The role of TNC in atherosclerosis and drug development opportunities.

Tenascin C (TNC), a rich glycoprotein of the extracellular matrix, exhibits a pro-atherosclerosis or anti-atherosclerosis effect depending on its location. TNC, especially its C domain/isoform (TNC-C), is strongly overexpressed in atherosclerotic plaque active areas but virtually undetectable in most normal adult tissues, suggesting that TNC is a promising delivery vector target for atherosclerosis-targeted drugs. Many delivery vectors were investigated by recognizing TNC-C, including G11, G11-iRGD, TN11, PL1, and PL3. F16 and FNLM were also investigated by recognizing TNC-A1 and TNC, respectively. Notably, iRGD was undergoing clinical trials. PL1 not only recognizes TNC-C but also the extra domain-B (EDB) of fibronectin (FN), which is also a promising delivery vector for atherosclerosis-targeted drugs, and several conjugate agents are undergoing clinical trials. The F16-conjugate agent F16IL2 is undergoing clinical trials. Therefore, G11-iRGD, PL1, and F16 have great development value. Furthermore, ATN-RNA and IMA950 were investigated in clinical trials as therapeutic drugs and vaccines by targeting TNC, respectively. Therefore, targeting TNC could greatly improve the success rate of atherosclerosis-targeted drugs and/or specific drug development. This review discussed the role of TNC in atherosclerosis, atherosclerosis-targeted drug delivery vectors, and agent development to provide knowledge for drug development targeting TNC.

A Correlation Analysis Between Adult Hepatic Fibrosis and Bone Mineral Density of the Lumbar Spine and Hip.

Context: Osteoporosis (OP) is a common complication for patients who have liver cirrhosis or cholestatic liver disease or who have received a liver transplantation. Osteoporotic fractures are serious clinical consequences of OP, and they often occur in the spine, hip, and wrist; have a high disability and mortality rate; cause a serious, social, medical burden; and threaten people's health. Objective: The study intended to explore the correlation between different degrees of liver fibrosis and bone mineral density (BMD) of the lumbar spine and hip as well as the factors influencing those differences. Design: The research team performed a retrospective observational study. Setting: The study took place at the First Affiliated Hospital of the Medical College at Ningbo University (Bund Courtyard) in Ningbo, China. Participants: Participants were 164 patients who had received two-dimensional shear wave elastography (2D-SWE) to measure liver stiffness and dual-energy X-ray absorptiometry (DEXA) to measure bone density at the First Affiliated Hospital of Ningbo University (Bund Courtyard) in Ningbo from May 2020 to April 2022. Groups: According to the liver-stiffness value, the research team divided participants into three groups: (1) the F0-F1 group with no or mild liver fibrosis, (2) the F2 group with significant liver fibrosis, and (3) F3-F4 group with severe liver fibrosis. For the three groups, the research team also compared the differences between the groups-F0-F1 to F2, F0-F1 to F3-F4, and F2 to F3-F4-in the BMD of the lumbar spine-Total, L2, L3, L4-and of the hip-Total, Neck, and Troch. Outcome Measures: The research team: (1) determined participants' degrees of liver fibrosis to create the F0-F1, F2, and F3-F4 groups and compared the BMDs of the lumbar spine and hip among those groups; (2) compared the degrees of liver fibrosis for three age groups-<40, 40-60, and ≥60 years old; (3) compared the degrees of liver fibrosis for participants with two etiologies of the disease-hepatitis or other causes; and (4) analyzed the correlations between different degrees of liver fibrosis and BMD of the lumbar spine and hip and the factors influencing those relationships. Results: The study revealed significant differences among the F0-F1, F2, and F3-F4 groups in terms of age group, degree of liver fibrosis, and bone mineral density (BMD) at various sites. Specifically, there were significant age group differences between individuals aged 40-60 years and those aged ≥60 years (P < .05). There were also significant differences noted in the degree of liver fibrosis with mean values of 5.59 ± 0.81, 7.43 ± 0.26, and 15.48 ± 10.02 for the F0-F1, F2, and F3-F4 groups, respectively (P < .05). The BMDs of the lumbar spine (L2, L3, L4, and Total values) and hip (Total values, right femoral neck (Neck), and trochantor (Troch)) showed significant differences (all P < .05). However, no significant differences were found in the BMDs for the L1 vertebra and Ward's triangle among the groups (both P > .05). The analysis also revealed that the mean BMDs of the F2 group were significantly higher than those of the F0-F1 and F3-F4 groups. Furthermore, there was a positive correlation between the F2 and F0-F1 groups and a negative correlation between the F2 and F3-F4 groups (P < .05). The logistic regression analysis showed that age group (OR = 2.047, 95% CI: 0.135-1.298, P = .016) and Total BMD for the hip (OR = 176.368, 95% CI: 0.233-10.112, P = .040) were significantly, independently correlated with the degree of liver fibrosis. Conclusions: According to the findings of the present study, a positive correlation was observed between liver stiffness and bone mineral density (BMD) values in patients at the F0-F1 to F2 stage of liver fibrosis. In contrast, a significant negative correlation was identified between these parameters in patients at the F2 to F3-F4 stage, indicating that BMD tends to decrease as the degree of liver fibrosis increases. These results suggest a potential link between liver fibrosis and bone health. The comparisons between groups F0-F1 and F3-F4 with group F2. Specifically, the study found that the BMD values of the F2 group were significantly higher than those of the F0-F1 and F3-F4 groups.

