Optogenetic engineered umbilical cord MSC-derived exosomes for remodeling of the immune microenvironment in diabetic wounds and the promotion of tissue repair.

BACKGROUND: Angiogenesis and tissue repair in chronic non-healing diabetic wounds remain critical clinical problems. Engineered MSC-derived exosomes have significant potential for the promotion of wound healing. Here, we discuss the effects and mechanisms of eNOS-rich umbilical cord MSC exosomes (UCMSC-exo/eNOS) modified by genetic engineering and optogenetic techniques on diabetic chronic wound repair. METHODS: Umbilical cord mesenchymal stem cells were engineered to express two recombinant proteins. Large amounts of eNOS were loaded into UCMSC-exo using the EXPLOR system under blue light irradiation. The effects of UCMSC-exo/eNOS on the biological functions of fibroblasts and vascular endothelial cells in vitro were evaluated. Full-thickness skin wounds were constructed on the backs of diabetic mice to assess the role of UCMSC-exo/eNOS in vascular neogenesis and the immune microenvironment, and to explore the related molecular mechanisms. RESULTS: eNOS was substantially enriched in UCMSCs-exo by endogenous cellular activities under blue light irradiation. UCMSC-exo/eNOS significantly improved the biological functions of cells after high-glucose treatment and reduced the expression of inflammatory factors and apoptosis induced by oxidative stress. In vivo, UCMSC-exo/eNOS significantly improved the rate of wound closure and enhanced vascular neogenesis and matrix remodeling in diabetic mice. UCMSC-exo/eNOS also improved the inflammatory profile at the wound site and modulated the associated immune microenvironment, thus significantly promoting tissue repair. CONCLUSION: This study provides a novel therapeutic strategy based on engineered stem cell-derived exosomes for the promotion of angiogenesis and tissue repair in chronic diabetic wounds.

Role of Treg/Th17 Imbalance, Microbiota and miRNAs in Pancreatic Cancer: Therapeutic Options.

Pancreatic cancer is one of the most lethal kinds of cancer; numerous patients die from it every year all over the word. Fewer than 5% of people with pancreatic cancer survive death and recover. Recent evidence suggests that inflammation parameters, such as Th17 cells and Tregs, affect the progression and even the diagnosis and treatment of pancreatic cancer. In the inflammation process, T lymphocytes play an essential role in inflammation intensity, and related cytokines modulate immune responses in the tumor microenvironment. Their function is to establish a balance between destructive inflammation and defense against tumor cells via immune system, and Treg/Th17 imbalance is a common problem in this cancer. The role of microbiota in the development of some cancers is clear; microbiota may also be involved in the pancreatic cancer development. All risk factors for pancreatic cancer, such as chronic pancreatitis-related to microbiota, influence the acute or chronic immune response. Some evidence has been presented regarding the role of the immune response in carcinogenesis. In addition, miRNAs are very important in suppressing and stimulating the growth of cancer cells, and a variety of them have been identified. Some miRNAs are abnormally expressed in many cancers and have main roles as post-transcriptional regulators. They show oncogenic or tumor-suppressive functions by binding to marked mRNAs. In this review, we highlight recent findings regarding the role of Treg/Th17 imbalance, microbiota functions, and miRNAs performance in pancreatic cancer. We also present the evidence regarding therapeutic options.

The roles of tumor-associated macrophages in tumor angiogenesis and metastasis.

Tumor associated macrophages (TAMs) are the most frequent immune cells within tumor microenvironment (TME). There is growing evidence that TAMs are involved in tumor progression via multiple mechanisms. TAMs create an immunosuppressive TME by producing growth factors, chemokines, and cytokines which modulate recruitment of immune cells and inhibit anti-tumor responses. They also serve as angiogenesis promoting cells by production of pro-angiogenic factors and matrix metalloproteinases (MMPs) and vascular constructing which guarantee supplying oxygen and nutrients to solid tumor cells. Furthermore, TAMs play important functions in tumor metastasis through contributing to invasion, extravasation, survival, intravasation, and colonization of tumor cells. In this review, we summarized macrophage classification, TAMs polarization, and mechanisms underlying TAM-promoting angiogenesis and metastasis.

Nitrogen removal and water microbiota in grass carp culture following supplementation with Bacillus licheniformis BSK-4.

