of cancers, but its role in pancreatic carcinogenesis is unclear. This study aimed to ...investigate the role of TLR4 in the angiogenesis of pancreatic cancer and the underlying molecular mechanisms.
The culture supernatant (conditioned medium) of PANC-1 cells after appropriate treatment was used for the treatment of HUVECs. The proliferation, migration and tube formation of HUVECs were assessed by MTT, Transwell and Matrigel, respectively. In pancreatic cancer tissues, TLR4, VEGF and CD31 were upregulated as determined by immunohistochemistry and the expression of TLR4 and VEGF was positively correlated with microvessel density as detected by CD31 staining. Activation of TLR4 signaling by LPS in PANC-1 cells resulted in increased VEGF and phosphorylation of AKT, which were abolished by TLR4 silencing with siRNA and PI3K/AKT signaling inhibitor LY294002.
The conditioned medium from PANC-1 cells treated with LY294002 or transfected with TRL4 siRNA reduced the proliferation, migration and tube formation of HUVECs. In contrast, the conditioned medium from PANC-1 cells treated with LPS stimulated the proliferation, migration and tube formation of HUVECs, which was however significantly inhibited by pretreatment of PANC-1 cells with LY294002 or transfection with TRL4 siRNA.
Our findings suggest TLR4 may promote angiogenesis in pancreatic cancer by activating the PI3K/AKT signaling pathway to induce VEGF expression.
It is extremely difficult to develop targeted treatments for triple-negative breast (TNB) cancer, because these cells do not express any of the key biomarkers usually exploited for this goal.
In this ...work, we develop a solution in the form of a cascade responsive nanoplatform based on thermo-sensitive poly(N-vinylcaprolactam) (PNVCL)-chitosan (CS) nanoparticles (NPs). These are further modified with the cell penetrating peptide (CPP) and loaded with the chemotherapeutic drug doxorubicin (DOX). The base copolymer was optimized to undergo a phase change at the elevated temperatures of the tumor microenvironment. The acid-responsive properties of CS provide a second trigger for drug release, and the inclusion of CPP should ensure the formulations accumulate in cancerous tissue. The resultant CPP-CS-co-PNVCL NPs could self-assemble in aqueous media into spherical NPs of size < 200 nm and with low polydispersity. They are able to accommodate a high DOX loading (14.8% w/w). The NPs are found to be selectively taken up by cancerous cells both in vitro and in vivo, and result in less off-target cytotoxicity than treatment with DOX alone. In vivo experiments employing a TNB xenograft mouse model demonstrated a significant reduction in tumor volume and prolonging of life span, with no obvious systemic toxicity.
The system developed in this work has the potential to provide new therapies for hard-to-treat cancers.
Scutellarin (SCU) is an active ingredient extracted from
. Its main physiological functions are anti-inflammatory and antioxidant. In this study, we established a STZ-induced model of type 2 diabetes ...(T2DM) and a homocysteine (Hcy)-induced apoptosis model of LO2 to investigate whether SCU can alleviate liver damage by regulating Hcy in type 2 diabetes. Biochemical analysis indicated that SCU could improve the lipid metabolism disorder and liver function in diabetic rats by downregulating the levels of triglycerides (TG), cholesterol (CHO), low-density lipoprotein (LDL), alanine transaminase (ALT) and aspartate transaminase (AST), and by upregulating the level of high-density lipoprotein (HDL). Interestingly, SCU also could down-regulate the levels of Hcy and insulin and enhance the ability of type 2 diabetic rats to regulate blood glucose. Mechanistically, our results indicated that SCU may control the level of Hcy through regulating the levels of β-Cystathionase (CBS), γ-Cystathionase (CSE) and 5,10-methylenetetrahydrofolate (MTHFR) in liver tissue, and up-regulate folic acid, VitB
and VitB
levels in serum. Furthermore, SCU inhibits apoptosis in the liver of T2DM rats and in cultured LO2 cells treated with Hcy. Together, our findings suggest that SCU may alleviate the liver injury thorough downregulating the level of Hcy in T2DM rats.