Target Separation and Potential Anticancer Activity of Withanolide-Based Glucose Transporter Protein 1 Inhibitors from Physalis angulata var. villosa.

The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.

Meta-analysis of the diagnostic value of 3.0t mr dynamic enhancement in prostate cancer among fitness andathletic patients

Objective: To systematically evaluate the diagnostic value of 3.0T MR Dynamic enhancement in prostate cancer among fitness and athletic patients, aiming to offer insights for the selection of early diagnostic techniques in this specific population. Methods: This study conducted a comprehensive search in Cochrane Library, Web of Science, PubMed, Proquest, and Chinese biomedical literature databases including Wanfang, Wipu, and CNKI, focusing on literature published until September 2022. The search was tailored to assess the value of 3.0T MR dynamic enhancement in diagnosing prostate cancer in fitness and athletic individuals. A meta-analysis was performed on the selected studies to calculate combined sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio. Sensitivity-specific forest plots, SROC curves, and funnel plots were employed to evaluate publication bias. Results: The metaanalysis included seven studies, comprising a total of 516 subjects who were actively involved in fitness or athletic activities. Among these, 216 were true positive cases, 204 true negative, 43 false positive, and 53 false negative. The analysis revealed that the combined sensitivity of 3.0T MR Dynamic enhancement for prostate cancer diagnosis in this population was 0.82 (95% CI: 0.73, 0.90), and the combined specificity was 0.83 (95% CI: 0.77, 0.88). The combined positive likelihood ratio was 4.91 (95% CI: 3.25, 7.16), and the negative likelihood ratio was 0.21 (95% CI: 0.12, 0.26). The diagnostic odds ratio was 35.28 (95% CI: 16.57, 40.32), with an AUC of 0.86 (95% CI: 0.81, 0.92). No significant heterogeneity due to non-threshold effects (p>0.01) was observed, and a fixed effect model was applied. No publication bias was detected (P>0.05) (AU)

The association between biomarkers of acrylamide and cancer mortality in U.S. adult population: Evidence from NHANES 2003-2014.