This experiment was designed to study the effects of Bacillus licheniformis BSK-4 on nitrogen removal and microbial community structure in a grass carp (Ctenopharyngodon idellus) culture. The selected strain Bacillus licheniformis BSK-4 significantly decreased nitrite, nitrate and total nitrogen levels in water over an extended, whereas increased ammonia level. Pyrosequencing showed that Proteobacteria, Actinobacteria, Firmicutes, and Bacteroidetes were dominant in grass carp culture water. Compared with the control group, the number of Proteobacteria and Firmicutes were increased, while Actinobacteria and Bacteroidetes decreased in treatment group. At the genus level, some genera, such as Bacillus, Prosthecobacter, Enterococcus, etc., appear only in the treatment, while many other genera exist only in the control group; Lactobacillus, Luteolibacter, Phenylobacterium, etc. were increased in treatment group compared to those in control group. As above, the results suggested that supplementation with B. licheniformis BSK-4 could remove some nitrogen and cause alterations of the microbial composition in grass carp water.

Effect of photosynthetic bacteria on water quality and microbiota in grass carp culture.

To investigate the effects of photosynthetic bacteria as additives on water quality, microbial community structure and diversity, a photosynthetic purple non-sulfur bacteria, Rhodopseudamonas palustris, was isolated and used to remove nitrogen in the aquaculture water. The results of water quality showed that the levels of ammonia nitrogen, nitrite nitrogen, total inorganic nitrogen and total nitrogen in the treatment group were significantly lower (p < 0.05) than the nitrogen levels of the controls in an extended range. A 454-pyrosequencing analysis revealed that at the level of phylum, Proteobacteria and Firmicutes were dominant in the control group respectively, compared to the dominance of the phyla Proteobacteria, Bacteroidetes and Actinobacteria in the treatment group. The relative abundance of phyla Bacteroidetes and Actinobacteria in treatment witnessed an increase than that in the control. The results also indicated that the treatment group enjoyed a higher microbial diversity than that of the control group. Based on the oxygen requirement and metabolism, the authors observed that the water supplementation with photosynthetic bacteria could significantly decrease (p < 0.05) the number of nitrite reducer and anaerobic bacteria. Therefore, the results suggested that adding photosynthetic bacteria to water improves the water quality as it changes the microbial community structure.

Oral administration of grape-derived nanovesicles for protection against LPS/D-GalN-induced acute liver failure.

Although the exploration of the molecular mechanisms of Acute liver failure (ALF) is supported by a growing number of studies, the lack of effective therapeutic agents and measures indicates an urgent clinical need for the development of new drugs and treatment strategies. Herein, we focused on the treatment of ALF with grape-derived nanovesicles (GDNVs), and assessed its protective effects and molecular mechanisms against liver injury. In the mice model of ALF, prophylactic administration for three consecutive days and treatment with GDNVs after successful induction of ALF showed a significant reduction of ALT and AST activity in mouse serum, as well as a blockade of the release of inflammatory cytokines IL6, IL-1ß and TNF-α. Treatment with GDNVs significantly prevented the massive apoptosis of hepatocytes caused by LPS/D-GalN and down-regulated the activation and expression of the mitochondrial apoptosis-related proteins p53, Caspase 9, Caspase 8, Caspase 3 and Bax. GDNVs downregulated the release of chemokines during the inflammatory eruption in mice and inhibited the infiltration of peripheral monocytes into the liver by inhibiting CCR2/CCR5. Moreover, the pro-inflammatory phenotype of macrophages in the liver was reversed by GDNVs. GDNVs further reduced the activation of NLRP3-related pathways, and treatment with GDNVs activated the expression of autophagy-related proteins Foxo3a, Sirt1 and LC3-II in the damaged mouse liver, inducing autophagy to occur. GDNVs could exert hepatoprotective and inflammatory suppressive functions by increasing nuclear translocation of Nrf2 and upregulating HO-1 expression against exogenous toxin-induced oxidative stress in the liver. In conclusion, these results demonstrate that GDNVs alleviate LPS/D-GalN-induced ALF and have the potential to be used as a novel hepatoprotective agent for clinical treatment.

Bacillus subtilis SC02 supplementation causes alterations of the microbial diversity in grass carp water.

