Immune checkpoint inhibitors in the treatment of hepatocellular carcinoma.

Despite advances in cancer treatment, hepatocellular carcinoma (HCC), the most common form of liver cancer, remains a major public health problem worldwide. The immune microenvironment plays a critical role in regulating tumor progression and resistance to therapy, and in HCC, the tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells and signals that facilitate immune evasion and metastasis. Recently, anti-cancer immunotherapies, therapeutic interventions designed to modulate the immune system to recognize and eliminate cancer, have become an important cornerstone of cancer therapy. Immunotherapy has demonstrated the ability to improve survival and provide durable cancer control in certain groups of HCC patients, while reducing adverse side effects. These findings represent a significant step toward improving cancer treatment outcomes. As demonstrated in clinical trials, the administration of immune checkpoint inhibitors (ICIs), particularly in combination with anti-angiogenic agents and tyrosine kinase inhibitors, has prolonged survival in a subset of patients with HCC, providing an alternative for patients who progress on first-line therapy. In this review, we aimed to provide an overview of HCC and the role of the immune system in its development, and to summarize the findings of clinical trials involving ICIs, either as monotherapies or in combination with other agents in the treatment of the disease. Challenges and considerations regarding the administration of ICIs in the treatment of HCC are also outlined.

Relationship between immune checkpoint proteins and neoadjuvant chemotherapy response in breast cancer.

INTRODUCTION: Following major developments in cancer immunotherapy, treatments targeting immune checkpoint proteins (ICP) gained interest in breast cancer, though studies mostly focus on patients with metastatic disease as well as patients nonresponsive to the conventional treatments. Herein, we aimed to investigate the levels of ICP in tumor stroma and tumor infiltrating lymphocytes, and tumor tissue prior to neoadjuvant chemotherapy administration to evaluate the relationship between ICP levels, clinicopathological parameters, and NAC response. MATERIALS AND METHODS: This study was conducted with 51 patients where PD-1, PD-L1, CTLA-4, TIM-3, CD24 and CD44 levels were investigated in CD45+ cells while CD326, CD24, CD44 and PD-L1 protein expression levels were investigated in CD45- population. In addition, CD44 and CD24 levels were evaluated in the tumor stroma. TIL levels were investigated according to the TILS Working Group. Treatment responses after NAC were evaluated according to the MD Anderson RCB score. RESULTS: Our results revealed positive correlation between CTLA-4 and CD44 expression in cases with high TIL levels as well as TIL levels and CTLA-4 expression in cases with partial response. Similarly, positive correlation was detected between TIM3 and PD-L1 levels in cases with good response. In addition, a negative correlation between TILs after NAC and PD-1/PD-L1 expression in lymphocytes in cases with partial complete response. CONCLUSIONS: Our study provides preliminary data about the correlation between ICP and clinicopathological status and NAC response in breast cancer, in addition to underlining the requirement for further research to determine their potential as therapeutic targets.

Could we use PD-1 and PD-L1 expression on lymphocytes and monocytes as predictive markers for prognosis of acute biliary pancreatitis?

PURPOSE: This study aimed to assess the significance of immunophenotyping and serum cytokines in predicting the clinical progression of acute biliary pancreatitis (ABP). MATERIALS AND METHODS: Cytokine levels, T-helper, cytotoxic T, natural killer (NK) cells, monocytes, HLA-DR, and PD-1, as well as PDL-1 immune checkpoints, were measured in ABP patients at the time of diagnosis and compared with results from healthy volunteers. The study also compared leukocyte counts, hematocrit, immunophenotyping results, cytokine statuses, and PD-1, PDL-1 expression between healthy volunteers and ABP subgroups categorized by pancreatitis severity. RESULTS: The study included 65 ABP patients and 20 healthy volunteers. Significant differences were observed between groups in hematocrit, leukocyte counts, total monocytes, lymphocytes, CD3+ total T cells, CD4+ Th cells, PD-1 expression on CD4+ and CD8+T lymphocytes, HLA-DR expression on CD14+ monocytes, NK cells, PD-L1 expression on CD14+ monocytes, classical and intermediate monocytes, as well as levels of IL-6, IL-8, IL-10, IL-18, and IL-33 cytokines. Moderate correlations were found with lymphocyte counts, PD-1+CD4+ cells, PD-L1+CD14+ cells, and strong correlations with HLA-DR+CD14+ cells. Hematocrit, CD3+ total T cells, NK cells, CD4+PD-1 + T cells, and CD8+PD-1 + T cells showed independent associations with the severity of ABP. Lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, CD4+PD-1 + T cells, classical, and intermediate monocytes exhibited the highest Area Under the Curve rates in determining organ failure. CONCLUSIONS: Hematocrit, lymphocyte counts, CD14+HLA-DR+ cells, CD14+PD-L1+ cells, and intermediate monocytes emerged as parameters most closely associated with the severity and these parameters could be useful in predicting the severity of ABP.

