In Vitro Glioblastoma Model on a Plate for Localized Drug Release Study from a 3D-Printed Drug-Eluted Hydrogel Mesh.

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that has limited treatment options. Current standard therapies, including surgery followed by radiotherapy and chemotherapy, are not very effective due to the rapid progression and recurrence of the tumor. Therefore, there is an urgent need for more effective treatments, such as combination therapy and localized drug delivery systems that can reduce systemic side effects. Recently, a handheld printer was developed that can deliver drugs directly to the tumor site. In this study, the feasibility of using this technology for localized co-delivery of temozolomide (TMZ) and deferiprone (DFP) to treat glioblastoma is showcased. A flexible drug-loaded mesh (GlioMesh) loaded with poly (lactic-co-glycolic acid) (PLGA) microparticles is printed, which shows the sustained release of both drugs for up to a month. The effectiveness of the printed drug-eluting mesh in terms of tumor toxicity and invasion inhibition is evaluated using a 3D micro-physiological system on a plate and the formation of GBM tumoroids within the microenvironment. The proposed in vitro model can identify the effective combination doses of TMZ and DFP in a sustained drug delivery platform. Additionally, our approach shows promise in GB therapy by enabling localized delivery of multiple drugs, preventing off-target cytotoxic effects.

The Effect of 4 Weeks Aerobic Exercise Training with Detraining Courses in Various Prevention Phases on BCl-2 and BAX Genes Expression and Proteins.

Background: The aim of this study was to investigate the effect of aerobic exercise with detraining in different phases of prevention on BCL2 Associated X (BAX) and B-cell lymphoma 2 (BCl-2) gene expression and proteins. Methods: For this purpose, 32 female Balb-c mice (18-20 g) were purchased and randomly assigned to primordial prevention (A), primary prevention (B), secondary prevention (C), and control (D). A group performed aerobic exercise for 4 weeks, after 4T1 cells injection detrained for 8 weeks. Group B performed aerobic exercise for 4 weeks immediately after injecting 4T1 cells and then detrained for 4 weeks. In C group, the 4T1 cells were first injected and did not perform any activity for 4 weeks, followed by 4 weeks of aerobic exercise. Forty-eight hours after the last training session and detraining courses, after anesthesia, sacrificing, and tissue removal, were performed. Reverse transcription polymerase chain reaction (RT PCR) was used to measure gene expression and Western blot (WB) was used to measure protein content. One-way Analysis of variance (ANOVA) test was used to analyze data. Results: The results showed that aerobic exercise in A, B, and C groups compared to D group reduced BCl-2 gene expression and protein and increased BAX gene expression and protein. Conclusions: Therefore, exercise can cause apoptosis in tumor cells by increasing pre-apoptotic factors and decreasing antiapoptotic factors in tumor cells, and consequently improving the disease status.

Evaluation of Expression Level of miR-3135b-5p in Blood Samples of Breast Cancer Patients Experiencing Chemotherapy-Induced Cardiotoxicity.

The efficacy of chemotherapeutics in the treatment of breast cancer is limited by cardiotoxicity, which could lead to irreversible heart failure. The evaluation of miRNA levels as a vital biomarker could predict cardiotoxicity induced by chemotherapy. According to our previous meta-analysis study on patients with heart failure, we found that miR-3135b had a significant increase in patients with heart failure. Therefore, the present study aimed to evaluate the expression level of miR-3135b in the blood sample of patients experiencing chemotherapy-induced cardiotoxicity. Blood samples were collected from breast cancer patients or breast cancer patients who had received chemotherapy and had not experienced any chemotherapy-induced cardiotoxicity (N = 37, control group) and breast cancer patients experiencing chemotherapy-induced cardiotoxicity after chemotherapy (N = 33). The expression level of miR-3135b was evaluated using real-time polymerase chain reaction (RT-PCR). The 2-ΔCt values of miR-3135b were compared between two groups. We observed a significant increase in the expression level of miR-3135b between patients experiencing chemotherapy-induced cardiotoxicity and the control group (P = 0.0001). Besides, the ejection fraction parameter was correlated with the expression level of miR-3135b (r = 0.5 and P = 0.0001). To sum up, miR-3135b might be useful as a promising circulating biomarker in predicting cardiotoxicity induced by chemotherapy. However, more studies are needed to validate miR-3135b as a biomarker for the diagnosis of chemotherapy-induced cardiotoxicity. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01075-3.