This study was conducted to evaluate the effects of Bacillus subtilis SC02 supplement on water quality, microbial community diversity and structure in a grass carp (Ctenopharyngodon idellus) culture. Our selected strain, B. subtilis SC02, significantly reduced ammonia, nitrite and total nitrogen levels in water over an extended period compared with the control group. Pyrosequencing showed that the Shannon diversity index (Shannon) and species richness estimators (Chao) of the treatment group were higher, indicating that bacterial richness was significantly increased in the treatment group. The phyla Proteobacteria, Bacteroidetes and Actinobacteria were dominant in the treatment groups, accounting for 45, 21.9 and 21.9 % of the sequence reads, respectively. However, in sharp contrast, the control fishes were predominantly occupied by Proteobacteria (82.1 %) and Firmicutes (8.4 %). At the genus level, the microbial communities were different between the control and treatment groups, although the two groups shared similar genera. Additionally, some genera (such as Tepidimonas, Variovorax, Roseomonas, Rubritepida, Nitrobacter, etc.) only appeared in the treatment group, and many other genera only existed in the control group. Therefore, we conclude that the addition of the SC02 strain in water improves water quality, which may ultimately be a result of changes in microbial community diversity in grass carp cultures.

Integrated clinical analysis and data mining assessed the impact of NOX4 on the immune microenvironment and prognosis of pancreatic cancer.

Background: The tumor microenvironment (TME) of pancreatic cancer is complex. which forms forms a microenvironment with high immunosuppression, ischemia and hypoxia, which promotes tumor proliferation and migration, inhibit the anti-tumor immune response. NOX4 plays an important role in tumor microenvironment and has a significant relationship with the occurrence, development and drug resistance of tumor. Methods: Firstly, NOX4 expression in pancreatic cancer tissues under different pathological conditions was detected by applying immunohistochemical staining of tissue microarray (TMA). Transcriptome RNA sequencing data and clinical data of 182 pancreatic cancer samples were downloaded and collated from the UCSC xena database. 986 NOX4-related lncRNAs were filtered by Spearman correlation analysis. prognosis-related NOX4-related lncRNAs and NRlncSig Score were finally obtained by univariate and multivariate Cox regression with Least Absolute Shrinkage and Selection Operator (Lasso) analysis in pancreatic cancer patients. we plotted Kaplan -Meier and time-dependent ROC curves (ROC) to assess the validity in predicting the prognosis of pancreatic cancer. The ssGSEA analysis was applied to explore the immune microenvironment of pancreatic cancer patients as well as to discuss the immune cells and immune status separately. Results: We found that a mature tumor marker, NOX4, play different roles in different clinical subgroups by immunohistochemical analysis and clinical data. Finally, 2 NOX4-related lncRNAs were determined by least absolute shrinkage and selection operator (LASSO) analysis, univariate Cox analysis and multivariate COX analysis. The ROC curve and DCA curve showed that NRS Score had better predictive ability than independent prognosis-related lncRNA and other clinicopathologic indicators. We obtained the relative abundance of 28 infiltrating immune cells by ssGSEA analysis and found a significant positive correlation between the abundance of anti-tumor immune cells and tumor-promoting immune cells in the risk-classified microenvironment. No matter NRS Score or AC092667.2, RP11-349A8.3 was significantly correlated with immune infiltrating cells. Meanwhile, the IC50 of conventional chemotherapeutic agents in high-score group were significantly lower than those in low-score group. Conclusion: As a mature tumor marker, NOX4-related lncRNAs provide new research strategies for prognostic evaluation, molecular mechanism and clinical treatment of pancreatic cancer.

Garlic-derived exosome-like nanovesicles as a hepatoprotective agent alleviating acute liver failure by inhibiting CCR2/CCR5 signaling and inflammation.