Immunology of amyotrophic lateral sclerosis - role of the innate and adaptive immunity.

This review aims to summarize the latest evidence about the role of innate and adaptive immunity in Amyotrophic Lateral Sclerosis (ALS). ALS is a devastating neurodegenerative disease affecting upper and lower motor neurons, which involves essential cells of the immune system that play a basic role in innate or adaptive immunity, that can be neurotoxic or neuroprotective for neurons. However, distinguishing between the sole neurotoxic or neuroprotective function of certain cells such as astrocytes can be challenging due to intricate nature of these cells, the complexity of the microenvironment and the contextual factors. In this review, in regard to innate immunity we focus on the involvement of monocytes/macrophages, microglia, the complement, NK cells, neutrophils, mast cells, and astrocytes, while regarding adaptive immunity, in addition to humoral immunity the most important features and roles of T and B cells are highlighted, specifically different subsets of CD4+ as well as CD8+ T cells. The role of autoantibodies and cytokines is also discussed in distinct sections of this review.

The role of curcumin on apoptosis and NLRP3 inflammasome-dependent pyroptosis on colorectal cancer in vitro.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers worldwide. Many factors such as stress, lifestyle, and dietary habits are known to play a role in the initiation and progression of the disease. Herbal therapeutic agents including curcumin can hold a great potential against cancer treatment; however, their efficacy on CRC is still under investigation. Herein, we evaluated the anticancer mechanism of curcumin on four different CRC cell lines. METHODS: Cells were treated with curcumin for 24, 48 and 72 h, and IC50 doses for each cell line were calculated. Mechanistic studies were conducted with the lowest IC50 dose determined for each cell line by evaluating apoptosis and necrosis, cell division, and NLRP3-mediated pyroptosis. RESULTS: Curcumin treatment significantly decreased viability while increasing the SubG1 phase in all cell lines tested, indicating apoptosis is the main programmed cell death pathway activated upon curcumin treatment in CRC. In terms of pyroptosis, components of NLRP3 inflammasome were found to be elevated in SW480 and HCT116 cell lines, although to a lesser extent in the latter, and NLRP3 inflammasome activation was not observed in LoVo and HT29 cells. DISCUSSION: Our results reveal that while curcumin effectively induces apoptosis, its effects on NLRP3-inflammasome mediated pyroptosis vary. Our results underline the need for further research focusing on the other inflammasome complexes to confirm the differential effects of curcumin on CRC.

Isolation and characterisation of secondary metabolites from Trifolium vesiculosum Savi and their antiproliferative activities.

One unreported flavonol namely morin-7-O-methyl ether (1) along with seven known compounds were isolated from the aerial parts of Trifolium vesiculosum Savi which were elucidated by using extensive spectroscopic methods such as 1D and 2D NMR and HR-MS. According to the cell viability assay (MTS) on the purified compounds (1-8), quercetin-3-O-(6''-trans-p-coumaroyl)-ß-galactoside (4) revealed remarkable antiproliferative activity most particularly against breast cancer cells (IC50 = 2.90 ± 0.25 µM in HCC1937 and 7.98 ± 0.57 µM in MCF7) while moderate inhibitory activity (IC50 = 17.96 ± 0.51-51.70 ± 2.69 µM) on prostate, colorectal and liver cancer cell viability was observed. Further mechanistic examinations (Annexin V/PI staining, DNA content and detection of reactive oxygen species analyses) showed that compound 4 significantly induced apoptosis, enhanced mitochondrial reactive oxygen species (ROS) accumulation, and caused cell cycle arrest in cancer cells by increasing accumulation of cells at G0/G1 and/or G2/M phases of the cell cycle.

