Wnt signaling: Modulating tumor-associated macrophages and related immunotherapeutic insights.

Wnt signaling pathways are highly conserved cascades that mediate multiple biological processes through canonical or noncanonical pathways, from embryonic development to tissue maintenance, but they also contribute to the pathogenesis of numerous cancers. Recent studies have revealed that Wnt signaling pathways critically control the interplay between cancer cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) and potentially impact the efficacy of cancer immunotherapy. In this review, we summarize the evidence that Wnt signaling pathways boost the maturation and infiltration of macrophages for immune surveillance in the steady state but also polarize TAMs toward immunosuppressive M2-like phenotypes for immune escape in the TME. Both cancer cells and TAMs utilize Wnt signaling to transmit signals, and this interaction is crucial for the carcinogenesis and progression of common solid cancers, such as colorectal, gastric, hepatocellular, breast, thyroid, prostate, kidney, and lung cancers; osteosarcoma; and glioma. Specifically, compared with those in solid cancers, Wnt signaling pathways play a distinct role in the pathogenesis of leukemia. Efforts to develop Wnt-based drugs for cancer treatment are still ongoing, and some indeed enhance the anticancer immune response. We believe that the combination of Wnt signaling-based therapy with conventional or immune therapies is a promising therapeutic approach and can facilitate personalized treatment for most cancers.

WNT ligands in non-small cell lung cancer: from pathogenesis to clinical practice.

Non-small cell lung cancer (NSCLC) is the malignant tumor with the highest morbidity and leading cause of death worldwide, whereas its pathogenesis has not been fully elucidated. Although mutations in some crucial genes in WNT pathways such as ß-catenin and APC are not common in NSCLC, the abnormal signal transduction of WNT pathways is still closely related to the occurrence and progression of NSCLC. WNT ligands (WNTs) are a class of secreted glycoproteins that activate WNT pathways through binding to their receptors and play important regulatory roles in embryonic development, cell differentiation, and tissue regeneration. Therefore, the abnormal expression or dysfunction of WNTs undoubtedly affects WNT pathways and thus participates in the pathogenesis of diseases. There are 19 members of human WNTs, WNT1, WNT2, WNT2b, WNT3, WNT3a, WNT4, WNT5a, WNT5b, WNT6, WNT7a, WNT7b, WNT8a, WNT8b, WNT9a, WNT9b, WNT10a, WNT10b, WNT11 and WNT16. The expression levels of WNTs, binding receptors, and activated WNT pathways are diverse in different tissue types, which endows the complexity of WNT pathways and multifarious biological effects. Although abundant studies have reported the role of WNTs in the pathogenesis of NSCLC, it still needs further study as therapeutic targets for lung cancer. This review will systematically summarize current research on human WNTs in NSCLC, from molecular pathogenesis to potential clinical practice.

Aqueous green synthesis of organic/inorganic nanohybrids with an unprecedented synergistic mechanism for enhanced near-infrared photothermal performance.

Silver sulfide (Ag2S) nanoparticles (NPs) represent one of the most popular inorganic reagents for near-infrared (NIR) photothermal therapy (PTT). However, the extensive biomedical applications of Ag2S NPs are greatly compromised by the hydrophobicity of the NPs prepared in organic solvents, their low photothermal conversion efficiency, certain surface modification-induced damage to their intrinsic properties and short circulation time. To develop a facile yet efficient green approach to overcome these shortcomings for improved properties and performance of Ag2S NPs, we report herein the construction of Ag2S@polydopamine (PDA) nanohybrids via a "one-pot" organic-inorganic hybridization strategy, which produces uniform Ag2S@PDA nanohybrids with well-modulated sizes in the range of 100-300 nm via the self-polymerization of dopamine (DA) and subsequent synergistic assembly of PDA with Ag2S NPs in a three-phase mixed medium containing water, ethanol and trimethylbenzene (TMB). Integration of dual photothermal moieties, i.e., Ag2S and PDA at a molecular level, endows Ag2S@PDA nanohybrids with synergistically enhanced NIR photothermal properties that are much better than those of either PDA or Ag2S NPs due to calculated combination indexes (CIs) of 0.3-0.7 between Ag2S NPs and PDA based on a modified Chou-Talalay method. Therefore, this study not only developed a facile "one-pot" green approach toward producing uniform Ag2S@PDA nanohybrids with well-modulated dimensions, but also revealed an unprecedented synergistic mechanism for organic/inorganic nanohybrids that is based on dual photothermal moieties providing enhanced near-infrared photothermal performance.