Acute liver failure (ALF) is a life-threatening clinical syndrome mostly induced by viral infections or drug abuse. As a novel therapeutic adjuvant or delivery vehicle, plant-derived exosome-like nanovesicles (PELNVs) have been extensively studied in recent years. This study aimed to develop garlic-derived exosome-like nanovesicles (GaELNVs) in order to ameliorate liver injury induced by LPS/D-GalN in mice, inhibit inflammatory eruption and reduce inflammatory cells infiltration. The results showed that treatment with GaELNVs improved liver pathology and reduced the levels of soluble inflammatory mediators IL-6, IL-1ß and TNF-α in the serum of ALF mice. GaELNVs reversed the upregulation of Cleaved Caspase-9, Cleaved Caspase-3, p53 and Bax expression and decreased Bcl2 activation caused by D-GalN/LPS, and inhibited NF-κB p65 expression and translocation to the nucleus. Meanwhile, treatment with GaELNVs resulted significant reduction in NLRP3 activation and Caspase-1 maturation, as well as decrease in the release of the inflammatory mediator IL-18. Additionally, an upregulation of the expression of proteins related to energy metabolism and autophagy occurrence including Foxo3a, Sirt1, and LC3-II was detected in the liver. Oral administration of GaELNVs also led to significant alteration in the expression of F4/80 and CD11b in the liver. Furthermore, the detection of chemokines in mouse liver tissue revealed that GaELNVs exhibited minimal reduction in the expression of CCL2, CCL3, CCL5 and CCL8. The decreased expression of CCR2 and CCR5 in the liver suggests that GaELNVs have the ability to decrease the recruitment of monocytes from the circulation to the liver. A reduction in the infiltration of F4/80loCD11bhi monocyte-derived macrophages into the liver was also observed. This study provides novel evidence that GaELNVs can ameliorate inflammatory eruptions and hinder the migration of circulating monocytes to the liver, as well as decrease macrophage infiltration by inhibiting CCR2/CCR5 signaling. Consequently, GaELNVs hold promise as a novel therapeutic agent for clinical management of liver disease.

The Ethanolic Extract of Lindera aggregata Modulates Gut Microbiota Dysbiosis and Alleviates Ethanol-Induced Acute Liver Inflammation and Oxidative Stress SIRT1/Nrf2/NF-κB Pathway.

This study is an attempt to evaluate the therapeutic effect of the ethanolic extract of Lindera aggregata on the liver and intestinal microbiota in rats with alcohol-induced liver injury (ALI). Rats were treated with 70 mg probiotics, 1 g/kg, 2 g/kg, and 3 g/kg ethanolic extract of Lindera aggregata, respectively, for 10 days. We found that Lindera aggregata could significantly reduce the biochemical parameters in the serum of ALD rats. Lindera aggregata alleviates oxidative stress and inflammation by upregulating SIRT1 and Nrf2 and downregulating COX2 and NF-κB. The results of 16S rRNA gene sequencing showed that the medium dose of Lindera aggregata had the best effect on the growth of beneficial bacteria. Diversity analysis and LEfSe analysis showed that beneficial bacteria gradually occupied the dominant niche. The relative abundance of potential pathogens in the gut decreased significantly. We demonstrated that the ethanolic extract of Lindera aggregata can alleviate the oxidative stress and inflammation induced by alcohol through the SIRT1/Nrf2/NF-κB pathway and can modulate the disturbance of gut microbiota induced by alcohol intake.

Design and Development of Hybrid Hydrogels for Biomedical Applications: Recent Trends in Anticancer Drug Delivery and Tissue Engineering.

The applications of hydrogels in biomedical field has been since multiple decades. Discoveries in biology and chemistry render this platform endowed with much engineering potentials and growing continuously. Novel approaches in constructing these materials have led to the production of complex hybrid hydrogels systems that can incorporate both natural and synthetic polymers and other functional moieties for mediated cell response, tunable release kinetic profiles, thus they are used and research for diverse biomedical applications. Recent advancement in this field has established promising techniques for the development of biorelevant materials for construction of hybrid hydrogels with potential applications in the delivery of cancer therapeutics, drug discovery, and re-generative medicines. In this review, recent trends in advanced hybrid hydrogels systems incorporating nano/microstructures, their synthesis, and their potential applications in tissue engineering and anticancer drug delivery has been discussed. Examples of some new approaches including click reactions implementation, 3D printing, and photopatterning for the development of these materials has been briefly discussed. In addition, the application of biomolecules and motifs for desired outcomes, and tailoring of their transport and kinetic behavior for achieving desired outcomes in hybrid nanogels has also been reviewed.

The role of iron homeostasis and iron-mediated ROS in cancer.