A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia.

Acute myeloid leukemia (AML) arises from the cells of myeloid lineage and is the most frequent leukemia type in adulthood accounting for about 80% of all cases. The most common treatment strategy for the treatment of AML includes chemotherapy, in rare cases radiotherapy and stem cell and bone marrow transplantation are considered. Immune checkpoint proteins involve in the negative regulation of immune cells, leading to an escape from immune surveillance, in turn, causing failure of tumor cell elimination. Immune checkpoint inhibitors (ICIs) target the negative regulation of the immune cells and support the immune system in terms of anti-tumor immunity. Bone marrow microenvironment (BMM) bears various blood cell lineages and the interactions between these lineages and the noncellular components of BMM are considered important for AML development and progression. Administration of ICIs for the AML treatment may be a promising option by regulating BMM. In this review, we summarize the current treatment options in AML treatment and discuss the possible application of ICIs in AML treatment from the perspective of the regulation of BMM.

Testosterone Propionate Promotes Proliferation and Viability of Bone Marrow Mesenchymal Stem Cells while Preserving Their Characteristics and Inducing Their Anti-Cancer Efficacy

Background: Various studies have reported the effects of testosterone on different cell types, yet bone marrow-derived mesenchymal stem cells' cellular responses to testosterone remain unknown. Aims: To investigate the effects of testosterone propionate, an oil-soluble short-acting form of testosterone, on human bone marrow-derived mesenchymal stem cells' proliferation and viability after 24 hours of incubation. We also investigated the impact of testosterone propionate on bone marrow-derived mesenchymal stem cell's polarization and cytotoxicity on K562 leukemia cell line. Study Design: In vitro study. Methods: We expanded commercially available bone marrow derived mesenchymal stem cells in vitro and treated them with testosterone propionate at concentrations ranging from 10-6-10-10 M for 24 hours. Ideal concentration was determined by evaluating cellular viability and proliferation with Annexin V/Propidium Iodide assay and carboxyfluorescein succinimidyl ester staining. The characteristic features of bone marrow-derived mesenchymal stem cells were evaluated by immunophenotyping and investigating their differentiation capacities. Bone marrow-derived mesenchymal stem cells' cytotoxic properties upon testosterone propionate treatment were determined by co-culturing the cells with K562 cells and with confocal imaging investigating polarization. Results: Testosterone propionate promoted proliferation and maintained the viability of bone marrow-derived mesenchymal stem at 10-8 M concentration. Further evaluations were conducted with the determined dose. The results showed that, apart from promoting mesenchymal stem cells' polarization and increasing their cytotoxicity on K562 cells, testosterone propionate did not alter differentiation capacities of bone marrow-derived mesenchymal stem cells and certain cell surface markers, but led to a significant increase in HLA-DR expression. Conclusion: The findings reveal that testosterone propionate promotes the proliferation and survival of bone marrow-derived mesenchymal stem cells in a dose-dependent manner without hampering their differentiation capacities, induces their polarization to the pro-inflammatory phenotype, and increases their cytotoxicity on the K562 cell line.

Effect of rapamycin treatment in human seminoma TCam-2 cells through inhibition of G1-S transition.