Microfluidic-based technologies in cancer liquid biopsy: Unveiling the role of horizontal gene transfer (HGT) materials.

Liquid biopsy includes the isolating and analysis of non-solid biological samples enables us to find new ways for molecular profiling, prognostic assessment, and better therapeutic decision-making in cancer patients. Despite the conventional theory of tumor development, a non-vertical transmission of DNA has been reported among cancer cells and between cancer and normal cells. The phenomenon referred to as horizontal gene transfer (HGT) has the ability to amplify the advancement of tumors by disseminating genes that encode molecules conferring benefits to the survival or metastasis of cancer cells. Currently, common liquid biopsy approaches include the analysis of extracellular vesicles (EVs) and tumor-free DNA (tfDNA) derived from primary tumors and their metastatic sites, which are well-known HGT mediators in cancer cells. Current technological and molecular advances expedited the high-throughput and high-sensitive HGT materials analyses by using new technologies, such as microfluidics in liquid biopsies. This review delves into the convergence of microfluidic-based technologies and the investigation of Horizontal Gene Transfer (HGT) materials in cancer liquid biopsy. The integration of microfluidics offers unprecedented advantages such as high sensitivity, rapid analysis, and the ability to analyze rare cell populations. These attributes are instrumental in detecting and characterizing CTCs, circulating nucleic acids, and EVs, which are carriers of genetic cargo that could potentially undergo HGT. The phenomenon of HGT in cancer has raised intriguing questions about its role in driving genomic diversity and acquired drug resistance. By leveraging microfluidic platforms, researchers have been able to capture and analyze individual cells or genetic material with enhanced precision, shedding light on the potential transfer of genetic material between cancer cells and surrounding stromal cells. Furthermore, the application of microfluidics in single-cell sequencing has enabled the elucidation of the genetic changes associated with HGT events, providing insights into the evolution of tumor genomes. This review also discusses the challenges and opportunities in studying HGT materials using microfluidic-based technologies. In conclusion, microfluidic-based technologies have significantly advanced the field of cancer liquid biopsy, enabling the sensitive and accurate detection of HGT materials. As the understanding of HGT's role in tumor evolution and therapy resistance continues to evolve, the synergistic integration of microfluidics and HGT research promises to provide valuable insights into cancer biology, with potential implications for precision oncology and therapeutic strategies.

Effects of the Co-Administration of Morphine and Lipopolysaccharide on Toll-Like Receptor-4/Nuclear Factor Kappa ß Signaling Pathway of MDA-MB-231 Breast Cancer Cells.

Background: The Toll-like receptor 4 (TLR4) gene promotes migration in adenocarcinoma cells. Morphine is an agonist for TLR4 that has a dual role in cancer development. The promoter or inhibitor role of morphine in cancer progression remains controversial. This study aims to evaluate the effects of morphine on the TLR4, myeloid differentiation primary response protein 88-dependent (MyD88), and nuclear factor-kappa B (NF-κB) expressions in the human MDA-MB-231 breast cancer cell line. Materials and Methods: The cells were examined after 24 hours of incubation with morphine using the Boyden chamber system. TLR4, MyD88, and NF-κB mRNA expressions were assessed using quantitative real-time polymerase chain reaction (RT-PCR). The concentration of interleukin-2 beta was also measured using the ELISA assay. Results: According to the findings, three doses of morphine (0.25, 1.25, and 0.025 µM) increased the expression of the TLR4 and NF-κB genes, whereas no significant change was observed in the mRNA expression of MyD88. Furthermore, treatment with morphine and lipopolysaccharide (LPS) significantly decreased the expression of TLR4, MyD88, and NF-κB. However, no significant change was observed in interleukin 2 beta concentration. Conclusions: These findings confirmed the excitatory effects of morphine on TRL4 expression and the MYD88 signaling pathway in vitro.