As an important trace element, iron plays an essential role in many biology processes like cell proliferation, metabolism, and mitochondrial function. However, the disruption of iron homeostasis tends to cells death and human diseases due to it servers as mediator to promote the production of reactive oxygen species (ROS). In this review, first we introduced the mechanism of complex iron-mediated ROS involved in apoptosis, necroptosis, ferroptosis and pyroptosis. Next, we discussed the controversial role of excess iron and iron deficiency in tumor. Finally, we discussed the anti-cancer effects of iron on both sides, and novel iron-related strategies. This review outlined the mechanisms and regulation of iron homeostasis and iron-mediated ROS in tumors, and discussed the iron-related treatments.

CAP2 is a Valuable Biomarker for Diagnosis and Prognostic in Patients with Gastric Cancer.

Cyclase-associated protein 2 (CAP2) protein is reported to be upregulated in hepatocellular carcinoma (HCC), human breast cancer, and malignant melanoma. However, its expression in gastric cancer remains unknown, this study was to investigate CAP2 expression and its prognostic significance in gastric cancer. Firstly, we analyzed the Oncomine databases to compare CAP2 mRNA expression in gastric cancer and normal tissues. CAP2 protein expression was analyzed in gastric cancer samples and non-tumor mucosa by RT-PCR and immunohistochemical analysis. Consequently, statistical analyses were performed to evaluate the clinicopathological significance of CAP2 expression in gastric cancer. CAP2 expression was significant higher in gastric cancer tissues than that in non-tumor mucosa at protein levels. CAP2 was up-regulated in 57.8% (252/436) of gastric cancer samples, while detected in only 10.9% (10/92) of non-tumor mucosa. Statistical analysis shows that the expression of CAP2 was correlated with tumor size, Lauren's classification, depth of invasion, lymph node and distant metastases, and regional lymph node stage, TNM stage, but not with age, sex, histology classification, and histologic differentiation. Kaplan-Meier analysis indicated that high CAP2 expression was associated with poor overall survival (78.7%) in 203 of 252 gastic cancer patients. In stage I, II, and III tumors, the 5-year survival rate was lower in those with high expression of CAP2 than those with low expression. In stage IV tumors, the expression of CAP2 did not correlate with the 5-year survival rate. Multiple Cox regression analysis indicated CAP2 as an independent predictor for overall survival [hazard ratio (HR) = 2.045, 95% confidence interval: 1.445-2.895, p < 0.01], while Lauren's classification, TNM stage, and expression of CAP2 were independent prognostic factors in patients with gastric cancer. For the first time, we found that CAP2 was upregulated in gastic cancer, and was associated with lymph node and distant metastases. CAP2 may serve as a prognostic indicator for patients with gastic cancer.

Recent advances in natural therapeutic approaches for the treatment of cancer.

Plants and natural compounds have been widely recognized to have potential for the prevention of cancer progression and as complementary or standalone treatments for cancer patients. The major benefits of natural compounds are their reduced toxicity compared to more aggressive and widely utilized cancer treatment approaches. Preclinical studies have led to the discovery of a number of natural anticancer compounds, including preparations of Vitex negundo L., green tea, mandarin peel oil, ursolic acid, curcumin and resveratrol. Although the in vitro data highlights the potential of these natural alternatives, their benefits in clinical cancer treatment remain less conclusive. In this review, we will discuss some of the recent advances in natural anticancer treatment discovery for the four most prominent global cancers, namely, breast, lung, prostate and skin metastases. As the exploration of natural therapeutics continues to expand, these substances have the potential to be utilized as preventative strategies and complimentary therapeutics. In some cases, they may have sufficient anti-tumor and anti-carcinogenic properties to function as standalone cancer treatments.

Surface Engineered Metal-Organic Frameworks (MOFs) Based Novel Hybrid Systems for Effective Wound Healing: A Review of Recent Developments.

Wounds present serious medical complications and their healing requires strategies that promote angiogenesis, deposition of collagen as well as re-epithelialization of wounds. Currently used conventional wound healing strategies have become less effective due to various issues associated with them. Thus, novel strategies are needed to be developed for early and effective healing of wounds. Metal-organic frameworks (MOFs), formed by linking of metal ions through organic bridging ligands, are highly tunable hybrid materials and have attracted more considerable scientific attention due to their charming and prominent properties, such as abundant pore structures and multiple functionalities. Surface engineering of MOFs with unique ligands can overcome issues associated with conventional wound healing methods, thus resulting in early and effective wound healing. This review has been undertaken to elaborate wound healing, and the use of surface engineered MOFs for effective and rapid wound healing. The process of wound healing will be discussed followed by a detailed review of recent literature for summarizing applications of surface engineered MOFs for wound healing. MOFs wound healing will be discussed in terms of their use as antibacterial agents, therapeutic delivery vehicles, and dressing systems in wound healing.

