Comprehensive analysis identifies cuproptosis-related gene DLAT as a potential prognostic and immunological biomarker in pancreatic adenocarcinoma.

BACKGROUND: Cuproptosis is a regulated cell death form associated with tumor progression, clinical outcomes, and immune response. However, the role of cuproptosis in pancreatic adenocarcinoma (PAAD) remains unclear. This study aims to investigate the implications of cuproptosis-related genes (CRGs) in PAAD by integrated bioinformatic methods and clinical validation. METHODS: Gene expression data and clinical information were downloaded from UCSC Xena platform. We analyzed the expression, mutation, methylation, and correlations of CRGs in PAAD. Then, based on the expression profiles of CRGs, patients were divided into 3 groups by consensus clustering algorithm. Dihydrolipoamide acetyltransferase (DLAT) was chosen for further exploration, including prognostic analysis, co-expression analysis, functional enrichment analysis, and immune landscape analysis. The DLAT-based risk model was established by Cox and LASSO regression analysis in the training cohort, and then verified in the validation cohort. Quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) assays were performed to examine the expression levels of DLAT in vitro and in vivo, respectively. RESULTS: Most CRGs were highly expressed in PAAD. Among these genes, increased DLAT could serve as an independent risk factor for survival. Co-expression network and functional enrichment analysis indicated that DLAT was engaged in multiple tumor-related pathways. Moreover, DLAT expression was positively correlated with diverse immunological characteristics, such as immune cell infiltration, cancer-immunity cycle, immunotherapy-predicted pathways, and inhibitory immune checkpoints. Submap analysis demonstrated that DLAT-high patients were more responsive to immunotherapeutic agents. Notably, the DLAT-based risk score model possessed high accuracy in predicting prognosis. Finally, the upregulated expression of DLAT was verified by RT-qPCR and IHC assays. CONCLUSIONS: We developed a DLAT-based model to predict patients' clinical outcomes and demonstrated that DLAT was a promising prognostic and immunological biomarker in PAAD, thereby providing a new possibility for tumor therapy.

NFK prevent postoperative abdominal adhesion through downregulating the TGF-ß1 signaling pathway.

BACKGROUND: Postoperative abdominal adhesions (PAAs) represent a frequent condition occurring in more than 90% of patients undergoing abdomen and pelvic surgeries, which can cause chronic abdominal pain, female infertility, and repeated bowel obstruction, requiring repetitive surgical interventions causing morbidity and mortality, as well as high costs. It is therefore of paramount clinical importance and significance to develop practical and reliable strategies for preventing the occurrence of PAAs. METHODS AND RESULTS: In this study, we demonstrated that Nianfukang (NFK, composed of polyethylene glycol 1450 and diclofenac sodium) is highly effective in preventing PAAs, likely by reducing leukocytes and inflammatory factors in the abdominal cavity, and inhibiting intestinal fibrosis in a rat model of PAAs induced by postoperative cecum scraping. We further uncovered that NFK downregulates the expression of TGF-ß1, a key factor for adhesion formation, to suppress the TGF-ß1/TGF-ßRIII/Smad2 signaling pathway, thereby inhibiting the proliferation and migration of fibroblasts and provided evidences for the involvement of the TGF-ß1/TGF-ßRIII/Smad2 axis in the prevention of PAAs in normal human colon fibroblast CCD-18Co. CONCLUSIONS: Our findings support NFK as a potential anti-adhesive product that has the advantages of significant effectiveness, safety profile, and low cost, as well as clear mechanism of action.

Preparative separation of four isomers of synthetic anisodamine by HPLC and diastereomer crystallization.

Anisodamine (654-1), a well-known cholinergic antagonist, is marketed as synthetic anisodamine (mixture of four isomers, 654-2) in China. To preparative resolution and comparison of the bioactivities of the four isomers of synthetic anisodamine, current work explores an economic and effective separation method by using preparative high performance liquid chromatography (HPLC) and diastereomer crystallization. Their absolute configurations were established by single-crystal X-ray diffraction and circular dichroism method. The purities of each isomer were more than 95%. Among them, 654-2-A2 (6R, 2'S configuration) exhibited better effect on cabachol preconditioned small intestine tension more than 654-2 and other isomers. The direct separation method without using HPLC was tried as well, which was still on progress. This is the first report of the method for preparative separation of four isomers of synthetic anisodamine which could be used for large-scale production in industry.