Mammalian target of rapamycin (mTOR) is an important serine/threonine kinase that plays a critical role in several processes including cell cycle, protein synthesis, and energy metabolism. Due to its multiple roles and general dysregulation in cancer, the mTOR pathway is an important target in cancer therapy. However, studies on mTOR activity in seminoma are limited. Therefore, our aim was to investigate the expression of mTOR signaling pathway proteins in the TCam-2 cell line after rapamycin treatment. TCam-2 cells were treated with different concentrations of rapamycin (control (no rapamycin treatment), 4 nM, 20 nM, 100 nM, 500 nM, and 1000 nM rapamycin) for 48 h and 72 h. mTOR, p-mTOR, P70S6K, p-P70S6K, proliferating cell nuclear antigen (PCNA), and caspase-3 expression levels were analyzed by western blot. Apotosis and cell cycle were analyzed by flow cytometry. After 48 h of rapamycin administration, mTOR activity was significantly decreased at 1000 nM (p < 0.05). In addition, P70S6K acitivity significantly decreased in groups at all rapamycin concentrations (***p < 0.001, ****p < 0.0001). After 72 h of rapamycin administration, mTOR pathway activity were significantly decreased at 100, 500, and 1000 nM rapamycin-treated groups (p < 0.05). Moreover, P70S6K expression decreased in all treatment groups (****p < 0.0001). Caspase-3 expression were similar in all groups. While PCNA expression tended to decrease at 48 h in a dose-dependent manner, this decrease was not significant. We detected decreased PCNA expression at 1000 nM rapamycin at 72 h (p < 0.05). The rate of apoptosis increased especially at 1000 nM rapamycin at 72 h (***p < 0.001). On the other hand, according to the results of the cell cycle experiment, G1 phase arrest was detected at all rapamycin doses at 48 and 72 h (***p < 0.001). Our study indicated that 1000 nM rapamycin may inhibit TCam-2 seminoma cells growth by halting cell proliferation through inhibition of G1-S transition. Therefore, we believe that the findings obtained will contribute to the development of new treatment approaches for seminoma patients in the future and in the process of restoring testicular functions and preserving fertility.

Secondary metabolites from the underground parts of Valeriana sisymbriifolia Vahl. and their in vitro cytotoxic activities.

Cytotoxic activity-guided isolation studies on the underground parts of Valeriana sisymbriifolia Vahl. led to the isolation of 12 secondary metabolites including two undescribed iridoids, sisymbriifolivaltrate and sisymbriifolioside, and two unreported sesquiterpene lactones, sisymbriifolins A and B. Chemical structures of the isolates were established by extensive 1D and 2D NMR analyses as well as HR-ESI-MS. The in vitro cytotoxic activities of the extract, sub-fractions and isolates on lung (A549), breast (MCF7), gastric (HGC27) and prostate (PC3) cancer cell lines were evaluated by MTS assay. Sisymbriifolivaltrate, didrovaltrate, valtrate, 7-homovaltrate and 1-α-acevaltrate exhibited promising cytotoxic activity on MCF7 cell line with IC50 values ranging from 2.5 to 12.3 µM, while valtrate demonstrated the best cytotoxicity against A549 cells with the IC50 value of 7.5 µM. Valtrate and 7-homovaltrate were found to exert noteworthy cytotoxicity towards HGC27 cell line (IC50 values: 2.3 and 3.7 µM, respectively), whereas valtrate, 7-homovaltrate and 1-α-acevaltrate (IC50 values: 2.3-9.7 µM) were found to be potent cytotoxic against PC3 cells. Among the tested compounds, particularly valepotriate-type iridoids were found to be the main cytotoxic principles of V. sisymbriifolia.

Combinatorial effects of melatonin and paclitaxel differ depending on the treatment scheme in colorectal cancer in vitro.

AIMS: Colorectal carcinoma (CRC) is the third most prevalent cancer with high mortality. Besides regulating the circadian rhythm, melatonin (MTN) exerts anticancer activities. Paclitaxel (PTX) is successful against different malignancies, however, acquired resistance and variability in patient response restrict its use. mTOR and MAPK pathways are often deregulated in human cancers. We aimed to investigate whether MTN enhances or sensitizes the chemotherapeutic activity of PTX and if so, determine the underlying possible mechanisms in CRC in vitro. MAIN METHODS: Antiproliferative and cytotoxic activities of PTX and MTN were assessed alone and in combination, as well as with different treatment regimens (renewal or replacement of the treatment after 24 h), up to 48 h. Apoptosis, viability and autophagy were assessed by flow cytometry. mTOR and MAPK pathway activities were investigated by immunoblotting. KEY FINDINGS: Both drugs reduced cell viability in a dose-dependent manner at 24 and 48 h. Only the highest dose of MTN (500 µM) potentiated the cytotoxicity of PTX (50 nM). Replacement of PTX after 24 h with MTN was superior in reducing cell viability than vice versa via apoptosis induction. Renewal of MTN treatment every 24 h reduced autophagy compared to the control group, while other treatments did not alter the autophagic activity. A 24 h MTN treatment followed by 24 h PTX treatment increased S6 phosphorylation in a mTOR-independent manner and increased Erk1/2 phosphorylation. SIGNIFICANCE: The present study suggests that sequential treatment with MTN and PTX distinctly affect apoptosis and cytotoxicity via regulating mTOR and MAPK pathways differentially in CRC.