Ultra-efficient Antibacterial System Based on Photodynamic Therapy and CO Gas Therapy for Synergistic Antibacterial and Ablation Biofilms.

In recent years, with the emergence of various kinds of drug-resistant bacteria, existing antibiotics have become inefficient in killing these bacteria, and the formation of biofilms has further weakened the therapeutic effect. More problematically, the massive use and abuse of antibiotics have caused severe side effects. Thus, the development of ultra-efficient and safe antibacterial systems is urgently needed. Herein, a photodynamic therapy (PDT)-driven CO-controlled delivery system (Ce6&CO@FADP) is developed for synergistic antibacterial and ablation biofilms. Ce6&CO@FADP is constructed using a fluorinated amphiphilic dendritic peptide (FADP) and physically loaded with Ce6 and CORM-401. After efficiently entering the bacteria, Ce6&CO@FADP can rapidly release CO intracellularly by the massive consumption of the H2O2 generated during the PDT process, without affecting the generation of singlet oxygen (1O2). As such, the combination of CO and 1O2 exerts notable synergistic antibacterial and biofilm ablation effects both in vitro and in vivo (including subcutaneous bacterial infection and biofilm catheter models) experiments. More importantly, all biosafety assessments suggest the good biocompatibility of Ce6&CO@FADP. Together, these results reveal that Ce6&CO@FADP is an efficient and safe antibacterial system, which has essential application prospects for the treatment of bacterial infections and ablation of biofilms in vivo.

Recent advances in oncolytic virus-based cancer therapy.

Administration of oncolytic viruses (OVs) is an emerging anticancer strategy that exploits the lytic nature of viral replication to enhance the killing of malignant cells. OVs can be used as tools to directly induce cancer cell death and to trigger local and/or systemic immune responses to metastatic cancer in vivo. The effectiveness of OV therapy was initially highlighted by the clinical use of the genetically modified herpes virus, talimogene laherparepvec, for melanoma therapy. A number of OVs are now being evaluated as potential treatments for cancer in clinical trials. In spite of being engineered to specifically target tumor cells, the safety and off-target effects of OV therapy are a concern. The potential safety concerns of OVs are highlighted by current clinical trial criteria, which exclude individuals harbouring other viral infections and people who are immunocompromised. Despite the potential for adverse effects, clinical trials to date revealed relatively minimal adverse immune-related effects, such as fever. With advances in our understanding of virus replication cycles, several novel OVs have emerged. Reverse genetic systems have facilitated the insertion of anticancer genes into a range of OVs to further enhance their tumor-killing capacity. In this review, we highlight the recent advances in OV therapy for a range of human cancers in in vitro and in in vivo animal studies. We further discuss the future of OVs as a therapeutic strategy for a range of life-threatening cancers.

The Antihelminthic Niclosamide Inhibits Cancer Stemness, Extracellular Matrix Remodeling, and Metastasis through Dysregulation of the Nuclear ß-catenin/c-Myc axis in OSCC.

Niclosamide is an oral chlorinated salicylanilide antihelminthic agent with potential anticancer activity suggested in several cancer types, however, its anticancer action and likely molecular mechanism in malignant oral cells remain unclear. In the present study, we demonstrated that ALDH+ human oral squamous cell carcinoma (OSCC) cells are characterized by upregulated expression of the pluripotency transcription factors OCT4, Nanog and Sox2, as well as exhibit enhanced cancer stemness, as demonstrated by enhanced tumorsphere formation. We also showed that niclosamide effectively inhibits activation of the Wnt/ß-catenin signaling pathway by targeting multiple components of this pathway, including downregulating the expression ß-catenin, Dishevelled 2 (DVL2), phosphorylated glycogen synthase kinase-3ß (p-GSK3ß) and Cyclin D1, in human OSCC SCC4 and SCC25 cell lines, as well as reduced the formation of primary and secondary tumorspheres. In addition, we showed that niclosamide inhibits the epithelial-to-mesenchymal transition (EMT), migration and colony formation of the OSCC cells, by dose-dependently upregulating E-cadherin and the tissue inhibitor of metalloproteinases 2 (TIMP2) mRNA levels, while reducing the expression levels of vimentin, snail, MMP2 and MMP9 mRNA. These anticancer activities of niclosamide were similar to those caused by interference with nuclear ß-catenin/c-Myc expression using the siRNA transfection. Finally, we demonstrated that niclosamide inhibits cisplatin-induced OSCC stem cell enrichment and enhances sensitivity to cisplatin in ALDH+ tumorspheres. These experimental data, combined with accumulated evidence, are suggestive of the potential and efficacy of niclosamide in the treatment of OSCC.

