The nexus of natural killer cells and melanoma tumor microenvironment: crosstalk, chemotherapeutic potential, and innovative NK cell-based therapeutic strategies.

The metastasis of melanoma cells to regional lymph nodes and distant sites is an important contributor to cancer-related morbidity and mortality among patients with melanoma. This intricate process entails dynamic interactions involving tumor cells, cellular constituents, and non-cellular elements within the microenvironment. Moreover, both microenvironmental and systemic factors regulate the metastatic progression. Central to immunosurveillance for tumor cells are natural killer (NK) cells, prominent effectors of the innate immune system with potent antitumor and antimetastatic capabilities. Recognizing their pivotal role, contemporary immunotherapeutic strategies are actively integrating NK cells to combat metastatic tumors. Thus, a meticulous exploration of the interplay between metastatic melanoma and NK cells along the metastatic cascade is important. Given the critical involvement of NK cells within the melanoma tumor microenvironment, this comprehensive review illuminates the intricate relationship between components of the melanoma tumor microenvironment and NK cells, delineating their multifaceted roles. By shedding light on these critical aspects, this review advocates for a deeper understanding of NK cell dynamics within the melanoma context, driving forward transformative strategies to combat this cancer.

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.

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).

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.

A meta-analysis of microRNA expression profiling studies in heart failure.

Heart failure (HF) is a major consequence of many cardiovascular diseases with high rate of morbidity and mortality. Early diagnosis and prevention are hampered by the lack of informative biomarkers. The aim of this study was to perform a meta-analysis of the miRNA expression profiling studies in HF to identify novel candidate biomarkers or/and therapeutic targets. A comprehensive literature search of the PubMed for miRNA expression studies related to HF was carried out. The vote counting and robust rank aggregation meta-analysis methods were used to identify significant meta-signatures of HF-miRs. The targets of HF-miRs were identified, and network construction and gene set enrichment analysis (GSEA) were performed to identify the genes and cognitive pathways most affected by the dysregulation of the miRNAs. The literature search identified forty-five miRNA expression studies related to CHF. Shared meta-signature was identified for 3 up-regulated (miR-21, miR-214, and miR-27b) and 13 down-regulated (miR-133a, miR-29a, miR-29b, miR-451, miR-185, miR-133b, miR-30e, miR-30b, miR-1, miR-150, miR-486, miR-149, and miR-16-5p) miRNAs. Network properties showed miR-29a, miR-21, miR-29b, miR-1, miR-16, miR-133a, and miR-133b have the most degree centrality. GESA identified functionally related sets of genes in signaling and community pathways in HF that are the targets of HF-miRs. The miRNA expression meta-analysis identified sixteen highly significant HF-miRs that are differentially expressed in HF. Further validation in large patient cohorts is required to confirm the significance of these miRs as HF biomarkers and therapeutic targets.

Magnesium intake and lung cancer risk: A systematic review and meta-analysis.

Magnesium may reduce the risk of lung cancer by affecting cell proliferation, inflammation and by preserving lung function; however, the results of epidemiological studies on the potential benefits of magnesium in lung pathology are inconclusive. We conducted this meta-analysis to investigate the association between magnesium intake and the risk of lung cancer. A total of 5 studies were extracted from PubMed, SCOPUS, and the Cochrane Review (to May 2018). These studies involved 58,5821 participants with 8,977 lung cancer cases. The pooled relative risk (RR) indicated a significant association between lung cancer incidence and magnesium intake (RR = 0.88, 95% CI = 0.79 to 0.98; p = 0.018). To investigate the cause of heterogeneity of these studies (I2 = 75.8%, p < 0.001), we performed a subgroup analysis which was affected by the mean dose of magnesium intake, where doses of magnesium intake lower than 300 mg/d significantly decreased lung cancer risk (RR = 0.83, 95% CI = 0.70 to 0.99; p = 0.034). Increasing magnesium intake doses to over 300 mg/d did not reduce the incidence of lung cancer (RR = 0.89, 95% CI = 0.78 to 1.01; p = 0.076). Our meta-analysis suggests that magnesium intake of less than 300 mg/d may have protective effects in lung cancer.