Anti-atherosclerotic activities of flavonoids from the flowers of Helichrysum arenarium L. MOENCH through the pathway of anti-inflammation.

We have successfully established AS model using thoracic aortas vascular ring which evaluated by the morphological changes of blood vessels, the proliferation of VSMC, and the expression of inflammation factors VEGF, CRP, JNK2 and p38. This AS model has the advantages of low cost, convenient and short period of established time. Moreover, we investigated the anti-AS activities of 7 flavonoids Narirutin (1), Naringin (2), Eriodictyol (3), Luteolin (4), Galuteolin (5), Astragalin (6), Kaempferol (7) from flowers of Helichrysum arenarium L. MOENCH by examining the vascular morphology, the inhibition on the expression of inflammation factors CRP, VEGF, JNK2, p38. In addition, we investigated the anti-AS activities of these 7 flavonoids by examining NO secretion of RAW264.7 cells in response to LPS. All above inflammation factors have been proved to be involved in the formation of AS. After comprehensive analysis of all results to discuss the structure-activity relationship, we summarized the conclusions at follow: compounds 1-7 could inhibit the expression of VEGF, CRP, JNK2, p38 and NO at different level, and we evaluated that flavonol aglycone have more significant anti-inflammation than it's glycoside, and the anti-AS activity of flavonols were stronger than flavanones and flavones, which means that 3-group might be the effective group. Eventually, we supposed the main anti-inflammatory mechanism of these compounds was to reduce the expression of CRP, inhibit the kinases activity of JNK2 and p38, and then the MAPK pathway was suppressed, which resulted in the decrease of NO synthesis, VEGF expression and endothelial adhesion factor expression. And eventually, the scar tissue and vascular stenosis formations were prevented. This conclusion suggested flavonoids have the potential of preventing AS formation.

Phagocytosis by macrophages and endothelial cells inhibits procoagulant and fibrinolytic activity of acute promyelocytic leukemia cells.

The coagulopathy of acute promyelocytic leukemia (APL) is mainly related to procoagulant substances and fibrinolytic activators of APL blasts, but the fate of these leukemic cells is unknown. The aim of this study was to investigate the removal of APL blasts by macrophages and endothelial cells in vitro and consequent procoagulant and fibrinolytic activity of APL cells. We found that human umbilical vein endothelial cells as well as THP-1 and monocyte-derived macrophages bound, engulfed, and subsequently degraded immortalized APL cell line NB4 and primary APL cells. Lactadherin promoted phagocytosis of APL cells in a time-dependent fashion. Furthermore, factor Xa and prothrombinase activity of phosphatidylserine-exposed target APL cells was time-dependently decreased after incubation with phagocytes (THP-1-derived macrophages or HUVECs). Thrombin production on target APL cells was reduced by 40%-45% after 2 hours of coincubation with phagocytes and 80% by a combination of lactadherin and phagocytes. Moreover, plasmin generation of target APL cells was inhibited 30% by 2 hours of phagocytosis and ∼ 50% by lactadherin-mediated engulfment. These results suggest that engulfment by macrophages and endothelial cells reduce procoagulant and fibrinolytic activity of APL blasts. Lactadherin and phagocytosis could cooperatively ameliorate the clotting disorders in APL.

Facile fabrications of poly (acrylic acid)-mesoporous zinc phosphate/polydopamine Janus nanoparticles as a biosafe photothermal therapy agent and a pH/NIR-responsive drug carrier.