Activity-Guided Isolation of Cytotoxic Non-Glycosidic Ester Iridoids from Valeriana alliariifolia Adams and Unravelling Their Cell Death Mechanisms.

The aim of this study was to isolate the cytotoxic compounds from V. alliariifolia via activity-guided isolation and to determine the mechanism of actions of the most potent ones. The crude EtOH extract as well as CHCl3 and AcOEt subextracts demonstrated remarkable cytotoxic activities against A549, MCF7, HGC27 and PC3 cancer cells. Sequential chromatographic separations on active subextracts yielded 14 secondary metabolites, including 11 iridoids (1-11) most of which belong to non-glycosidic ester iridoids, two phenylpropanoids (12 and 13) and one lignan (14). The chemical structures of purified compounds were elucidated by NMR and MS analysis. Among the isolates, 7-deisovaleroylvaltrate (3) was isolated for the first time as a natural product. According to the cytotoxic assay compounds, 2, 4-6 and 8 were found to be the potent cytotoxic compounds (IC50 <10 µM) against at least one of the tested cancer cell lines. Thus, 2, 4-6 and 8 were investigated for their effects on apoptotic, necrotic and autophagic pathways as well as cell cycle progression. They exerted anticancer activities by inducing different cell death mechanisms depending on the cancer cells. The results demonstrated that 2, 4-6 and 8 could be potential anticancer drug leads that deserve further in vivo and clinical studies on the way to discover novel natural compounds with anticancer properties.

Chemo-photodynamic Activity of Silicon Phthalocyanines Bearing Cyclooxygenase Inhibitors on Colorectal Cancer Cell Lines.

Colorectal cancer ranks as the third most lethal cancer worldwide, resulting in over 1 million cases and 900 000 deaths per year. According to population-based studies, administration of long-term non-steroidal anti-inflammatory drugs (NSAIDs) was proven to reduce the risk of a subject developing colorectal cancer. In the present study, the anti-cancer activity of two different NSAIDs, sulindac- (Pc-1) or diclofenac-substituted (Pc-2) asymmetric silicon phthalocyanine derivatives, was evaluated in four different colorectal cancer cell lines bearing various carcinogenic mutations. In this context, the IC50 values of each compound after 24 and 48 h were determined on HCT116, SW480, LoVo, and HT29 cell lines, and the effects of the compounds on programmed cell death pathways apoptosis and autophagy, their impact on cell cycle progression, and the effect of NSAID moieties they bear on COX-1 and COX-2 proteins were analyzed. In addition, the photophysical and photochemical properties of a synthesized Pc derivative bearing axial diclofenac and triethylene glycol groups (Pc-2) have been investigated, and the compound has been characterized by using different analytical techniques. Our results indicated that both compounds inhibit COX protein expression levels, activate apoptosis in all cell lines, and lead to cell cycle arrest in the G2/M phase, depending on the COX expression profiles of the cell lines, indicating that NSAIDs can be coupled with Pc's to achieve increased anti-cancer activity, especially on cancer cells known to have high COX activity.

Comparison of Laboratory Methods for the Clinical Follow Up of Checkpoint Blockade Therapies in Leukemia: Current Status and Challenges Ahead.

The development of immune checkpoint inhibitors, the monoclonal antibodies that modulate the interaction between immune checkpoint molecules or their ligands on the immune cells or tumor tissue has revolutionized cancer treatment. While there are various studies proving their efficacy in hematological malignancies, there is also a body of accumulating evidence indicating that immune checkpoint inhibitors' clinical benefits are limited in such diseases. In addition, due to their regulatory nature that balances the immune responses, blockade of immune checkpoints may lead to toxic side effects and autoimmune responses, and even primary or acquired resistance mechanisms may restrict their success. Thus, the need for laboratory biomarkers to identify and monitor patient populations who are more likely respond to this type of therapy and the management of side effects seem critical. However, guidelines regarding the use of immune checkpoint inhibitors in hematological cancers and during follow-up are limited while there is no consensus on the laboratory parameters to be investigated for safety and efficacy of the treatment. This review aims to provide an insight into recent information on predictive and prognostic value of biomarkers and laboratory tests for the clinical follow up of hematological malignancies, with an emphasis on leukemia.