PPAR γ agonist, pioglitazone, suppresses melanoma cancer in mice by inhibiting TLR4 signaling.

BACKGROUND: Although previous studies demonstrated an anticancer effect for the ligands of peroxisome proliferator-activated receptor gamma (PPARγ) through activation of its anti-inflammatory responses, nevertheless the anti-tumor mechanism of PPARγ has not been intensively investigated. One of the molecules involved in cancer progression is toll-like receptor 4 (TLR4). METHODS: B16F10 melanoma cells were cultured with or without LPS for 24 hr. The cells were subcutaneously injected to two groups of C57BL/6 mice. After the development of palpable tumors each group of animals were divide to four sub-groups and received pioglitazone in different dose ranges (0,10,50,100 mg/kg/day) for 10 days. At the end of the study, the expression of Tlr4, Myd-88, Nf-kb1 genes was evaluated by qRT-PCR in different groups in mice tumor. The TLR-4 protein expression was evaluated by IHC. TNF-α level in mice tumor and serum were measured by ELISA kits. Tumor volume was measured with Vernier calipers. RESULTS: We observed that activation of PPARγ by its agonist, pioglitazone, reduces tumor volume, Tlr-4, Myd-88, Nf-kb1 mRNA expression, TLR4 protein expression and TNF-α production in melanoma tumor especially in groups that were injected with LPS -stimulated cells. Moreover, treatment of melanoma cells with pioglitazone showed that the inhibitory effects of pioglitazone on LPS-induced inflammatory responses were TLR4 dependent. CONCLUSIONS: The results indicate that pioglitazone, a PPARγ agonist, has a beneficial protective effect against melanoma via interfering with the TLR4-dependent signaling pathways.

Evolocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, promotes angiogenesis in vitro.

The proprotein convertases family is involved in several physiological processes such as cell growth, migration, and angiogenesis, and also in different pathological conditions. Evolocumab, an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9), has recently been approved for treatment of hypercholesterolemia. This study aimed to investigate the effect of evolocumab on angiogenesis in human umbilical vein endothelial cells (HUVECs). Cell proliferation and migration were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell methods. In vitro angiogenesis was assessed by tube formation assay. Vascular endothelial growth factor (VEGF) secretion by HUVECs was also determined using an enzyme-linked immunosorbent assay kit. Evolocumab significantly increased HUVECs viability at 100 µg/mL. Significant enhancement in cell migration, and mean tubules length and size was observed at the concentrations of 10 and 100 µg/mL and also in mean number of junctions at the concentration of 100 µg/mL. Administration of evolocumab at the concentration of 10 µg/mL increased VEGF release into supernatants of HUVECs. Findings of this investigation provided in vitro evidence for pro-angiogenic activity of evolocumab through promoting cell proliferation, migration, tubulogenesis, and VEGF secretion in HUVECs.

The dual role of Nrf2 in melanoma: a systematic review.

Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis remains poor. To improve current therapies and patients outcome, it is necessary to identify the influential elements in the development and progression of melanoma.Due to UV exposure and melanin synthesis, the melanocytic lineage seems to have a higher rate of ROS (reactive oxygen species) formation. Melanoma has been linked to an increased oxidative state, and all facets of melanoma pathophysiology rely on redox biology. Several redox-modulating pathways have arisen to resist oxidative stress. One of which, the Nrf2 (nuclear factor erythroid 2-related factor 2), has been recognized as a master regulator of cellular response to oxidative or electrophilic challenges. The activation of Nrf2 signaling causes a wide range of antioxidant and detoxification enzyme genes to be expressed. As a result, this transcription factor has lately received a lot of interest as a possible cancer treatment target.On the other hand, Nrf2 has been found to have a variety of activities in addition to its antioxidant abilities, constant Nrf2 activation in malignant cells may accelerate metastasis and chemoresistance. Hence, based on the cell type and context, Nrf2 has different roles in either preventing or promoting cancer. In this study, we aimed to systematically review all the studies discussing the function of Nrf2 in melanoma and the factors determining its alteration.

Leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Obesity may create a mitogenic microenvironment that influences tumor initiation and progression. The obesity-associated adipokine, leptin regulates energy metabolism and has been implicated in cancer development. It has been shown that some cell types other than adipocytes can express leptin and leptin receptors in tumor microenvironments. It has been shown that peroxisome proliferator-activated receptors (PPAR) agonists can affect leptin levels and vice versa leptin can affect PPARs. Activation of PPARs affects the expression of several genes involved in aspects of lipid metabolism. In addition, PPARs regulate cancer cell progression through their action on the tumor cell proliferation, metabolism, and cellular environment. Some studies have shown an association between obesity and several types of cancer, including breast cancer. There is some evidence that suggests that there is crosstalk between PPARs and leptin during the development of breast cancer. Through a systematic review of previous studies, we have reviewed the published relevant articles regarding leptin signaling in breast cancer and its crosstalk with peroxisome proliferator-activated receptors α and γ.

Carbon dot incorporated mesoporous silica nanoparticles for targeted cancer therapy and fluorescence imaging.

A new and efficient theranostic nanoplatform was developed via a green approach for targeted cancer therapy and fluorescence imaging, without the use of any anticancer chemotherapeutic drugs. Toward this aim, monodisperse and spherical mesoporous silica nanoparticles (MSNs) of approximately 50 nm diameter were first synthesized using the sol-gel method and loaded with hydrothermally synthesized anticancer carbon dots (CDs). The resulting MSNs-CDs were then functionalized with chitosan and targeted by an anti-MUC1 aptamer, using the glutaraldehyde cross-linker, and fully characterized by TEM, FE-SEM, EDS, FTIR, TGA, XRD, and BET analysis. Potent and selective anticancer activity was obtained against MCF-7 and MDA-MB-231 cancer cells with the maximum cell mortalities of 66.2 ± 1.97 and 71.8 ± 3%, respectively, after 48 h exposure with 100 µg mL-1 of the functionalized MSNs-CDs. The maximum mortality of 40.66 ± 1.3% of normal HUVEC cells was obtained under the same conditions. Based on the results of flowcytometry analysis, the apoptotic mediated cell death was recognized as the main anticancer mechanism of the MSNs-CDs. The fluorescence imaging of MCF-7 cancer cells was also studied after exposure with MSNs-CDs. The overall results indicated the high potential of the developed nanoplatform for targeted cancer theranostics.

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.

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.

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 effect of Aloe vera leaf gel on fatty streak formation in hypercholesterolemic rabbits.

BACKGROUND: Atherosclerosis is a complex disease that is associated with a variety of etiologic factors such as hyperlipidemia and inflammation. Aloe vera (Liliaceae family) has been used traditionally as an anti-inflammatory drug. The aims of this survey were to define the beneficial effects of Aloe vera leaf gel on some of the atherosclerosis risk factors, and also fatty streak formation in hypercholesterolemic rabbits. MATERIALS AND METHODS: [corrected] 32 white male rabbits were randomly divided into four experimental groups (n = 8, each). During the study, the animals had a standard diet (control group), high cholesterol diet (HC group), high cholesterol diet with Aloe vera leaf gel (3.2%v/v) (HC+ Aloe group) and Aloe vera leaf gel (Aloe group) for 30 days. Fasting blood samples were collected from all animals at the beginning and end of the study. Then total cholesterol (TC), fasting blood sugar (FBS), triglyceride (TG) and CRP were measured before and after experimental periods. By the end of the study, the aortas were removed and investigated for atherosclerosis plaque formation. RESULTS: Significant differences were observed in TC and CRP levels of the high-cholesterol diet with Aloe vera and the high-cholesterol diet alone (p < 0.05). The formation of fatty streaks in the aorta was also significantly lower in the same animals under the influence of dietary Aloe vera(p < 0.05). The control and Aloe group did not show any evidence of atherosclerosis. No significant difference was found between the groups in TG and FBS. CONCLUSIONS: The data suggests that Aloe vera has beneficial effects on the prevention of fatty streak development; it may reduce the development of atherosclerosis through modification of risk factors. However, further studies are needed to understand the mechanisms whereby this plant exerts its anti-atherosclerotic effects.