Shared Lifestyle-Related Risk Factors of Cardiovascular Disease and Cancer: Evidence for Joint Prevention.

Cardiovascular disease (CVD) and cancer are leading causes of mortality and morbidity worldwide and are the major focus of the World Health Organization's joint prevention programs. While, diverse diseases, CVD and cancer, have many similarities. These include common lifestyle-related risk factors and shared environmental, metabolic, cellular, inflammatory, and genetic pathways. In this review, we will discuss the shared lifestyle-related and environmental risk factors central to both diseases and how the strategies commonly used to prevent atherosclerotic vascular disease can be applied to cancer prevention.

Antimicrobial activity and wound healing effect of a novel natural ointment: an in vitro and in vivo study.

Infection and pathological disorders, such as cellular disorders, ischaemia, neuropathy and angiogenesis, are considered the most critical factors which cause a delay in the wound healing process in patients with diabetes. This study aimed to investigate the effect of an ointment based on ostrich oil containing honey, beeswax, and ethanolic extracts of Nigella sativa, propolis and Cassia angustifolia on the wound healing process of diabetic rats. Gas chromatography/mass spectrometry analysis showed caffeic acid and pinostrobin chalcone molecules present in propolis, giving antibacterial and antifungal properties to the compound. The antibacterial assessment showed the ointment had remarkable antibacterial activity against Staphylococcus aureus (8.6±0.28mm), Escherichia coli (9.4±0.31mm), Acinetobacter baumannii (7.2±0.23mm) and Pseudomonas aeruginosa (13.9±0.42mm). In vivo results showed the ointment significantly accelerated wound healing and increased collagen deposition compared with the control (p<0.05). Histopathology evaluation also showed hair follicles, sebaceous glands and vessels in the group that used the ointment. These results proved successful and diabetic wound healing was rapid. Therefore, it could be concluded that the fabricated ointment could be a suitable candidate for wound healing.

The Association of Thyroid-Stimulating Hormone (TSH) Levels and Lipid Profile in Euthyroid Patients with Familial Hypercholesterolemia.

Previous studies reported a relationship between thyroid-stimulating hormone (TSH) and low-density lipoprotein cholesterol (LDL-C) levels. In this study, we aim to evaluate the impact of TSH levels on lipid profile in patients with familial hypercholesterolemia (FH) and euthyroid state. Patients were selected from the Isfahan FH registry. The Dutch Lipid Clinic Network (DLCN) criteria are used to detect FH. Patients were classified into no FH, possible FH, probable FH, and definite FH groups based on the DLCN scores. Patients with any cause of secondary hyperlipidemia, including hypothyroidism, were excluded from this study. The study group consisted of 103 patients with possible FH, 25 patients with definite FH, and 63 individuals with no FH. The mean TSH and LDL-C levels among participants were 2.10 ± 1.22 mU/l and 142.17 ± 62.56 mg/dl, respectively. No positive or negative correlation was found between serum TSH and total cholesterol (P value = 0.438), high-density lipoprotein cholesterol (P = 0.225), triglycerides (P value = 0.863), and LDL-C (P value = 0.203). We found no correlation between serum TSH levels and lipid profiles in euthyroid patients with FH.

A comprehensive review on novel targeted therapy methods and nanotechnology-based gene delivery systems in melanoma.