Eupafolin is the main bioactive component extracted from the traditional Chinese medicine Ay Tsao (
Artemisia vulgaris
L.), and its anti-tumor activity has had been studied in previous researches. ...T-LAK cell-originated protein kinase (TOPK) belongs to serine/threonine protein kinase and is highly expressed in several cancer cells and tissues, such as colon cancer, lung cancer, esophagus cancer, and so on. Therefore, it was recognized as an important target for treating tumors. Nowadays, we found that eupafolin suppressed TOPK activities at the first time
in vitro
and
in vivo
. The cells study indicated that eupafolin suppressed TOPK activities in JB6 Cl41 and KYSE450 cells. Furthermore, knockdown of TOPK in KYSE450 cells decreased their sensitivities to eupafolin. The animal study showed that the injection of eupafolin in patient-derived xenograft (PDX) mouse effectively suppressed tumor growth. Histone H3 and Ki67 were reduced, and cleaved caspase 3 was increased in tumor tissues after eupafolin treatment. To sum up, eupafolin as an TOPK inhibitor can suppress growth of esophagus cancer
in vitro
and
in vivo
. The TOPK downstream signaling molecule histone H3 in tumor tissues was also reduced after eupafolin treatment. In short, eupafolin can suppress growth of esophagus cancer cells as an TOPK inhibitor both
in vitro
and
in vivo
.
To establish the molecular mechanism of ginsenoside Rg1 in nonalcoholic fatty liver disease (NAFLD), Sprague Dawley (SD) rats (180–220 g) were randomly divided into a control group, model group, ...ginsenoside Rg1 low-dose group (30 mg/(kg day)), high-dose (60 mg/(kg day)) group, and simvastatin group (1 mg/(kg day)), with 10 SD rats in each group. The control group was given a normal diet. The model group rats were given high-sugar and high-fat diets for 14 weeks. After the model of NAFLD was established successfully, ginsenoside Rg1 was administered orally for 4 or 8 weeks. The results showed that ginsenoside Rg1 decreased the levels of glucose (GLU), insulin (INS), triglyceride (TG), and total cholesterol (TC) and improved liver function. Meanwhile, ginsenoside Rg1 inhibited the secretion of interleukin-1 (IL-1), IL-6, IL-8, IL-18, and tumor necrosis factor-α (TNF-α) and improved hepatocyte morphology and lipid accumulation in the liver. Furthermore, ginsenoside Rg1 promoted the expression of peroxisome proliferator-activated receptor-α (PPAR-α), carnitine palmitoyl transferase 1α (CPT1A), carnitine palmitoyl transferase 2 (CPT2), and cholesterol 7α-hydroxylase (CYP-7A) and inhibited the expression of sterol regulatory element binding proteins-1C (SREBP-1C). In conclusion, ginsenoside Rg1 can inhibit inflammatory reaction, regulate lipid metabolism, and alleviate liver injury in NAFLD model rats.
Successful recovery from hepatectomy is partially contingent upon the rate of residual liver regeneration. The traditional Chinese medicines known as
Periplaneta americana
extracts (PAEs) positively ...influence wound healing by promoting tissue repair. However, the effect of PAEs on liver regeneration is unknown. We used a mouse liver regeneration model after 70% partial hepatectomy (PH) and a hepatocyte culture to determine whether PAEs can promote liver regeneration as effectively as skin regeneration and establish their modes of action. L02 cells were divided into serum-starved control (NC) and three PAEs (serum starvation + 0.1 mg/ml, 0.5 mg/ml, or 1 mg/ml PAEs) groups. L02 cell proliferation was assessed at 24 h, 48 h, and 72 h by CCK-8 assay. Forty male C57 mice were randomly divided into control (NC), normal saline (NS), PAEs400 (400 mg/kg/d), and PAEs800 (800 mg/kg/d) groups (n = 10 per group). The NS and both PAEs groups were administered normal saline and PAEs, respectively, by gavage for 10 days. Two hours after the tenth gavage, the NS and both PAEs groups were subjected to 70% PH and the residual liver was harvested after 48 h. The hepatic regeneration rate was evaluated and hepatocyte proliferation was estimated by immunohistochemical (IHC) staining for Ki-67. Twelve DEG libraries (three samples per group) were prepared and sequencing was performed in an Illumina HiSeq 2000 (Mus_musculus) at the Beijing Genomics Institute. The genes expressed in the liver tissues and their expression profiles were analyzed by bioinformatics. KEGG was used to annotate, enrich, and analyze the pathways. PAEs promoted hepatocyte proliferation
in vitro
and
in vivo
and accelerated mouse liver regeneration after 70% PH. The screening criteria were fold change (FC) ≥ 2 and q-value < 0.001. We identified 1,092 known DEGs in PAEs400 and PAEs800. Of these, 153 were categorized in cellular processes. The KEGG analysis revealed that the aforementioned DEGs participated in several signaling pathways closely associated with cell proliferation including PI3K-Akt, MAPK, Apelin, Wnt, FoxO, mTOR, Ras, VEGF, ErbB, Hippo, and AMPK. It was concluded that PAEs can effectively improve liver regeneration
via
the synergistic activation of different signaling pathways.