The association between acrylamide (AA) and the development of cancer has been extensively discussed but the results remained controversial, especially in population studies. Large prospective epidemiological studies on the relationship of AA exposure with cancer mortality were still lacking. Therefore, we aimed to assess the association between AA biomarkers and cancer mortality in adult population from National Health and Nutrition Examination Survey (NHANES) 2003-2014. We followed 3717 participants for an average of 10.3 years. Cox regression models with multivariable adjustments were performed to determine the relationship of acrylamide hemoglobin adduct (HbAA) and glycidamide hemoglobin adduct (HbGA) with cancer mortality. Mediation analysis was conducted to demonstrate the mediated role of low-grade inflammation score (INFLA-score) in this correlation. Compared with the lowest quintile, participants with the highest quintile of HbAA, HbGA and HbAA+HbGA had increased cancer mortality risk, and the hazard ratios(HRs) were 2.07 (95%CI:1.04-4.14) for HbAA, 2.39 (95%CI:1.29-4.43) for HbGA and 2.48 (95%CI:1.28-4.80) for HbAA+HbGA, respectively. And there was a considerable non-linearity association between HbAA and cancer mortality (p for non-linearity = 0.0139). We further found that increased INFLA-score significantly mediated 71.67% in the effect of HbGA exposure on increased cancer mortality risk. This study demonstrates that hemoglobin biomarkers of AA are positively associated with cancer mortality in adult American population and INFLA-score plays a mediated role in this process. Our findings can raise public awareness of environmental and dietary exposure to acrylamide and remind people to refrain from smoking or having acrylamide-rich foods.

Dual-action nanoplatform with a synergetic strategy to promote oxygen accumulation for enhanced photodynamic therapy against hypoxic tumors.

With the development of redox-related therapy modalities in cancer therapy, photodynamic therapy (PDT) has gradually become the most widely used type in the clinic. However, the hypoxic tumor microenvironment restricted the curative effect of PDT. Here, a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy was designed to alleviate tumor hypoxia on the basis of PDT. Specifically, the oxygen producer MnO2, oxygen consumption inhibitor atovaquone (ATO) and photosensitizer hypericin (HY) were loaded in SHRN. MnO2 reacted with excess H2O2 in the tumor microenvironment to increase oxygen generation, while ATO inhibited electron transfer in the aerobic respiratory chain to decrease oxygen consumption. Then, HY utilized this sufficient oxygen to produce ROS under irradiation to enhance the PDT effect. In vitro and in vivo assays confirmed that SHRN exhibits powerful and overall antitumor PDT effects. This formulation may provide an alternative strategy for the development of PDT effects in hypoxic tumor microenvironments. STATEMENT OF SIGNIFICANCE: We constructed a strategic hypoxia relief nanodrug delivery system (SHRN) with a synergetic strategy to alleviate tumor hypoxia on the basis of photodynamic therapy (PDT). This work uniquely aimed at not only increased O2 generation in hypoxic tumor microenvironment but also reduced O2 consumption. Moreover, we designed a nanodrug delivery system to enhance the tumor permeability of SHRN. In vitro and in vivo assays all confirmed that SHRN exhibited powerful and overall antitumor effects. This formulation may provide an alternative strategy for the development of the PDT effect in hypoxic solid tumor.

Theranostic nanosystem with supramolecular self-assembly for enhanced reactive oxygen species-mediated apoptosis guided by dual-modality tumor imaging.

With the development of precision medicine, visual and traceable treatments are highly desirable for cancer therapy. However, researchers and clinicians remain confused regarding where the drug distributes and location of the tumor, when the drug is released and when to irradiate the tumor, and how the drug presents antitumor activity, all of which hinders assessment of the cancer patient's condition and formulation of a follow-up treatment scheme for clinicians. Here, a supramolecular self-assembly theranostic nanosystem (MWNs) was designed for enhanced reactive oxygen species (ROS)-mediated cell apoptosis guided by dual-modality tumor imaging. Specifically, merocyanine was introduced in cyanine dye to extend its conjugated π-scaffolds, which could preferentially self-assemble into nanovesicles owing to its amphipathy. Furthermore, withaferin A (WA), used as a chemotherapeutic drug, was loaded to construct MWNs. The assembled or disassembled MWNs behaved differently in photoacoustic (PA) intensity and fluorescence signal intensity. The MWNs exhibited stronger PA signals and quenched fluorescence, which monitors their distribution and images the tumor location in vivo, while the disassembled MWNs showed weak PA signals and recovered fluorescence, indicating the release of drug and instructing the appropriate time to irradiate for photodynamic therapy (PDT). Thus, ROS generation introduced by PDT and released WA led to cell apoptosis. This intelligent nanosystem for precise cancer therapy that reveals where the tumor is, when to irradiate the tumor, and how the tumor is cured might establish the basis for biomedical applications of finely controlled platform.