Melanoma, a malignant form of skin cancer, has been swiftly increasing in recent years. Although there have been significant advancements in clinical treatment underlying a well-understanding of melanoma-susceptible genes and the molecular basis of melanoma pathogenesis, the permanency of response to therapy is frequently constrained by the emergence of acquired resistance and systemic toxicity. Conventional therapies, including surgical resection, chemotherapy, radiotherapy, and immunotherapy, have already been used to treat melanoma and are dependent on the cancer stage. Nevertheless, ineffective side effects and the heterogeneity of tumors pose major obstacles to the therapeutic treatment of malignant melanoma through such strategies. In light of this, advanced therapies including nucleic acid therapies (ncRNA, aptamers), suicide gene therapies, and gene therapy using tumor suppressor genes, have lately gained immense attention in the field of cancer treatment. Furthermore, nanomedicine and targeted therapy based on gene editing tools have been applied to the treatment of melanoma as potential cancer treatment approaches nowadays. Indeed, nanovectors enable delivery of the therapeutic agents into the tumor sites by passive or active targeting, improving therapeutic efficiency and minimizing adverse effects. Accordingly, in this review, we summarized the recent findings related to novel targeted therapy methods as well as nanotechnology-based gene systems in melanoma. We also discussed current issues along with potential directions for future research, paving the way for the next-generation of melanoma treatments.

The Effects of 4-Week Aerobic Exercise on the Levels of CCl2, CCl5, and their Respective Receptors in Female BALB/C Mice Suffering from Breast Cancer.

Background: The studies reported that chemokines Chemokine (C-C motif) ligand 2 (CCL2) and Chemokine (C-C motif) ligand 5 (CCL5) have tumor-promoting roles in breast cancer (BC). The aim of the present study was to evaluate the effect of 4 weeks of continuous aerobic exercise (AE) on chemokines CCL2 and CCL5 and their relative receptors in animal model of human BC. Materials and Methods: BALB/c mice were divided randomly into four groups included cancer control (CC) and three other groups. The total duration of the experiment was 14 weeks, including 2 weeks of familiarization of mice with treadmills and three of 4-week periods of experiment. Tumor inoculation and formation were performed in the second 4-week period. Group 1 received AE in the first 4-week, Group 2 received AE in the second 4-week and Group 3 in the third 4-week. Results: The CCL2 was reduced significantly in Groups 1, 2, and 3 compared to control (F3,12= 4705, P = 0.0001). In terms of CCL5, a significant decrease was seen only between Group 3 and control. Western blot results showed a significant reduction in C-C chemokine receptor Type 2 (CCR2) between Group 1 versus CC and Group 2 versus CC (F3,20= 1.812, P = 0.004). In terms of C-C chemokine receptor Type 5 (CCR5) a significant decrease was observed between Group 2 versus control and Group 3 versus control (F3,20= 273.3, P = 0.042), (P = 0.004). Conclusion: It can be concluded that 4-week AE significantly reduces the chemokines CCL2 and CCL5 and their respective receptors levels CCR5 and CCR2 in different stages, and it may have an inhibitory effect on tumor growth.

Corrigendum to "Hematological Inflammatory Markers in Patients with Clinically Confirmed Familial Hypercholesterolemia".

[This corrects the article DOI: 10.1155/2022/5051434.].

Effect of serum magnesium levels on outcomes of patients hospitalized with COVID-19.

BACKGROUND:  The coronavirus disease 2019 (COVID-19) causes acute respiratory illness and multi-organ failure. The critical roles of magnesium in human health suggest that it could have an active role in the prevention and treatment of COVID-19. We measured magnesium levels in hospitalized COVID-19 patients concerning disease progression and mortality. MATERIALS AND METHODS:  This study was conducted in 2321 hospitalized COVID-19 patients. Clinical characteristics from each patient were recorded, and blood samples were collected from all patients upon their first admission to the hospital to determine serum magnesium levels. Patients were divided into two groups based on discharge or death. The effects of magnesium on death, severity, and hospitalization duration were estimated by crude and adjusted odds ratio using Stata Crop (version 12) software. RESULTS:  Mean magnesium levels in patients who died were higher than in discharged patients (2.10 vs 1.96 mg/dl, p 0.05). CONCLUSIONS: We found no relation between hypomagnesaemia on COVID-19 progression, although hypermagnesaemia could affect COVID-19 mortality (Tab. 4, Ref. 34).