[Effect of Sparganii Rhizoma-Curcumae Rhizoma-medicated serum on proliferation, apoptosis, and migration of human ectopic endometrial stromal cells: based on JAK2/STAT3 signaling pathway].

Based on the Janus kinase 2/signal transducer and activator of transcription 3(JAK2/STAT3) signaling pathway, this study investigated the effect of medicated serum of Sparganii Rhizoma(SR) and Curcumae Rhizoma(CR) on the proliferation, apoptosis, migration, and secretion of inflammatory factors of ectopic endometrial stromal cells(ESCs). Specifically, human ESCs were primary-cultured. The effect of different concentration(5%, 10%, 20%) of SR-, CR-, and SR-CR combination-medicated serum, and AG490 solution(50 µmol·L~(-1)) on the proliferation of ESCs was detected by methyl thiazolyl tetrazolium(MTT) assay, and the optimal dose was selected accordingly for further experiment. The cells were classified into normal serum(NS) group, SR group(10%), CR group(10%), combination(CM) group(10%), and AG490 group. The apoptosis level of ESCs was detected by flow cytometry, and the migration ability was examined by wound healing assay. The secretion of interleukin(IL)-1ß, IL-6, and tumor necrosis factor(TNF)-α was determined by enzyme-linked immunosorbent assay(ELISA). The protein levels of cysteinyl aspartate specific protei-nase-3(caspase-3), B-cell lymphoma(Bcl-2), and Bcl-2-associated X protein(Bax) and the levels of phosphorylated(p)-JAK2 and p-STAT3 were detected by Western blot. The results showed that the viability of ESCs cells was lowered in the administration groups compared with the blank serum group(P<0.01), especially the 10% drug-medicated serum, which was selected for further experiment. The 10% SR-medicated serum, 10% CR-medicated serum, and 10% CM-medicated serum could increase the apoptosis rate(P<0.01), up-regulate the protein expression of caspase-3 and Bax in cells(P<0.05 or P<0.01), down-regulate the expression of Bcl-2(P<0.01), decrease the cell migration rate(P<0.05 or P<0.01), and reduce the secretion levels of IL-1ß, IL-6, and TNF-α(P<0.05 or P<0.01), and levels of p-JAK2 and p-STAT3(P<0.05 or P<0.01). Compared with the SR and CR groups, CM group showed low cell viability(P<0.01), high protein expression of caspase-3 and Bax(P<0.05 or P<0.01), and low protein expression of Bcl-2 and p-JAK2(P<0.05). After incubation with CM, the apoptosis rate was higher(P<0.05) and the migration rate was lower(P<0.01) than that of the CR group. The p-STAT3 protein level of CM group was lower than that of the RS group(P<0.05). The mechanism of SR, CR, and the combination underlying the improvement of endometriosis may be that they blocked JAK2/STAT3 signaling pathway, inhibited ESC proliferation, promoted apoptosis, weakened cell migration, and reduced the secretion of inflammatory factors. The effect of the combination was better than that of RS alone and CR alone.

Deficiency of miRNA-149-3p shaped gut microbiota and enhanced dextran sulfate sodium-induced colitis.