Ovatodiolide targets chronic myeloid leukemia stem cells by epigenetically upregulating hsa-miR-155, suppressing the BCR-ABL fusion gene and dysregulating the PI3K/AKT/mTOR pathway.

Chronic myeloid leukemia (CML) is a myeloproliferative pathology, originating from the hematopoietic cancer stem cells (hCSCs) due to the Bcl-Abl Philadelphia chromosome transformation. However, targeting these hCSCs as an effective anti-CML strategy is relatively less explored. Ovatodiolide (Ova) is a natural diterpenoid isolate of Anisomeles indica with broad anticancer activity. In this study, we investigated the anti-hCSCs potential of Ova against CD34+/CD38-, CD34+/CD38+, and unsorted K562 cell lines using flow cytometry, western blot, RT-PCR, genomic mapping, and tumorsphere formation assays. We demonstrated that compared to unsorted K562 and CD34+/CD38+, CD34+/CD38- cells were significantly enriched with Oct4, Sox2, CD133, Bcr-Abl, p-CrkL and p-Stat5 protein and/or mRNA. Furthermore, we showed that Ova alone or by enhancing the therapeutic potential of Imatinib, reduced the viability of CML cell lines, dose-dependently, irrespective of the cancer stemness, as well as markedly inhibit the Bcr-Abl, p-CrkL, Stat5, and MDR protein expression levels in CD34+ cells. Mechanistic investigations revealed a significant up-regulation of hsa-miR-155, which resulted in the reduction of dysregulating the PIK3CA expression in Ova-treated K562 CD34+/CD38- cells. Additionally, Ova alone or in combination with Imatinib suppressed the hCSC traits of the CD34+/CD38- cells, resulting in loss of their ability to form tumorspheres, enhanced apoptosis, increase in the Bax/Bcl-2 ratio, and dysregulation of the PI3K/AKT/mTOR signaling pathway. Together, these results demonstrate the PI3K/AKT/mTOR signaling-mediated anti-hCSC effect of Ova in CML, as well as suggest a likely role for Ova as a small molecule PI3K/mTOR dual inhibitor, thus, extending its potential benefit to other mTOR-mediated pathologies.

Decreased CRHBP expression is predictive of poor prognosis in patients with hepatocellular carcinoma.

Corticotropin releasing hormone binding protein (CRHBP) mediates the reaction between corticotropin releasing hormone (CRH) and corticotropin releasing hormone receptors (CRHRs). It is expressed in a number of organs, and the expression of CRHBP is associated with tumorigenesis and cancer progression. The aim of the present study was to investigate CRHBP expression levels in hepatocellular carcinoma (HCC) and its association with patient clinicopathological characteristics as well as prognosis. The expression of CRHBP was examined by immunohistochemistry in 169 HCC tissues and 151 adjacent non-tumorous tissues. The results were validated by western blotting using patient tissues and liver cancer cell lines. The association of CRHBP expression with clinicopathological patient characteristics and survival rate was analyzed statistically. Expression of CRHBP was detected in 142/151 (94.0%) non-tumorous liver tissues, and 84/169 (49.7%) HCC tissues (P<0.001). The expression of CRHBP was negatively associated with tumor size (P=0.013), Edmondson Grade (P=0.002), hepatitis B virus antigen (P=0.020), and α-fetoprotein levels (P=0.014). Patients exhibiting low CRHBP expression were associated with shorter survival time compared with those exhibiting high CRHBP expression (P=0.012). The results of western blotting analysis suggest that reduced CRHBP expression is frequently observable in patients with HCC. Low CRHBP expression in HCC tissues may be a predictor of clinical prognosis and a potential therapeutic target for HCC.