Does LH supplementation in poor responders affect granulosa cells apoptosis rate in ART? A prospective randomised controlled trial.

The aim was to compare granulosa cell's (GCs) apoptosis rate with (group A) or without (group B) luteinising hormone (LH) supplementation in poor ovarian responders (PORs) during controlled ovarian stimulation (COS). After oocyte retrieval, the follicular fluid was analysed by cytoflowmetry. Primary outcomes were GCs apoptosis rate in terms of viability, early apoptosis, late apoptosis and necrosis. Secondary outcome was clinical pregnancy rate. The viability was 96.7{IQR: 8} and 83.5{IQR: 20} for groups A and B, respectively (p < .001). Late apoptosis rates were significantly lower in group A (median 1.5, {IQR: 3.1}) than group B (median 9.5, {IQR: 20.6}) (p < .001). Median early apoptosis rates were 1.4 {IQR: 2.9} and 5.2 {IQR: 6.5} for group A and B respectively (p = .04). No significant difference was observed in the clinical pregnancy rate. Although LH seems necessary in PORs to decrease late granulosa apoptosis rates, this does not improve clinical pregnancy rates.IMPACT STATEMENTWhat is already known on this subject? LH supplementation during COS has long been an issue in PORs to overcome the rFSH responsiveness due to the LH polymorphism. LH receptors have also been on GCs and their expression increases in preovulatory follicles. GCs apoptosis rates may show the oocyte quality and reproductive potential of oocyte retrieved and the requirement for LH supplementation.What do the results of this study add? The present study shows that LH supplementation during COS for PORs promotes the GC viability and reduces early/late apoptosis rates. Similarly, the number of MII oocytes was significantly higher in the LH regimen group. However, there was no significant difference in terms of clinical pregnancy rates.What are the implications of these findings for clinical practice and/or further research? The oocyte quality parameters such as higher GC viability and lower GC early/late apoptosis rates verify the LH supplementation in PORs during COS. However, the limited size of this study requires further multi-centre research in a larger cohort of patients. Results obtained with a sensitive and validated method will help clinicians to make better decisions in patient care.

Evaluation of histone deacetylase inhibitor substituted zinc and indium phthalocyanines for chemo- and photodynamic therapy.

In this study, we synthesized and characterized 3-hydroxypyridin-2-thione (3-HPT) bearing zinc (ZnPc-1 and ZnPc-2) and indium (InPc-1 and InPc-2) phthalocyanine (Pc) derivatives, either non-peripherally or peripherally substituted as photosensitizer (PS) agents and evaluated their anti-cancer efficacy on two breast cancer cell lines, MDA-MB-231 and MCF-7 as well as a human endothelial cell line, HUVEC. Our results indicated different localization patterns between ZnPcs and InPcs in addition to enhanced effects on the mitochondrial network for InPcs. Moreover, peripheral or non-peripheral substitution of HDACi moieties altered cellular localization between ZnPc-1 and ZnPc-2, leading to increased IC50 values along with decreased anti-cancer activity for non-peripheral substitution. When considering the compounds' differential effects in vitro, our data indicates that further research is required to determine the ideal Pcs for anti-cancer PDT treatments since the core metals of the compounds have affected the cellular localization, and positioning of the chemotherapeutic residues may inhibit cellular penetrance.

Zero-valent iron nanoparticles containing nanofiber scaffolds for nerve tissue engineering.