Balancing biocompatibility and drug-loading efficiency in nanoparticles presents a significant challenge. In this study, we describe the facile fabrication of poly (acrylic acid)-mesoporous zinc phosphate/polydopamine (PAA-mZnP/PDA) Janus nanoparticles (JNPs). The PDA half-shell itself can serve as a photothermal agent for photothermal therapy (PTT), as well as to offers sites for polyethylene glycol (PEG) to enhance biocompatibility. Concurrently, the mesoporous ZnP core allows high loading of doxorubicin (DOX) for chemotherapy and the Cy5.5 dye for fluorescence imaging. The resultant PAA-mZnP/PDA-PEG JNPs exhibit exceptional biocompatibility, efficient drug loading (0.5 mg DOX/1 mg JNPs), and dual pH/NIR-responsive drug release properties. We demonstrate the JNPs' satisfactory anti-cancer efficacy, highlighting the synergistic effects of chemotherapy and PTT. Furthermore, the potential for synergistic fluorescence imaging-guided chemo-phototherapy in cancer treatment is illustrated. Thus, this work exemplifies the development of biosafe, multifunctional JNPs for advanced applications in cancer theranostics. STATEMENT OF SIGNIFICANCE: Facile fabrication of monodispersed nanomedicine with multi-cancer killing modalities organically integrated is nontrivial and becomes more challenging under the biocompatibility requirement that is necessary for the practical applications of nanomedicines. In this study, we creatively designed PAA-mZnP/PDA JNPs and fabricated them under mild conditions. Our method reliably yields uniform JNPs with excellent monodispersity. To maximize functionalities, we achieve fourfold advantages including efficient drug/fluorescent dye loading, PTT, pH/NIR dual-responsive properties, and optimal biocompatibility. The as-fabricated JNPs exhibit satisfactory anti-cancer performance both in vitro and in vivo, and demonstrate the potential of JNPs in fluorescence imaging-guided synergistic cancer chemo-phototherapy. Overall, our research establishes a pathway in versatile inorganic/polymer JNPs for enhanced cancer diagnosis and therapy.

Meaningful nomograms based on systemic immune inflammation index predicted survival in metastatic pancreatic cancer patients receiving chemotherapy.

OBJECTIVE: The purpose of the study is to construct meaningful nomogram models according to the independent prognostic factor for metastatic pancreatic cancer receiving chemotherapy. METHODS: This study is retrospective and consecutively included 143 patients from January 2013 to June 2021. The receiver operating characteristic (ROC) curve with the area under the curve (AUC) is utilized to determine the optimal cut-off value. The Kaplan-Meier survival analysis, univariate and multivariable Cox regression analysis are exploited to identify the correlation of inflammatory biomarkers and clinicopathological features with survival. R software are run to construct nomograms based on independent risk factors to visualize survival. Nomogram model is examined using calibration curve and decision curve analysis (DCA). RESULTS: The best cut-off values of 966.71, 0.257, and 2.54 for the systemic immunological inflammation index (SII), monocyte-to-lymphocyte ratio (MLR), and neutrophil-to-lymphocyte ratio (NLR) were obtained by ROC analysis. Cox proportional-hazards model revealed that baseline SII, history of drinking and metastasis sites were independent prognostic indices for survival. We established prognostic nomograms for primary endpoints of this study. The nomograms' predictive potential and clinical efficacy have been evaluated by calibration curves and DCA. CONCLUSION: We constructed nomograms based on independent prognostic factors, these models have promising applications in clinical practice to assist clinicians in personalizing the management of patients.

Large T-antigen up-regulates Kv4.3 K⁺ channels through Sp1, and Kv4.3 K⁺ channels contribute to cell apoptosis and necrosis through activation of calcium/calmodulin-dependent protein kinase II.

Down-regulation of Kv4.3 K⁺ channels commonly occurs in multiple diseases, but the understanding of the regulation of Kv4.3 K⁺ channels and the role of Kv4.3 K⁺ channels in pathological conditions are limited. HEK (human embryonic kidney)-293T cells are derived from HEK-293 cells which are transformed by expression of the large T-antigen. In the present study, by comparing HEK-293 and HEK-293T cells, we find that HEK-293T cells express more Kv4.3 K⁺ channels and more transcription factor Sp1 (specificity protein 1) than HEK-293 cells. Inhibition of Sp1 with Sp1 decoy oligonucleotide reduces Kv4.3 K⁺ channel expression in HEK-293T cells. Transfection of pN3-Sp1FL vector increases Sp1 protein expression and results in increased Kv4.3 K⁺ expression in HEK-293 cells. Since the ultimate determinant of the phenotype difference between HEK-293 and HEK-293T cells is the large T-antigen, we conclude that the large T-antigen up-regulates Kv4.3 K⁺ channel expression through an increase in Sp1. In both HEK-293 and HEK-293T cells, inhibition of Kv4.3 K⁺ channels with 4-AP (4-aminopyridine) or Kv4.3 small interfering RNA induces cell apoptosis and necrosis, which are completely rescued by the specific CaMKII (calcium/calmodulin-dependent protein kinase II) inhibitor KN-93, suggesting that Kv4.3 K⁺ channels contribute to cell apoptosis and necrosis through CaMKII activation. In summary, we establish: (i) the HEK-293 and HEK-293T cell model for Kv4.3 K⁺ channel study; (ii) that large T-antigen up-regulates Kv4.3 K⁺ channels through increasing Sp1 levels; and (iii) that Kv4.3 K⁺ channels contribute to cell apoptosis and necrosis through activating CaMKII. The present study provides deep insights into the mechanism of the regulation of Kv4.3 K⁺ channels and the role of Kv4.3 K⁺ channels in cell death.