Effect of Anti-Podoplanin on Malignant Glioma Cell Viability, Invasion and Tumor Cell-Induced Platelet Aggregation.

BACKGROUND: The transmembrane receptor podoplanin (PDPN) is a platelet aggregation-inducing factor, which is widely expressed in various malignant tumors such as squamous cell carcinomas, mesotheliomas, glioblastomas. Podoplanin regulates a pathway leading to cell invasion and migration. Glioblastoma multiforme (GBM) is the most aggressive and invasive tumor of the central nervous system. A high level of PDPN expression has been reported to be associated with reduced survival, cancer aggression and migration. Aim of study to determine the effect of anti-podoplanin antibody on cell-platelet aggregation, cell invasion and viability in Uppsala 87 malignant glioma (U87MG) cell lines. METHODS: The expression of podoplanin on U87MG cells was measured using flowcytometry. The dimethyl-thiazol diphenyl-tetrazolium bromide (MTT) assay was used to measure U87MG cell proliferation after treatment by anti-podoplanin monoclonal antibody (NZ-1.3). The invasion of cancer cells was assessed by using a novel microfluidic based assay. RESULTS: The results show reduction of cell viability and cell migration after treatment with anti-podoplanin antibody. After co- treatment of U87MG cells and platelets with and without anti-podoplanin antibody, the cell-platelet aggregation was significantly reduced in anti-podoplanin treated cell. CONCLUSIONS: Podoplanin is involved in aggregation of gliobastoma cells, and their viability and invasion and its neutralizing antibody can inhibit this process. So, blocking of podoplanin may be representing a promising therapeutic approach to glioblastoma multiform cancer therapy.

Vitamin D Level in Laboratory Confirmed COVID-19 and Disease Progression.

OBJECTIVE: There is no conclusive evidence to suggest vitamin D level can prevent or treat infection with the new coronavirus disease 2019. This study aimed to investigate the effects of serum level of vitamin D in patients with coronavirus disease 2019 on death, severity, and hospitalization duration. MATERIALS AND METHODS: Baseline characteristic of patients was extracted from the Isfahan coronavirus disease 2019 registry database (I-CORE). Blood samples were taken from all patients to measure the level of vitamin D (25-hydroxyvitamin D) and categorized. The effect of 25(OH) D on death, severity, and hospitalization duration was analyzed by logistic regression. RESULTS: Among our study patients, 5.5% had a severe deficiency of vitamin D, 23.7% deficiency, and 24.8% insufficiency. Of the 107 patients who died, 7.5% were severely deficient in vitamin D. We found that vitamin D deficiency had no significant effect on death, disease severity, and hospitalization (P > .05). However, having at least one comorbidity increased the odds of death five times after adjusting age > 60 years and gender (P < .0001). The results showed that among all comorbidities, diabetes has the greatest impact on the outcomes as it raised the odds of death, disease severity, and length of hospital stay by 2.23,1.72, and 1.48, respectively, after controlling the age > 60 and gender (P = .0002, P=.08, P=.012). CONCLUSIONS: The mortality, disease severity, and hospitalization of coronavirus disease 2019 patients seem to be not affected by the low levels of 25(OH)D. However, the synergy between vitamin D levels and comorbidities, age, and gender could affect the outcome of coronavirus disease 2019 patients.

Cancer Occurrence as the Upcoming Complications of COVID-19.

Previous studies suggested that patients with comorbidities including cancer had a higher risk of mortality or developing more severe forms of COVID-19. The interaction of cancer and COVID-19 is unrecognized and potential long-term effects of COVID-19 on cancer outcome remain to be explored. Furthermore, whether COVID-19 increases the risk of cancer in those without previous history of malignancies, has not yet been studied. Cancer progression, recurrence and metastasis depend on the complex interaction between the tumor and the host inflammatory response. Extreme proinflammatory cytokine release (cytokine storm) and multi-organ failure are hallmarks of severe COVID-19. Besides impaired T-Cell response, elevated levels of cytokines, growth factors and also chemokines in the plasma of patients in the acute phase of COVID-19 as well as tissue damage and chronic low-grade inflammation in "long COVID-19" syndrome may facilitate cancer progression and recurrence. Following a systemic inflammatory response syndrome, some counterbalancing compensatory anti-inflammatory mechanisms will be activated to restore immune homeostasis. On the other hand, there remains the possibility of the integration of SARS- CoV-2 into the host genome, which potentially may cause cancer. These mechanisms have also been shown to be implicated in both tumorigenesis and metastasis. In this review, we are going to focus on potential mechanisms and the molecular interplay, which connect COVID-19, inflammation, and immune-mediated tumor progression that may propose a framework to understand the possible role of COVID-19 infection in tumorgenesis and cancer progression.