Altered gene methylation, regulated by DNA methyltransferases (DNMT) 1, 3a and 3b, contributes to tumorigenesis. However, the role of DNMT in pancreatic ductal adenocarcinoma (PDAC) remains unknown.
...Expression of DNMT 1, 3a and 3b was detected in 88 Pancreatic ductal adenocarcinoma (PDAC) and 10 normal tissue samples by immunohistochemistry. Changes in cell viability, cell cycle distribution, and apoptosis of PDAC cell lines (Panc-1 and SW1990) were assessed after transfection with DNMT1 and 3b siRNA. Levels of CDKN1A, Bcl-2 and Bax mRNA were assessed by qRT-PCR, and methylation of the Bax gene promoter was assayed by methylation-specific PCR (MSP).
DNMT1, 3a and 3b proteins were expressed in 46.6%, 23.9%, and 77.3% of PDAC tissues, respectively, but were not expressed in normal pancreatic tissues. There was a co-presence of DNMT3a and DNMT3b expression and an association of DNMT1 expression with alcohol consumption and poor overall survival. Moreover, knockdown of DNMT1 and DNMT3b expression significantly inhibited PDAC cell viability, decreased S-phase but increased G1-phase of the cell cycle, and induced apoptosis. Molecularly, expression of CDKN1A and Bax mRNA was upregulated, and the Bax gene promoter was demethylated. However, a synergistic effect of combined DNMT1 and 3b knockdown was not observed.
Expression of DNMT1, 3a and 3b proteins is increased in PDAC tissues, and DNMT1 expression is associated with poor prognosis of patients. Knockdown of DNMT1 and 3b expression arrests tumor cells at the G1 phase of the cell cycle and induces apoptosis. The data suggest that DNMT knockdown may be a novel treatment strategy for PDAC.
High-frequency hearing is required for echolocating bats to locate, range and identify objects, yet little is known about its molecular basis. The discovery of a high-frequency hearing-related gene, ...KCNQ4, provides an opportunity to address this question. Here, we obtain the coding regions of KCNQ4 from 15 species of bats, including echolocating bats that have higher frequency hearing and non-echolocating bats that have the same ability as most other species of mammals. The strongly supported protein-tree resolves a monophyletic group containing all bats with higher frequency hearing and this arrangement conflicts with the phylogeny of bats in which these species are paraphyletic. We identify five parallel evolved sites in echolocating bats belonging to both suborders. The evolutionary trajectories of the parallel sites suggest the independent gain of higher frequency hearing ability in echolocating bats. This study highlights the usefulness of convergent or parallel evolutionary studies for finding phenotype-related genes and contributing to the resolution of evolutionary problems.
In order to solve the problem of premature grape ripening due to global warming, inter-row peanut growing in viticulture was applied. In this two-year (2018-2019) study, the peanut (
L.) was used to ...cover the ground between rows in the vineyards located in the semi-arid Northwest China, Xinjiang. The results showed that reflected solar radiation and temperature around the fruit zone with the peanuts growing were decreased. Compared with clean tillage, the grapes with covering peanuts had lower total soluble solids (TSS) and higher titratable acidity (TA) in the berries. Lower alcohol content and higher total acid (TA) was also found in their corresponding wines. Inter-row peanut growing treatment significantly decreased the contents of flavonols in the grapes and their wines in the two consecutive years, but no significant effect on flavanols was observed in the resulting wines. Norisoprenoids and esters in the grapes and the wines were increased with the peanut growing treatment, respectively. Additionally, compared to clean tillage, the peanut covering significantly improved the sensory value of the wines, especially the aroma complexity of the wines. This study helps us to better understand the feasibility of applying inter-row peanut growing in the viticulture of ground management in the semi-arid climate of Northwest China.
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