Design, synthesis and anticancer activity of N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide.

A series of novel N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxamide, three N(3),N(11)-bis(2-hydroxyethyl)-14-aryl-14H-dibenzo[a,j]xanthene-3,11-dimethanamine derivatives and their intermediates 14-aryl-14H-dibenzo[a,j]xanthenes-3,11-dicarboxylic acid, were synthesized, and the structures of which were characterized by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and IR spectra. The antitumor activities of these molecules were evaluated on five cancer cell lines. The results of in vitro assay against human hepatocellular carcinoma cell lines (SK-HEP-1 and HepG2 and SMMC-7721 cells), acute promyelocytic leukemia NB4 cells and uterine cervix cancer HeLa cells, show several compounds to be endowed with cytotoxicity in micromolar to submicromolar range. The carboxamide derivatives 6c and 6e exhibitted good inhibition on NB4 cancer cells, and the IC(50) values of which were 0.82 µM and 0.96 µM, respectively, much lower than 5.01 µM of the positive control As(2)O(3). Flow cytometric analysis results revealed that compounds 6e and 6f may induce tumor cell apoptosis.

Mild hypoxia-induced cardiomyocyte hypertrophy via up-regulation of HIF-1α-mediated TRPC signalling.

Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study was designed to investigate the role of HIF-1α in mild hypoxia-induced cardiomyocytes hypertrophy and its underlying mechanism. Mild hypoxia (MH, 10% O(2)) caused hypertrophy in cultured neonatal rat cardiac myocytes, which was accompanied with increase of HIF-1α mRNA and accumulation of HIF-1α protein in nuclei. Transient receptor potential canonical (TRPC) channels including TRPC3 and TRPC6, except for TRPC1, were increased, and Ca(2+)-calcineurin signals were also enhanced in a time-dependent manner under MH condition. MH-induced cardiomyocytes hypertrophy, TRPC up-regulation and enhanced Ca(2+)-calcineurin signals were inhibited by an HIF-1α specific blocker, SC205346 (30 µM), whereas promoted by HIF-1α overexpression. Electrophysiological voltage-clamp demonstrated that DAG analogue, OAG (30 µM), induced TRPC current by as much as 170% in neonatal rat cardiomyocytes overexpressing HIF-1α compared to negative control. These results implicate that HIF-1α plays a key role in development of cardiac hypertrophy in responses to hypoxic stress. Its mechanism is associated with up-regulating TRPC3, TRPC6 expression, activating TRPC current and subsequently leading to enhanced Ca(2+)-calcineurin signals.

Homocysteine enhances clot-promoting activity of endothelial cells via phosphatidylserine externalization and microparticles formation.

Total elevated plasma homocysteine (Hcy) is a risk factor for thromboembolism. Vascular endothelium is important to regulate coagulation, but the impact of Hcy on the clot-promoting activity (CPA) of endothelial cells has not been fully understood. In our study, human umbilical vein endothelial cells (HUVECs) were treated with Hcy (8, 20, 80, 200, 800 µmol/L) for 24 h. Annexin V was utilized to detect phosphatidylserine (PS) externalization and endothelial microparticles (MPs) formation. CPA was assessed by recalcification time and purified clotting complex tests. We found that Hcy enhanced the externalized PS and consequent CPA of HUVECs in a dose-dependent fashion, effect of Hcy had statistical significance at 800 µmol/L. In addition, Hcy also increased the shedding of procoagulant endothelial MPs. Blocking of PS with 128 nmol/L annexin V reduced approximately 70% CPA of HUVECs and endothelial MPs, but human anti-tissue factor antibody had little inhibitive effect. Our results showed that Hcy increased CPA of HUVECs via PS externalization and MPs release. Our present study has implications for hyperhomocysteinemia-related hypercoagulability.