Morphine upregulates Toll-like receptor 4 expression and promotes melanomas in mice.

BACKGROUND: Morphine and other opioids are used to manage cancer-related pain; however, the role of these drugs in cancer progression remains controversial. Emerging evidence indicates that morphine can activate Toll-like receptor 4 (TLR4) and its signaling pathways, by the way the activation and expression of TLR4 can promote melanoma. In this study, we investigated the effects of morphine on the expression of TLR4 and promotion of melanoma in mice. METHODS: Mice melanoma cells (B16F10) were cultured with morphine (0.1, 1 and 10 µM) for 24 h. In the other experiment, cells were treated with morphine with or without TLR4 agonist (LPS) or antagonist (TAK-242). In in-vivo model, B16F10 cells were subcutaneously injected to C57BL/6 mice, and morphine was administrated in three different treatment protocols after developing palpable tumors (acute treatment, chronic daily injections, escalating doses of morphine). In another set of experiments, B16F10 cells were pretreated with LPS (5 µg/ml) 24 h before injection into mice. Control group received normal saline. We measured cell proliferation, the expression level of Tlr4, Nuclear factor kappa-light-chain-enhancer of activated B cells 1 (Nf-κb1) genes, TLR4 protein expression, and tumor volume. RESULTS: Chronic, acute, and escalating doses of morphine increased tumor. Morphine increased the expression of Tlr4 and Nf-κb1 regardless of the treatment protocol used. CONCLUSION: Morphine increases the progression of melanoma cancer and may be related to the increased expression of TLR4. Our results suggest that morphine should be used with caution in patients with melanoma.HighlightsMorphine increases the expression of TLR4 in melanoma.Morphine increases melanoma progression.These effects are mostly observed with chronic and escalating morphine administration.

Comorbidities with Familial Hypercholesterolemia (FH): A Systematic Review.

Familial hypercholesterolemia (FH) is linked to high levels of low-density lipoprotein cholesterol (LDL-C), atherosclerotic, and aortic stenosis to a lesser extent. We looked at the incidence of prevalent comorbid disorders other than cardiovascular disease (CVD), such as diabetes, chronic kidney disease (CKD), hypertension, and cancer in heterozygous FH (HeFH) patients. PubMed, Web of Science, and Google Scholar were searched systematically for studies reporting comorbidities in FH patients. Finally, 23 studies were included after excluding duplicates, papers with unrelated titles, reviews, abstracts, and papers with not sufficient data. Results showed that among the comorbidities that have been studied; FH patients had a greater prevalence of CKD. In terms of diabetes, the data are inconsistent, with some research indicating a higher prevalence of diabetes in FH patients and mostly indicating the opposite. Polymorphism study showed that hypertension has been linked to FH; however, the prevalence of the hypertensive subjects varies among FH groups. In comparison to the general population, cancer was found to have a lower or similar prevalence in FH patients. More research is needed in this area due to the variability of the results of the relationship between diabetes and FH and the small number of studies on cancer. In conclusion only CKD can be considered as an important and prevalent comorbidity in FH population after CVDs.

Effect of Oat (Avena sativa L.) Consumption on Lipid Profile With Focus on Triglycerides and High-density Lipoprotein Cholesterol (HDL-C): An Updated Systematic Review.