Intelligent phototriggered nanoparticles induce a domino effect for multimodal tumor therapy.

Rationale: Integration of several monotherapies into a single nanosystem can produce remarkable synergistic antitumor effects compared with separate delivery of combination therapies. We developed near-infrared (NIR) light-triggered nanoparticles that induce a domino effect for multimodal tumor therapy. Methods: The designed intelligent phototriggered nanoparticles (IPNs) were composed of a copper sulfide-loaded upconversion nanoparticle core, a thermosensitive and photosensitive enaminitrile molecule (EM) organogel shell loaded with anticancer drugs, and a cancer cell membrane coating. Irradiation with an NIR laser activated a domino effect beginning with photothermal generation by copper sulfide for photothermal therapy that also resulted in phase transformation of the EM gel to release the anticancer drug. Meanwhile, the NIR light energy was converted to ultraviolet light by the upconversion core to excite the EM, which generated reactive oxygen species for photodynamic therapy. Results: IPNs achieved excellent antitumor effects in vitro and in vivo with little systemic toxicity, indicating that IPNs could serve as a safe and high-performance instrument for synergetic antitumor therapy. Conclusion: This intelligent drug delivery system induced a chain reaction generating multiple antitumor therapies after a single stimulus.

DT-diaphorase triggered theranostic nanoparticles induce the self-burst of reactive oxygen species for tumor diagnosis and treatment.

On-demand therapy following effective tumor detection would considerably reduce the side effects of traditional chemotherapy. DT-diaphorase (DTD), whose level is strongly elevated in various tumors, is a cytosolic flavoenzyme that promotes intracellular reactive oxygen species (ROS) generation via the redox cycling of hydroquinones. Incorporation of the DTD-responsive substrate to the structures of the probe and prodrug may facilitate the tumor detection and therapy. Herein, we established an multifunctional drug delivery nanosystem (HTLAC) that rapidly responds to the DTD enzyme, leads to the early-stage precise detection and termination of tumors. Firstly, the synthesis of DTD-responsive withaferin A (DT-WA) and indocyanine green (DT-Cy5) was performed. In the presence of DTD, WA, which produces ROS in cells, was released from DT-WA, and the red fluorescence of DT-Cy5 was detected for tumor imaging. Additionally, these DTD enzyme reaction processes of DT-WA and DT-Cy5 induced ROS. The self-burst of ROS generation by the two enzyme reaction processes as well as the released WA then led to the apoptosis of tumor cells. To increase the bioavailability and tumor targeting of drugs, cell-penetrating peptide and hyaluronic acid functionalized liposomes were used to encapsulate the drugs. The detailed in vitro and in vivo assays showed that HTLAC achieved enhanced tumor detection and superior antitumor efficiency. According to above outcomes, results showed that HTLAC might provide an efficacious approach for the fabrication of enzyme-triggering nanosystems to detect tumor and induce the self-burst of ROS for an efficient tumor treatment. STATEMENT OF SIGNIFICANCE: We have fabricated a HTLAC nanosystem to address the need of bursting reactive oxygen species (ROS) generation within tumor site. Our goal uniquely aims at not only augmentation of ROS-inducing anticancer efficacy, but also to meet the challenges of tumor dynamic detection in the clinical practices. In this work, the DT-diaphorase responsive withaferin A (DT-WA) and indocyanine green (DT-Cy5) are synthesized, and observed more specifically toward DTD under physiological conditions. As the cell-penetrating peptide and hyaluronic acid functionalized liposome, the HTLAC not only induces antiproliferative activity by generating self-burst of ROS, but also effectively accumulate and restore its fluorescence at the tumor site because of the HA actively targeting tumor along with the prolonged presence in blood circulation. Besides, this enzyme-triggering nanosystem exhibited an effective tumor inhibition with a low systemic toxicity.