Bioactivity-guided fractionation of the triglyceride-lowering component and in vivo and in vitro evaluation of hypolipidemic effects of Calyx seu Fructus Physalis.

BACKGROUND: In folklore, some people take the decoction of Calyx seu Fructus Physalis (CSFP) for lowering blood lipids. The present study is designed to evaluate the lipid-lowering activities of CSFP, and search for its pharmacodynamical material. METHODS: CSFP was extracted by water and 75% ethanol, respectively. The extracts of CSFP for reducing serum lipid levels were evaluated on mouse model of hyperlipidemia. The optimized extract was subjected to the bioactivity-guided fractionation in which the liquid-liquid extraction, collumn chromatography, the in vivo and in vitro models of hyperlipidemia were utilized. The structure of active component was determined by ¹³C-NMR and ¹H-NMR. RESULTS: The 75% ethanol extract of CSFP decreased the serum total cholesterol (TC) and triglyceride (TG) levels in mouse model of hyperlipidemia. Followed a separation process for the 75% ethanol extract of CSFP, the fraction B was proved to be an active fraction for lowering lipid in vivo and in vitro experiments, which could significantly decrease the serum TC and TG levels in mouse model of hyperlipidemia, and remarkably decrease the increase of TG in primary mouse hepatocytes induced by high glucose and the increase of TG in HepG2 cells induced by oleic acid. The fraction B2, isolated from B on bioactivity-guided fractionation, could significantly decrease TG level in HepG2 cells. One compound with the highest content in B2 was isolated and determined as luteolin-7-O-beta-D-glucopyranoside by NMR spectra. It could significantly reduce the TG level in HepG2 cells, and inhibited the accumulation of lipids by oil red O stain. CONCLUSION: Our results demonstrated that the 75% ethanol extract of CSFP could improve in vitro and in vivo lipid accumulation. Luteolin-7-O-beta-D-glucopyranoside might be a leading pharmacodynamical material of CSFP for lowering lipids.

HIV Tat protein inhibits hERG K+ channels: a potential mechanism of HIV infection induced LQTs.

HIV-infected patients have a high prevalence of long QT syndrome (LQTs). hERG K(+) channel encoded by human ether-a-go-go related gene contributes to IKr K(+) currents responsible for the repolarization of cardiomyocytes. Inhibition of hERG K(+) channels leads to LQTs. HIV Tat protein, the virus transactivator protein, plays a pivotal role in AIDS. The aim of the present study is to examine the effects of HIV Tat protein on hERG K(+) channels stably expressed in HEK293 cells. The hERG K(+) currents were recorded by whole-cell patch-clamp technique and the hERG channel expression was measured by real-time PCR and Western blot techniques. HIV Tat protein at 200 ng/ml concentration showed no acute effect on hERG currents, but HIV Tat protein (200 ng/ml) incubation for 24 h significantly inhibited hERG currents. In HIV Tat incubated cells, the inactivation and the recovery time from inactivation of hERG channels were significantly changed. HIV Tat protein incubation (200 ng/ml) for 24h had no effect on the hERG mRNA expression, but dose-dependently inhibited hERG protein expression. The MTT assay showed that HIV Tat protein at 50 ng/ml and 200 ng/ml had no effect on the cell viability. HIV Tat protein increased reactive oxygen species (ROS) generation and the inhibition of hERG channel protein expression by HIV Tat protein was prevented by antioxidant tempol. HIV Tat protein in vivo treatment reduced IKr currents and prolonged action potential duration of guinea pig cardiomyocytes. We conclude that HIV Tat protein inhibits hERG K(+) currents through the inhibition of hERG protein expression, which might be the potential mechanism of HIV infection induced LQTs.

GPC3-targeted and curcumin-loaded phospholipid microbubbles for sono-photodynamic therapy in liver cancer cells.