Activation of PPARγ Inhibits TLR4 Signal Transduction Pathway in Melanoma Cancer In Vitro.

Purpose: Although peroxisome proliferator-activated receptor γ (PPARγ) is known as a regulator of fatty acid storage, fat cell differentiation, glucose and lipid metabolism, recent studies show that PPARγ has anticancer effects. The mechanisms of PPARγ activation in melanoma cancer remain unclarified. Recently, increased TLR4 expression has been associated with the melanoma cancer progression. We investigated whether the anti-cancer effect of PPARγ is through regulating TLR4 signaling pathway. Methods: Mouse melanoma cells (B16F10) were treated in different groups: control, pioglitazone (1, 10, 100, 300 µmol/L), lipopolysaccharide (LPS) (5 µg/mL) and LPS + pioglitazone. In another experiment, they were treated with CLI-095 (1 µM), and after 1 hour pioglitazone was added and subsequently stimulated with LPS. MTT assay was performed to measure the cell viability in vitro. The expression of Tlr4, Myd88, Nf-κb genes were evaluated by quantitative reverse transcription PCR (qRT-PCR) in different groups. The concentration of tumor necrosis factor alpha and Interleukin 1 beta in the cell culture medium were measured by enzyme-linked immunosorbent assay (ELISA) kits. Results: We show that activation of PPARγ by its agonist, pioglitazone, reduces cell proliferation, Tlr-4, Myd-88, Nf-kb mRNA expression, and tumor necrosis factor-alpha (TNF-α) production but not interleukin-1 ß (IL-1ß) in B16F10 LPS-stimulated cells in vitro. Moreover, treatment of B16F10 cells with TLR4 inhibitor prior treatment with pioglitazone indicate that the anticancer effects of pioglitazone on melanoma cells was dependent on TLR4. Conclusion: The results indicate that pioglitazone has a beneficial protective effect against melanoma by affecting the TLR4 signaling pathway.

Effects of standardized Cannabis sativa extract and ionizing radiation in melanoma cells in vitro.

CONTEXT: Melanoma causes the highest number of skin cancer-related deaths worldwide. New treatment methods are essential for the management of this life-threatening disease. AIMS: In this study, we investigated the efficacy of a standardized Cannabis sativa extract alone or in combination with single radiation dose (6 Gy) in B16F10 mouse melanoma cells in an extract dose-dependent manner. MATERIALS AND METHODS: C. sativa extract at three concentrations (25, 12.5, and 6.25 µg/mL) alone for 72 h or in combination with radiation (24 h incubation after the extract treatment + 48 h incubation after exposure to radiation) were evaluated for cell viability of melanoma cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cells were also treated with 6.25 µg/mL extract alone for 72 h before analyzing C. sativa-induced cell death by flow cytometry. RESULTS: Administration of the extract alone or alongside radiation substantially inhibited melanoma cell viability and proliferation in the extract dose response-dependent manner. The inhibition of melanoma cell viability was paralleled by an increase in necrosis but not apoptosis when melanoma cells were treated with the extract alone. Radiation alone did not have any antiproliferative effects, and radiation also did not synergize antiproliferative effects of the extract when the extract and radiation were combined. CONCLUSION: Our data suggest that C. sativa extract may have significant health and physiological implications for the treatment of melanoma. The results of this study also indicate that B16F10 mouse melanoma cells are radioresistant. Taken together, these findings may lead to the identification of new therapeutic strategy for the management of melanoma.