Regeneration of nerve tissue is a challenging issue in regenerative medicine. Especially, the peripheral nerve defects related to the accidents are one of the leading health problems. For large degeneration of peripheral nerve, nerve grafts are used in order to obtain a connection. These grafts should be biodegradable to prevent second surgical intervention. In order to make more effective nerve tissue engineering materials, nanotechnological improvements were used. Especially, the addition of electrically conductive and biocompatible metallic particles and carbon structures has essential roles in the stimulation of nerves. However, the metabolizing of these structures remains to wonder because of their nondegradable nature. In this study, biodegradable and conductive nerve tissue engineering materials containing zero-valent iron (Fe) nanoparticles were developed and investigated under in vitro conditions. By using electrospinning technique, fibrous mats composed of electrospun poly(ε-caprolactone) (PCL) nanofibers and Fe nanoparticles were obtained. Both electrical conductivity and mechanical properties increased compared with control group that does not contain nanoparticles. Conductivity of PCL/Fe5 and PCL/Fe10 increased to 0.0041 and 0.0152 from 0.0013 Scm-1 , respectively. Cytotoxicity results indicated toxicity for composite mat containing 20% Fe nanoparticles (PCL/Fe20). SH-SY5Y cells were grown on PCL/Fe10 best, which contains 10% Fe nanoparticles. Beta III tubulin staining of dorsal root ganglion neurons seeded on mats revealed higher cell number on PCL/Fe10. This study demonstrated the impact of zero-valent Fe nanoparticles on nerve regeneration. The results showed the efficacy of the conductive nanoparticles, and the amount in the composition has essential roles in the promotion of the neurites.

A Translational Study of a Silicon Phthalocyanine Substituted with a Histone Deacetylase Inhibitor for Photodynamic Therapy.

In this study, we synthesized and characterized a silicon phthalocyanine substituted with 3-hydroxypyridin-2-thione (SiPc-HDACi), designed to be a chemophotodynamic therapy agent acting as a histone deacetylase inhibitor, and we determined its photophysical, photochemical, and photobiological properties. Next, we evaluated its anticancer efficacy on MCF-7, double positive and MDA-MB-231, triple negative breast cancer cell lines, as well as on a healthy human endothelial cell line (HUVEC). Our results indicate that SiPc-HDACi can target nucleoli of cells, effectively inducing apoptosis while promoting cell cycle arrest thanks to its high singlet oxygen yield and its histone deacetylase downregulating properties, suggesting a powerful anticancer effect on breast cancer in vitro. Our further studies will be conducted with primary breast cancer cell culture to give a better insight into the anticancer mechanism of the compound.

Process optimisation, biocompatibility and anti-cancer efficacy of curcumin loaded gelatine microparticles cross-linked with dialdeyhde carboxymethyl cellulose.

In this study, we produced curcumin loaded gelatine microparticles, through spray-drying method, with dialdehyde carboxymethyl cellulose (DCMC) which is introduced as a new cross-linking agent for drug delivery systems and examined toxicities by comparison of traditional cross-linking agents. We employed various parameters in the production and tried to develop the most efficient drug delivery system through Taguchi method by examining efficiencies on gastric cancer under in vitro conditions. The results indicated gelatine microparticles cross-linked with DCMC offers more biocompatible drug delivery systems. The particle size of the microparticles produced via different parameters varies from 1.926 to 3.357 µm. Curcumin was substantially remained stable after 6 months. This study indicates potential use of DCMC cross-linked gelatine microparticles as drug delivery vehicle.

Antiproliferative Activity of Chemically Characterized Propolis from Turkey and Its Mechanisms of Action.

The aim of this study was to evaluate the ethanolic extract of propolis originated from northern Turkey for its antiproliferative, apoptotic and cell cycle arrest promoting effects on MCF7, HGC27, A549 cancer cell lines and a healthy cell line (HUVEC) in terms of DNA content, morphological features, expression of cell cycle checkpoint proteins p21, p53, Cyclin D1 and immune checkpoint protein PD-L1. The extract showed moderate antiproliferative activity against all tested cancer cell lines with IC50 values in the range of 58.6-90.7 µg/mL in MTS assay. Further studies indicated that propolis extract exerted apoptotic effect on cancer cell lines, promoted cell cycle arrest through activation of p21 and resulted in accumulation at G0/G1 phase of cancer cells. Propolis treatment caused increased cell size, according to fluorescent imaging except for MCF7. HPTLC analysis revealed that 3-O-methylquercetin, chrysin, caffeic acid, CAPE, galangin and pinocembrin were the main components of the extract. The amounts of caffeic acid and CAPE in the extract were found to be 5.5 and 11.1 mg/g, respectively, by a validated HPLC method. Our study is the first one, revealing effect of propolis on PD-L1 expression on certain cancer cell lines.