Target separation and antitumor metastasis activity of sesquiterpene-based lysine-specific demethylase 1 inhibitors from zedoary turmeric oil.

Lysine-specific histone demethylase 1 (LSD1) was the first histone demethylase identified in epigenetics and has recently emerged as an attractive therapeutic target for treating tumors. To date, almost all reported LSD1 inhibitors have been chemosynthesized; however, natural products possess pharmacological and biological activity and can be sources for drug development. Here, we established a target separation countercurrent chromatography technique to isolate LSD1 inhibitors from zedoary turmeric oil. Four sesquiterpene-based LSD1 inhibitors were efficiently obtained with an inhibition ratio equal to or less than that of the positive control drug. Compound 2 showed the most potent inhibitory activity, with a half-maximal inhibitory concentration of 3.97 µM, and was further tested to determine its ability to inhibit LSD1 and its antitumor metastatic effects in MDA-MB-231 cells. These four compounds are the first sesquiterpene-based natural LSD1 inhibitors to be characterized. Our findings provide a new molecular framework for studying LSD1 inhibitors and offer a template for designing more sesquiterpene-based LSD1 inhibitors with potential antitumor activity.

High expression of density-regulated re-initiation and release factor drives tumourigenesis and affects clinical outcome.

Previously, certain experiments have suggested that density-regulated re-initiation and release factor (DENR) could serve important roles in cancer, however, to the best of our knowledge, a comprehensive analysis of DENR and its association with cancer patient survival is lacking. The aim of the current study was to investigate the expression of DENR in multiple tumour types and to evaluate the effects of DENR on survival in malignancies. Sample expression profiles were downloaded from the Gene Expression Omnibus database. Association between DENR expression and clinicopathological features was analysed by Chi-square tests. The effects of DENR on survival were evaluated by Kaplan-Meier analysis. The results of the current study demonstrate that DENR expression was upregulated in nine cancer types. High DENR expression indicated poor prognosis of patients. The results of the present study demonstrated that DENR is highly expressed in multiple tumour types and may be used as a potential prognostic marker and therapeutic target.

High Expression of ABRACL Is Associated with Tumorigenesis and Affects Clinical Outcome in Gastric Cancer.

BACKGROUND: The ABRA C-terminal like (ABRACL) protein belongs to a novel family of low-molecular weight proteins that increase actin dynamics and cell motility. It is involved in various diseases including cancer; however, its role in gastric cancer is unclear. In this study, the expression of ABRACL in gastric cancer and its relationships with patients' clinicopathological features and survival are examined. METHODS: Sample expression profiles were downloaded from the Gene Expression Omnibus database and the Cancer Genome Atlas. ABRACL expression at the protein level in normal gastric and gastric cancer tissues was compared by using immunohistochemistry staining data provided by the Human Protein Atlas. Correlations between ABRACL expression and clinicopathological features are analyzed by chi-square tests. Patient survival was evaluated by Kaplan-Meier analysis. RESULTS: ABRACL expression is upregulated in gastric cancer tissues than in normal tissues. High ABRACL levels indicated a poor prognosis. ABRACL expression (low ABRACL, n = 96; high ABRACL, n = 96) in gastric cancer tissues (primary data from GSE15459) is significantly correlated with poor overall survival (χ2 = 4.078, p = 0.043; log-rank test). ABRACL protein levels (low ABRACL, n = 172, high ABRACL, n = 171) in gastric cancer tissues (primary data from www.kmplot.com ) are significantly correlated with poor overall survival (χ2 = 4.305, p = 0.038, log-rank test). CONCLUSIONS: Our results indicate that ABRACL is highly expressed in gastric cancer and is a potential prognostic marker and therapeutic target for this disease.