Genetic predisposition and disruption of host gut microbiota and immune system can result in inflammatory bowel disease (IBD). Here, we show that miRNA-149-5p (miR-149-5p) and miRNA-149-3p (miR-149-3p) play crucial roles in IBD. Mice lacking miR-149-3p were considerably more susceptible to dextran sulfate sodium (DSS)-induced colitis than wild-type (WT) mice, accompanied by more serious inflammatory symptoms and increased gene expression of certain inflammatory cytokines. Both miR-149-5p and miR-149-3p suppressed colon inflammatory response in vitro and in vivo. Furthermore, we found significant differences in the composition of the gut microbiota between WT and miR-149-3p-/- mice by 16S rRNA sequencing. Co-housing endowed susceptibility to WT mice against DSS-induced colitis compared with the WT control group. However, susceptibility of miR-149-3p-/- mice against DSS-induced colitis was still present after antibiotic treatment. These findings suggest that the deletion of miR-149-3p altered gut microbiota and influenced pathogenesis of intestinal inflammation, but sensitivity of miR-149-3p-/- mice to DSS-induced colitis is not conferred by microbiota. In addition, we identified the roles of miR-149-5p and miR-149-3p in colon inflammation, which may serve as an attractive therapeutic tool for colitis or IBD, and even colitis-associated carcinoma.

An Improved Deep Neural Network Model of Intelligent Vehicle Dynamics via Linear Decreasing Weight Particle Swarm and Invasive Weed Optimization Algorithms.

We propose an improved DNN modeling method based on two optimization algorithms, namely the linear decreasing weight particle swarm optimization (LDWPSO) algorithm and invasive weed optimization (IWO) algorithm, for predicting vehicle's longitudinal-lateral responses. The proposed improved method can restrain the solutions of weight matrices and bias matrices from falling into a local optimum while training the DNN model. First, dynamic simulations for a vehicle are performed based on an efficient semirecursive multibody model for real-time data acquisition. Next, the vehicle data are processed and used to train and test the improved DNN model. The vehicle responses, which are obtained from the LDWPSO-DNN and IWO-DNN models, are compared with the DNN and multibody results. The comparative results show that the LDWPSO-DNN and IWO-DNN models predict accurate longitudinal-lateral responses in real-time without falling into a local optimum. The improved DNN model based on optimization algorithms can be employed for real-time simulation and preview control in intelligent vehicles.

Rhynchophylline Regulates Calcium Homeostasis by Antagonizing Ryanodine Receptor 2 Phosphorylation to Improve Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a serious complication of diabetes that can lead to heart failure and death, for which there is no effective treatment. Rhynchophylline (Rhy) is the main effective component of the Chinese herbal medicine Uncaria rhynchophylla, which mainly acts on the cardiovascular and nervous systems. However, its role in protecting against DCM remains unexplored. The present study sought to reveal the mechanism of Rhy in improving type 2 diabetes mellitus (T2DM) myocardial lesions from the perspective of regulating calcium homeostasis in cardiomyocytes. We prepared a mouse model of T2DM using a high-fat diet combined with low doses of streptozotocin. The T2DM mice were given 40 mg/kg of Rhy for 8 weeks. The results showed that Rhy can attenuate cardiac pathological changes, slow down the heart rate, decrease serum cardiac enzyme levels, reduce cardiomyocyte apoptosis, enhance cardiomyocyte contractility, and raise the calcium transient amplitude in T2DM mice. Further, Rhy downregulated the phosphorylation level of ryanodine receptor 2, upregulated the phosphorylation level of phospholamban, protected mitochondrial structure and function, and increased adenosine triphosphate levels in the cardiac tissue of T2DM mice. Our results demonstrated that Rhy may protect against myocardial damage in T2DM mice and promote cardiomyocyte contraction, and its mechanism of action seems to be related to the regulation of intracellular calcium homeostasis.

Epidemiological features and dynamic changes in blood biochemical indices for COVID-19 patients in Hebi.