More effective strategies are needed to improve the treatment of liver cancer. Sono-photodynamic therapy (SPDT) has a more obvious antitumor effect than sonodynamic therapy (SDT) or photodynamic therapy (PDT). We aimed to investigate Glypican-3-targeted, curcumin-loaded microbubbles (GPC3-CUR-MBs)-mediated SPDT in liver cancer cells in vitro and in vivo. GPC3-CUR-MBs were prepared by streptavidin-biotin interactions and the immune ligation method. The characterization and toxicity of GPC3-CUR-MBs and the anti-liver cancer effects of GPC3-CUR-MB-mediated SPDT in vitro and in vivo were studied. We synthetized GPC3-CUR-MBs and found that GPC3-CUR-MBs had no significant toxicity to HepG2 liver cancer cells. In terms of the anti-liver cancer effects in vitro and in vivo, when we used CUR, CUR-MBs or GPC3-CUR-MBs as the sono/photosensitizers, the outcome of SPDT was superior to that of SDT or PDT alone. The outcomes with GPC3-CUR-MBs were better than those with CUR or CUR-MBs in the SDT, PDT or SPDT groups. During the treatment period, the weight of the HepG2 tumor-bearing mice did not decrease significantly, and no significant evidence of lung, heart, liver, spleen and kidney damage was found with H&E staining. Our results indicated that the anti-liver tumor effect of SPDT was better than that of SDT and PDT and that GPC3-CUR-MBs were promising sono/photosensitizers.

5-Aminolevulinic acid hydrochloride loaded microbubbles-mediated sonodynamic therapy in pancreatic cancer cells.

5-Aminolevulinic acid hydrochloride (ALA)-mediated sonodynamic therapy (SDT) had anti-tumour effect on pancreatic cancer cells. Hence, ALA loaded lipid/poly(lactic-co-glycolic acid) (PLGA) microbubbles (MBs)-mediated SDT for pancreatic cancer has great potential. The average size of ALA-lipid MBs and ALA-PLGA MBs was about 3.0 µm. The two kinds of MBs had good biocompatibility to normal HPDE6-C7 cells and were not toxic to pancreatic cancer cells. Compared with ALA-induced SDT, a statistically significant decrease in cell viability was observed in ALA lipid/PLGA MBs combined with ultrasound groups in AsPC-1 and BxPC-3 cells (p < .05). Obvious effect on the apoptotic rate, apoptosis and pyroptosis morphology, enhanced reactive oxygen species was found in ALA-lipid/PLGA MBs mediated SDT in vitro. Through in vivo study, we found ALA-lipid/PLGA MBs-mediated SDT was a promise treatment for pancreatic cancer.

Curcumin-Loaded Poly(L-lactide-co-glycolide) Microbubble-Mediated Sono-photodynamic Therapy in Liver Cancer Cells.

Sono-photodynamic therapy (SPDT) activates the same photo-/sonosensitizer and exerts more marked antitumor effects than sonodynamic therapy or photodynamic therapy. We aimed to explore the utilization of curcumin (CUR)-loaded poly(L-lactide-co-glycolide) microbubble (MB)-mediated SPDT (CUR-PLGA-MB-SPDT) in HepG2 liver cancer cells. The cytotoxicity and intracellular accumulation of CUR were determined. We used 40 µM CUR as the photo-/sonosensitizer for 3 h. In a comparison of CUR-SDT or CUR-PDT, HepG2 cell viability decreased and apoptotic rate increased in CUR-SPDT. The CUR-PLGA MBs had round spheres with smooth surfaces and an average size of 3.7 µm. In CUR-PLGA MBs, drug entrapment efficiency and drug-loading capacity were 74.29 ± 2.60% and 17.14 ± 0.60%, respectively. CUR-loaded PLGA MBs (CUR-PLGA MBs) had good biocompatibility with normal L02 cells and were almost non-cytotoxic to HepG2 cells. Among CUR-SDT, CUR-PDT, CUR-SPDT or CUR-PLGA-MB-SDT, the cell CUR-PLGA-MB-SPDT had the lowest viability. Transmission electron microscopy revealed pyroptosis and apoptosis in the CUR-PLGA-MB-SPDT group; the potential mechanism was related to the mitochondrial membrane potential loss and increased production of intracellular reactive oxygen species. These findings suggested that CUR-PLGA-MB-SPDT may be a promising treatment for liver cancer.

Kanglexin protects against cardiac fibrosis and dysfunction in mice by TGF-ß1/ERK1/2 noncanonical pathway.

Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF ß1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-ß1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.

Kang Le Xin Reduces Blood Pressure Through Inducing Endothelial-Dependent Vasodilation by Activating the AMPK-eNOS Pathway.