Hypercholesterolemia is a significant risk factor for heart disease. The soluble fiber in oat (Avena sativa L.), beta-glucan has been shown to significantly lower serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels but not triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) according to previous studies, reviews, and meta-analyses. However, the effect of oat consumption on the TG and HDL-C is controversial and has not been expanded enough. We did this review study to find out about the effect of oat on lipid profile especially TG and HDL-C more specifically and meticulously with their details. After searching PubMed, Web of Science, and Google scholar we included 17 studies in our review. Our results similar to other reviews showed that oat reduced the TC, VLDL, and LDL-C more significantly than TG. Of 17 included studies 6 studies reported reduction of TG level, and only 1 study reported HDL-C improvement followed by oat consumption. A more detailed review of studies that reported positive effects of oat/ beta-glucan consumption on TG showed that in healthy people with normal lipid profile oat intake might reduce TG effectively and also in overweight people/those with diabetes or metabolic syndrome if a higher amount of oat or/and longer duration applied. Consuming oat in conjunction with calorie-reducing diets or using it with DHA can cause a significant TG reduction. It may be concluded that, in addition to lowering TC and LDL-C, a considerable improvement in TG or HDL-C can be accomplished by adjusting factors such as oat consumption dose or consumption duration or utilizing oat in conjunction with a proper diet program. To conclude, more research on this topic is required.

Morphine promotes migration and lung metastasis of mouse melanoma cells.

BACKGROUND: Morphine is an analgesic agent used for cancer pain management. There have been recent concerns that the immunosuppressant properties of morphine can also promote cancer metastasis. Morphine is an agonist for toll like receptor 4 (TLR4) that has a dual role in cancer development. The promotor or inhibitor role of morphine in cancer progression remains controversial. We investigated the effects of morphine on migration and metastasis of melanoma cells through TLR4 activation. METHODS: Mouse melanoma cells (B16F10) were treated with only morphine (0, 0.1, 1, and 10 µM) or in combination with a TLR4 inhibitor (morphine10 µM +CLI-095 1µM) for either 12 or 24 hours. Migration of cells was analyzed by transwell migration assays. Twenty C57BL/6 male mice were inoculated with B16F10 cells via the left ventricle of the heart and then randomly divided into two groups (n = 10 each) that received either morphine (10 mg.kg-1, sub-q) or PBS injection for 21 days (control group). Animals were euthanized and their lungs removed for evaluation of metastatic nodules. RESULTS: Morphine (0.1, 1, and 10 µM) increased cell migration after 12 hours (p < 0.001) and after 24 hours of treatment with morphine (10 µM) (p < 0.001). Treatment with CLI-095 suppressed migration compared to cells treated with morphine alone (p < 0.001). Metastatic nodules in the morphine-treated group (64 nodules) were significantly higher than in the control group (40 nodules) (p < 0.05). CONCLUSION: Morphine increases the migration and metastasis of mouse melanoma cells by activating TLR4.

The effects of morphine on vascular cell adhesion molecule 1(VCAM-1) concentration in lung cancer cells.

OBJECTIVE: Vascular cell adhesion molecule 1 (VCAM-1) plays an important role in tumour cell adhesion to endothelial cells. Some tumour cells also show aberrant expression of VCAM-1. Toll-like receptor 4 (TLR4) agonists can increase VCAM-1 expression. Morphine, an opioid receptor agonist, is also a TLR4 agonist. In this study, we aimed to evaluate whether morphine increase VCAM-1 expression in a TLR4 dependent manner. METHODS: A549 Lung cancer cells were treated with different doses of morphine and TLR4 antagonist for 24 and 48 h. TLR4 gene expression was evaluated by real-time PCR and VCAM-1 protein was measured by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Morphine enhanced mRNA expression of TLR4 and protein level of VCAM-1. TLR4 antagonist returned VCAM-1expression to the normal level. CONCLUSION: Morphine effects VCAM-1expressions via TLR4 in lung cancer cell line.

The potential interplay between opioid and the toll-like receptor 4 (TLR-4).