BACKGROUND: Millions of people have died of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and retrospective studies of the disease in local regions are necessary. AIM: To characterize the epidemiological features and dynamic changes in blood biochemical indices for SARS-CoV-2-infected patients in Hebi, a representative city with a large floating population in North China. METHODS: From January 25 to February 10, 2020, the clinical data of patients who tested positive for SARS-CoV-2 by quantitative real-time polymerase chain reaction in Hebi city (China) were evaluated at admission, and laboratory data for hematologic parameters, inflammatory indices, coagulation function indices, liver function indices, blood lipid indices, renal function indices, myocardial enzyme activities and five blood biochemical markers of immunity were evaluated at admission, upon hospitalization and before discharge. RESULTS: Sixteen confirmed COVID-19 patients developed pneumonia but were cured after adequate treatment. Fever and fatigue were the common symptoms. The most common laboratory abnormalities of patients at admission were leukopenia, eosinopenia, decreased percentage of eosinophils, elevated high sensitivity C-reactive protein and fibrinogen levels, hypoalbuminemia, mildly increased aspartate transferase activity and levels of bilirubin, and increased levels of ß2-microglobulin. Importantly, aggravated liver dysfunction was detected in most patients, which may be partially attributed to virus infection as well as medicinal treatment. CONCLUSION: This study provides several potential diagnostic markers and dynamic biochemical indices of disease progression to better prevent, diagnose and treat COVID-19 infection.

Deep-Neural-Network-Based Modelling of Longitudinal-Lateral Dynamics to Predict the Vehicle States for Autonomous Driving.

Multibody models built in commercial software packages, e.g., ADAMS, can be used for accurate vehicle dynamics, but computational efficiency and numerical stability are very challenging in complex driving environments. These issues can be addressed by using data-driven models, owing to their robust generalization and computational speed. In this study, we develop a deep neural network (DNN) based model to predict longitudinal-lateral dynamics of an autonomous vehicle. Dynamic simulations of the autonomous vehicle are performed based on a semirecursive multibody method for data acquisition. The data are used to train and test the DNN model. The DNN inputs include the torque applied on wheels and the vehicle's initial speed that imitates a double lane change maneuver. The DNN outputs include the longitudinal driving distance, the lateral driving distance, the final longitudinal velocities, the final lateral velocities, and the yaw angle. The predicted vehicle states based on the DNN model are compared with the multibody model results. The accuracy of the DNN model is investigated in detail in terms of error functions. The DNN model is verified within the framework of a commercial software package CarSim. The results demonstrate that the DNN model predicts accurate vehicle states in real time. It can be used for real-time simulation and preview control in autonomous vehicles for enhanced transportation safety.

Curcumol Attenuates Endometriosis by Inhibiting the JAK2/STAT3 Signaling Pathway.

BACKGROUND Curcumol is a hydrogenated austenitic compound with hemiketal. In this study we evaluated the effects of curcumol on local inflammatory response, cell proliferation, and metastasis in endometriosis, and elucidated the underlying mechanisms. MATERIAL AND METHODS Ectopic endometrial stromal cells were treated with increasing doses of curcumol. The MTT assay was used to assess cell viability. FITC-labeled annexin-V/PI double-staining method and flow cytometry were used to determine cell apoptosis. Cell migration was evaluated using a wound healing assay. ELISA kits were used to detect the levels of TNF-alpha, IL-6, and IL-1ß. Western blot assay was used to examine the phosphorylation degree of JAK2 and STAT3 and the expression of Bax, Bcl2, and caspase-3 proteins. Autologous endometrial transplantation was used to establish a rat model to assess the anti-EMS effect of curcumol in vivo. RESULTS Curcumol can inhibit the proliferation of ectopic endometrial stromal cells, promote cell apoptosis, and weaken cell migration ability. Curcumol can reduce the expression of Bax and caspase-3 protein and increase the expression of Bcl2 protein. Curcumol also can inhibit the secretion of inflammatory cytokines, including tumor necrosis cytokines (TNF)-alpha, interleukin (IL)-6, and IL-1ß, by ectopic endometrial stromal cells. In addition, curcumol can also inhibit the phosphorylation of JAK2 and STAT3. In vivo experiments also proved that curcumol could inhibit the growth of ectopic lesions in EMS model rats. CONCLUSIONS Curcumol can inhibit the JAK2/STAT3 pathway, reduce the inflammatory cytokines secreted by ectopic endometrial stromal cells, inhibit cell proliferation and migration, and reduce the volume of ectopic lesions.