Hypertension is a major risk factor for stroke and cardiovascular events in clinic, which is accompanied by the abnormality of vascular tone and endothelial dysfunction of small artery. Here we report that Kang Le Xin (KLX), a novel anthraquinones compound, could reduce blood pressure and the underlying mechanisms involves that KLX induces endothelium-dependent vasodilation. KLX significantly decreases the arterial blood pressure of spontaneous hypertensive rats (SHR), decreases the contractile reactivity of superior mesenteric artery to phenylephrine and increases the vasodilatory reactivity of superior mesenteric artery to carbachol in a dose-dependent manner. Besides, KLX reduces vascular tension of endothelium-intact mesenteric artery pre-constricted with phenylephrine in a dose-dependent manner, while this effect is inhibited by depriving vascular endothelium or pretreating vascular rings with L-NAME (endothelial nitric oxide synthase inhibitor) or compound C (AMP-activated protein kinase inhibitor). Moreover, KLX increases nitric oxide (NO) generation, endothelial nitric oxide synthase (eNOS), AKT and AMP-activated protein kinase (AMPK) phosphorylation in cultured human umbilical vein endothelial cells (HUVECs), while these effects are inhibited by pretreating cells with compound C. In conclusion, KLX is a new compound with the pharmacological action of reducing arterial blood pressure. The underlying mechanism involves KLX induces endothelium-dependent vasodilation through activating AMPK-AKT-eNOS signaling pathway.

808 nm Near-Infrared Light-Excited UCNPs@mSiO2-Ce6-GPC3 Nanocomposites For Photodynamic Therapy In Liver Cancer.

BACKGROUND: It is important to explore effective treatment for liver cancer. Photodynamic therapy (PDT) is a novel technique to treat liver cancer, but its clinical application is obstructed by limited depth of visible light penetration into tissue. The near-infrared (NIR) photosensitizer is a potential solution to the limitations of PDT for deep tumor tissue treatment. PURPOSE: We aimed to investigate 808 nm NIR light-excited UCNPs@mSiO2-Ce6-GPC3 nanocomposites for PDT in liver cancer. METHODS: In our study, 808 nm NIR light-excited upconversion nanoparticles (UCNPs) were simultaneously loaded with the photosensitizer chlorin e6 (Ce6) and the antibody glypican-3 (GPC3), which is overexpressed in hepatocellular carcinoma cells. The multitasking UCNPs@mSiO2-Ce6-GPC3 nanoparticles under 808 nm laser irradiation with enhanced depth of penetration would enable the effective targeting of PDT. RESULTS: We found that the UCNPs@mSiO2-Ce6-GPC3 nanoparticles had good biocompatibility, low toxicity, excellent cell imaging in HepG2 cancer cells and high anti-tumor effect in vitro and in vivo. CONCLUSION: We believe that the utilization of 808 nm NIR excited UCNPs@mSiO2-Ce6-GPC3 nanoparticles for PDT is a safe and potential therapeutic option for liver cancer.

ANXA2 Silencing Inhibits Proliferation, Invasion, and Migration in Gastric Cancer Cells.

Annexin A2 (ANXA2) has been well known to associate with the progress of malignant tumor. However, the biological behavior of ANXA2 in gastric cancer (GC) remains unclear. We made a hypothesis in transcriptome level from TCGA datasets. Then, we used immunohistochemical staining to quantify the expression level of ANXA2 protein in GC tissues compared with adjacent tissues. Quantitative real-time PCR and western blot were used for analyzing ANXA2 expression in human GC (SGC-7901, MKN-45, BGC-823, and AGS) cell lines. We investigated the effect of a lentivirus-mediated knock-down of ANXA2 on the proliferation, invasion and migration of gastric cancer AGS cells. Cell proliferation was examined by MTT and colony formation tests. Cell apoptosis and cycle were measured by flow cytometry. Migration and invasion were detected by transwell assay. We found that high expression of ANXA2 can increase the mobility of cancer cells from TCGA datasets. ANXA2 was upregulated in GC tissues compared with adjacent tissues. AGS cell line displayed significantly higher expression of ANXA2 among the four GC cell lines. In addition, ANXA2 silencing led to a weakened ability of proliferation, invasion, and migration in GC cells; targeting of ANXA2 may be a potential therapeutic strategy for GC patients.