CONTEXT: Opioids are available for the management of severe and chronic pain. However, long-term use of high-dose opioids could lead to physiologic tolerance, hyperalgesia, gastrointestinal immobility, addiction, respiratory depression, tumor progression, and inhibition of the immune system. It seems some of these adverse effects of opioids might be induced by TLR-4 signaling. OBJECTIVE: The review aims to investigate the potential interplay between opioids and TLR-4 in CNS, gastrointestinal, cancer, and immune system. METHODS: The search of PubMed, Embase, Scopus, web of sciences, and Google scholar was performed for all relevant studies published. From a total of 513 papers obtained at the initial database search, publications including in silico, in vitro, and in vivo studies were selected for the review. RESULTS: A comprehensive review of studies indicated that using opioids for the reduction of pain might induce adverse effects such as analgesic tolerance, hyperalgesia, cancer progression, and suppression of the immune system. Some studies have indicated these effects may be due to a change in the level of expression and signaling pathway of TLR-4. The generalizability of the results was limited due to the inconsistency of findings. CONCLUSIONS: More studies are needed to clarify TLR-4-mediated opioid effects on the biology or stages of the disease as well as the role of different types of opioids, appropriate dosage, and exposure in various contexts. Designing the drug candidate and doing many formulation studies for different diseases and various stages of disease could be associated with effective treatment and pain management.

Morphine promotes migration and lung metastasis of mouse melanoma cells

Abstract Background Morphine is an analgesic agent used for cancer pain management. There have been recent concerns that the immunosuppressant properties of morphine can also promote cancer metastasis. Morphine is an agonist for toll like receptor 4 (TLR4) that has a dual role in cancer development. The promotor or inhibitor role of morphine in cancer progression remains controversial. We investigated the effects of morphine on migration and metastasis of melanoma cells through TLR4 activation. Methods Mouse melanoma cells (B16F10) were treated with only morphine (0, 0.1, 1, and 10 μM) or in combination with a TLR4 inhibitor (morphine10 μM +CLI-095 1μM) for either 12 or 24 hours. Migration of cells was analyzed by transwell migration assays. Twenty C57BL/6 male mice were inoculated with B16F10 cells via the left ventricle of the heart and then randomly divided into two groups (n = 10 each) that received either morphine (10 mg.kg−1, sub-q) or PBS injection for 21 days (control group). Animals were euthanized and their lungs removed for evaluation of metastatic nodules. Results Morphine (0.1, 1, and 10 μM) increased cell migration after 12 hours (p < 0.001) and after 24 hours of treatment with morphine (10 μM) (p < 0.001). Treatment with CLI-095 suppressed migration compared to cells treated with morphine alone (p < 0.001). Metastatic nodules in the morphine-treated group (64 nodules) were significantly higher than in the control group (40 nodules) (p < 0.05). Conclusion Morphine increases the migration and metastasis of mouse melanoma cells by activating TLR4.

Low-Dose Atorvastatin has Promoting Effect on Melanoma Tumor Growth and Angiogenesis in Mouse Model.

Background: Preclinical evidence indicates that statins possess diverse antineoplastic effects in different types of tumors. However, clinical studies have yielded conflicting results regarding the potential of statins to either increase or decrease the risk of cancer. Our objective was to examine the relationship between the dose of a treatment and its impact on melanoma tumor growth and angiogenesis in an in vivo setting. Materials and Methods: Melanoma cells were injected into C57BL6 mice in four groups. They received 0, 1, 5, and 10 mg/kg of atorvastatin daily. Three others received the mentioned doses one week before the inoculation of melanoma animals. At the end of the third week, the animals were euthanized in a humane manner, and both blood samples and tumor specimens were collected for subsequent analysis. Results: The tumor size was 1.16 ± 0.25 cm3 in a group treated with therapeutic dose of atorvastatin and was significantly larger than that in the control group (0.42 ± 0.08 cm3). However, there were no significant differences between the two other doses and the control group (0.72 ± 0.22, 0.46 ± 0.08 cm3 in atorvastatin-treated groups with 5 and 10 mg/kg). The vascular density of the tumors was significantly increased in the lowest dose of the atorvastatin treatment group, similar to the results of tumor size (P < 0.05). Conclusion: Atorvastatin, at low therapeutic concentrations, has been observed to stimulate tumor growth and exhibit pro-angiogenic effects. Therefore, it is advised to exercise caution and recommend clinically relevant doses of statins to patients with cancer.