LRP5 promotes cancer stem cell traits and chemoresistance in colorectal cancer.

The overactivation of canonical Wnt/ß-catenin pathway and the maintenance of cancer stem cells (CSCs) are essential for the onset and malignant progression of most human cancers. However, their regulatory mechanism in colorectal cancer (CRC) has not yet been well demonstrated. Low-density lipoprotein receptor-related protein 5 (LRP5) has been identified as an indispensable co-receptor with frizzled family members for the canonical Wnt/ß-catenin signal transduction. Herein, we show that activation of LRP5 gene promotes CSCs-like phenotypes, including tumorigenicity and drug resistance in CRC cells, through activating the canonical Wnt/ß-catenin and IL-6/STAT3 signalling pathways. Clinically, the expression of LRP5 is upregulated in human CRC tissues and closely associated with clinical stages of patients with CRC. Further analysis showed silencing of endogenous LRP5 gene is sufficient to suppress the CSCs-like phenotypes of CRC through inhibiting these two pathways. In conclusion, our findings not only reveal a regulatory cross-talk between canonical Wnt/ß-catenin signalling pathway, IL-6/STAT3 signalling pathway and CD133-related stemness that promote the malignant behaviour of CRC, but also provide a valuable target for the diagnosis and treatment of CRC.

LRP5 Promotes Gastric Cancer via Activating Canonical Wnt/ß-Catenin and Glycolysis Pathways.

The overactivation of canonical Wnt/ß-catenin pathway is one of the main cascades for the initiation, progression, and recurrence of most human malignancies. As an indispensable coreceptor for the signaling transduction of the canonical Wnt/ß-catenin pathway, LRP5 is up-regulated and exerts a carcinogenic role in most types of cancer. However, its expression level and role in gastric cancer (GC) has not been clearly elucidated. The current work showed that LRP5 was overexpressed in GC tissues and the expression of LRP5 was positively associated with the advanced clinical stages and poor prognosis. Ectopic expression of LRP5 enhanced the proliferation, invasiveness, and drug resistance of GC cells in vitro, and accelerated the tumor growth in nude mice, through activating the canonical Wnt/ß-catenin signaling pathway and up-regulating aerobic glycolysis, thus increasing the energy supply for GC cells. Additionally, the expression of LRP5 and glycolysis-related genes showed an obviously positive correlation in GC tissues. By contrast, the exact opposite results were observed when the endogenous LRP5 was silenced in GC cells. Collectively, these results not only reveal the carcinogenic role of LRP5 during GC development through activating the canonical Wnt/ß-catenin and glycolysis pathways, but also provide a valuable candidate for the diagnosis and treatment of human GC.

miRNA-382-5p Suppresses the Expression of Farnesoid X Receptor to Promote Progression of Liver Cancer.

BACKGROUND: The dysregulation of microRNAs (miRNAs) and hepatotoxicity due to the aberrant accumulation of bile acids (BAs) are notorious causes that predispose an individual to the development of hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), encoded by NR1H4 gene, has been identified as a crucial BA receptor to maintain the homeostasis of BA pool and its expression is decreased in HCC. miR-382-5p plays an important role in the pathogenesis of many human malignancies and was reported to promote the proliferation and differentiation of normal liver cells and liver regeneration. However, there is still some controversy about its role in HCC microenvironment. This study aims to explore the expression pattern of miR-382-5p in HCC and its role in regulating FXR during the development of HCC. METHODS: Tissues collected from 30 HCC patients were subjected to extraction of total RNA and quantitative real-time PCR (qRT-PCR) for the analyses of miR-382-5p expression and NR1H4 mRNA levels, and their expressions were verified by analyzing the online HCC-related GSE datasets. The role of miR-382-5p in regulating cellular proliferation and expression of FXR in different HCC cell lines was analyzed by qRT-PCR, Western Blot, real-time cellular analysis (RTCA) and luciferase reporter assays. The role of miR-382-5p in regulating downstream genes of FXR in HCC cells was also analyzed. RESULTS: miR-382-5p was upregulated in HCC tissues and inversely associated with the downregulation of NR1H4 mRNA levels. The luciferase reporter assay proved that miR-382-5p directly targeted the 3'-untranslated region (3'-UTR) of human NR1H4 mRNA. Overexpression of miR-382-5p led to a malignant proliferation of HCC cells by suppressing the expression of FXR. In contrast, blocking the endogenous miR-382-5p was sufficient to suppress the cellular proliferation rate of HCC through increasing FXR expression. Additionally, miR-382-5p inhibited the expression of some target genes of FXR, including SHP, FGF19 and SLC51A, and this inhibitory effect was FXR-dependent. CONCLUSION: Therefore, miR-382-5p promotes the progression of HCC in vitro by suppressing FXR and could serve as a valuable therapeutic target for HCC treatment.

Observation of Dominant Nuclei and Magic-Sized CdS Nanoparticles in a Single-Phase System.

Cadmium sulfide nanoparticles (CdS NPs) were synthesized by using cadmium acetate and thiourea as precursors and sodium oleate as the surfactant under different cadmium acetate concentrations in anhydrous ethanol. Cadmium (Cd) precursor concentration greatly affected the nucleation-growth of CdS NPs. In extremely dilute solution with a Cd precursor concentration of 0.1 mmol · L-1, an overlapped nucleation and growth corresponding to two pronounced absorption peaks at 310 nm and 350 nm, respectively, was observed. Unparalleled nucleation was dominant within very long reaction time until 10 hours. The nuclei and the resulting magic-sized CdS NPs may be used as seeds to prepare size and shape controllable nanoparticles. On the contrary, at a high Cd precursor concentration (5 mmol · L-1), nucleation and growth were separated. Only one first exciton absorption peak standing for the growth of regular CdS NPs appeared at 440 nm. Many techniques including transmission electron microscopy (TEM), X-ray powder diffraction (XRD), ultraviolet-visible (UV-Vis) absorption and photoluminescence (PL) spectrometers were applied to characterize the morphology, crystalline structure, and optical properties of CdS NPs.

The complex role of Wnt ligands in type 2 diabetes mellitus and related complications.

Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non-canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF-1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt-based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic-related diseases will ultimately result in a better management of these diseases.

Influence of doping for InSb on ultrafast carrier dynamics measured by time-resolved terahertz spectroscopy.

The influence of doping on the ultrafast carrier dynamics in InSb has been studied by time-resolved terahertz spectroscopy with photogenerated carrier densities from 1.5×1018 to 9.5×1019cm-3 at 800 nm. The photoinduced absorption and carrier recovery process show doping type dependence. The carrier recovery time of intrinsic InSb is greater than that of p-doped InSb but less than that of n-doped InSb at low carrier densities. At high carrier densities, compared with intrinsic InSb, the doped InSb is more prone to transient Auger recombination, which indicates that the appearance of the fast decay process depends on the carrier densities. The photoinduced absorption of terahertz probe pulse of n-doped InSb is significantly less than that of p-doped and intrinsic InSb; however, that of p-doped InSb is close to that of intrinsic InSb, which demonstrates that the high concentration of electrons can accelerate the efficiency of transient Auger recombination. Our analysis provides assistance to the design, manufacture, and improvement of photovoltaic detectors.

Emerging Roles of Wnt Ligands in Human Colorectal Cancer.

Colorectal cancer (CRC) is the fourth leading cause of cancer death worldwide, and constitutive activation of the Wnt signaling pathway is universal in most CRC cases. Wnt ligands (Wnts) are secreted glycoproteins and fundamentally essential for the transduction of Wnt signaling pathway. However, the 19 members of Wnts in humans imply a daunting complexity of Wnt signaling and biological effects, and our understanding of their roles in CRC tumorigenesis is still quite rudimentary. This review will give an overview of the structural characteristics and maturation process of Wnts. The expression pattern of all human Wnts in CRC tissues, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11, and Wnt16, and their relationship with the tumorigenesis and the progression of CRC will be specifically summarized separately. Despite certain challenges, Wnt-based therapeutics for CRC emerge continuously and some are now in clinical trials. In conclusion, a deep understanding of Wnts is very helpful for a better management of this disease.

Periodic Dynamic Regulation of MSCs Differentiation on Redox-Sensitive Elastic Switched Substrates.

The biomechanical properties of cell culture substrates can affect cell morphology, cytoskeletal structure, and cell differentiation. However, most of the elastic substrates reported to regulate the behavior of stem cells are often limited to model the static surface, such as providing a constant elasticity modulus for the substrates. In this article, we synthesized a redox-sensitive smart hydrogel with a programmed switchover of elastic substrates in response to glutathione (GSH)/oxidizided glutathione (GSSG) concentration change. The hydrogel is made up of a mixture six-arm poly(ethylene glycol)-poly(ε-caprolactone)-3,3'-dithiodipropionic acid gels (6A PECL-SS) and six-arm poly(ethylene glycol)-poly(ε-caprolactone)-acryloyl (6A PECL-AC). Under different redox stimulus (+GSH or +GSSG), the redox-sensitive substrate can act as a cross-linked switch to adjust the elasticity modulus. RT-PCR results based on cell culture evaluation indicate that the reversibly controlled elastic substrates cultured on a flat and microgroove surface exhibited good osteoinduction under different inversion frequencies. Therefore, our results indicate that this redox-responsive substrate has great potential in bone tissue engineering.

miR-149* Suppresses Liver Cancer Progression by Down-Regulating Tumor Necrosis Factor Receptor 1-Associated Death Domain Protein Expression.

Liver cancer is the third leading cause of cancer-related death worldwide. Herein, we show that miR-149* serves as a novel tumor suppressor for liver tumorigenesis. Mice with genetic deletion of miR-149* (miR-149*-/- mice), which caused loss of both miR-149 and miR-149*, were considerably more susceptible to acute liver injury and hepatic carcinogenesis induced by diethylnitrosamine than wild-type mice, accompanied by increased compensatory proliferation and up-regulated gene expression of certain inflammatory cytokines. miR-149* mimics dramatically impaired liver cancer cell proliferation and migration in vitro and blocked liver cancer progression in a xenograft model. Furthermore, miR-149* strongly suppressed NF-κB signaling and repressed tumor necrosis factor receptor type 1-associated death domain protein expression in the NF-κB signaling pathway. These results reveal that miR-149*, as a novel liver tumor suppressor, may serve as a potential therapeutic target for liver cancer treatment.

Downregulation of Wnt3 Suppresses Colorectal Cancer Development Through Inhibiting Cell Proliferation and Migration.

The aberrant expression of Wnt3 has linked to several types of human malignancies. However, it is not known for its role in tumorigenesis of colorectal cancer (CRC). Herein, we show that Wnt3 is upregulated in human CRC tissues and is essential for the CRC progression. Knockdown of Wnt3 in human CRC cells delayed tumor formation in nude mouse xenografts through silencing of canonical Wnt pathway and glycolysis. We further found that silencing of Wnt3 enhanced the sensitivity of CRC cells to cisplatin through inducing apoptotic cell death. Taken together, it demonstrates that Wnt3 is a novel clinical biomarker for the detection of CRC and plays an important role in colorectal tumorigenesis. Therefore, downregulation of Wnt3 will be a valuable strategy in CRC treatment.