In vivo clinical molecular imaging of T cell activity.

Tumor immunotherapy is refashioning traditional treatments in the clinic for certain tumors, especially by relying on the activation of T cells. However, the safety and effectiveness of many antitumor immunotherapeutic agents are suboptimal due to difficulties encountered in assessing T cell responses and adjusting treatment regimens accordingly. Here, we review advances in the clinical visualization of T cell activity in vivo, and focus particularly on molecular imaging probes and biomarkers of T cell activation. Current challenges and prospects are also discussed that aim to achieve a better strategy for real-time monitoring of T cell activity, predicting prognoses and responses to tumor immunotherapy, and assessing disease management.

An efficient genetic transformation system mediated by Rhizobium rhizogenes in fruit trees based on the transgenic hairy root to shoot conversion.

Genetic transformation is a critical tool for gene editing and genetic improvement of plants. Although many model plants and crops can be genetically manipulated, genetic transformation systems for fruit trees are either lacking or perform poorly. We used Rhizobium rhizogenes to transfer the target gene into the hairy roots of Malus domestica and Actinidia chinensis. Transgenic roots were generated within 3 weeks, with a transgenic efficiency of 78.8%. Root to shoot conversion of transgenic hairy roots was achieved within 11 weeks, with a regeneration efficiency of 3.3%. Finally, the regulatory genes involved in stem cell activity were used to improve shoot regeneration efficiency. MdWOX5 exhibited the most significant effects, as it led to an improved regeneration efficiency of 20.6% and a reduced regeneration time of 9 weeks. Phenotypes of the overexpression of RUBY system mediated red roots and overexpression of MdRGF5 mediated longer root hairs were observed within 3 weeks, suggesting that the method can be used to quickly screen genes that influence root phenotype scores through root performance, such as root colour, root hair, and lateral root. Obtaining whole plants of the RUBY system and MdRGF5 overexpression lines highlights the convenience of this technology for studying gene functions in whole plants. Overall, we developed an optimized method to improve the transformation efficiency and stability of transformants in fruit trees.

Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation.

Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

Evaluation of Antibiotic Penicillin G Activities Based on Electrochemical Measurement of a Tetrazolium Salt.

This study focused on the electrochemical properties of tetrazolium salts to develop a simple method for evaluating viable bacterial counts, which are indicators of drug susceptibility. Considering that the oxidized form of tetrazolium, which has excellent cell membrane permeability, changes to the insoluble reduced form formazan inside the cell, the number of viable cells was estimated based on the reduction current of the tetrazolium remaining in the bacterial suspension. Dissolved oxygen is an important component of bacterial activity. However, it interferes with the electrochemical response of tetrazolium. We estimated the number of viable bacteria in the suspension based on potential-selective current responses that were not affected by dissolved oxygen. Based on solubility, cell membrane permeability, and characteristic electrochemical properties of the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium, we developed a method for rapidly measuring viable bacteria within one-fifth of the time required by conventional colorimetric methods for drug susceptibility testing.

Diterpenoid alkaloids from Delphinium sherriffii.

Three new diterpenoid alkaloids (1, 2, 3) and seventeen known (4-20) compounds were isolated from the whole plant of Delphinium sherriffii Munz (Ranunculaceae). Their structures were elucidated by various spectroscopic analyses, including IR, HR-ESI-MS, 1D and 2D NMR spectra. All compounds were evaluated for the inhibitory activity of Sf9 cells and compound 5 exhibited the strongest cytotoxicity (IC50 = 8.97 µM) against Sf9 cell line.

Impact of Skin Exposure to Benzo[a]pyrene in Rat Model: Insights into Epidermal Cell Function and Draining Lymph Node Cell Response.

The skin is a direct target of the air pollutant benzo[a]pyrene (BaP). While its carcinogenic qualities are well-studied, the immunotoxicity of BaP after dermal exposure is less understood. This study examines the immunomodulatory effects of a 10-day epicutaneous BaP application, in environmentally/occupationally relevant doses, by analyzing ex vivo skin immune response (skin explant, epidermal cells and draining lymph node/DLN cell activity), alongside the skin's reaction to sensitization with experimental hapten dinitrochlorobenzene (DNCB). The results show that BaP application disrupts the structure of the epidermal layer and promotes immune cell infiltration in the dermis. BaP exposure led to oxidative stress in epidermal cells, characterized by decreased reduced glutathione and increased AHR and Cyp1A1 expression. Production and gene expression of proinflammatory cytokines (TNF, IL-1ß) by epidermal cells decreased, while IL-10 response increased. Decreased spontaneous production of IFN-γ and IL-17, along with unchanged IL-10, was observed in DLC cells, whereas ConA-stimulated production of these cytokines was elevated. Local immunosuppression caused by BaP application seems to reduce the skin's response to an additional stimulus, evidenced by decreased effector activity of DLN cells three days after sensitization with DNCB. These findings provide new insight into the immunomodulatory effects and health risks associated with skin exposure to BaP.

Natural Killer Cell Activity Test Helps to Suspect Aggressive Natural Killer Cell Leukemia - Diagnostic Challenge.

Aggressive natural killer cell leukemia (ANKL) is a rare disease with an aggressive clinical course. We aimed to assess the clinicopathological characteristics of the difficult to diagnose ANKL. During ten years, nine patients with ANKL were diagnosed. All the patients exhibited aggressive clinical course and underwent the BM study to rule out lymphoma and hemophagocytic lymphohistiocytosis (HLH). BM examination showed varying degrees of infiltration of neoplastic cells, which were mainly positive for CD2, CD56, cytoplasmic CD3 and EBV in situ hybridization. Five BM aspirates showed histiocytic proliferation with active heomphagocytosis. Normal or increased NK cell activity test results were obtained from 3 patients who were available for testing. Four had multiple BM studies until diagnosis. An aggressive clinical course and positive EBV in situ hybridization, often with associated secondary HLH, should raise the suspicion of an ANKL. Conducting additional supplementary tests such as NK cell activity and NK cell proportion would be helpful for the diagnosis of ANKL.

Effect of surgical pleth index-guided remifentanil administration on perioperative outcomes in elderly patients: a prospective randomized controlled trial.

BACKGROUND: During general anesthesia, the surgical pleth index (SPI) monitors nociception. The evidence of SPI in the elderly remains scarce. We aimed to investigate whether there is a difference in perioperative outcomes following intraoperative opioid administration according to the surgical pleth index (SPI) value versus hemodynamic parameters (heart rate or blood pressure) in elderly patients. METHODS: Patients aged 65-90 years who underwent laparoscopic colorectal cancer surgery under sevoflurane/remifentanil anesthesia were randomized to receive remifentanil guided by SPI (SPI group) or conventional clinical judgment based on hemodynamic parameters (conventional group). The primary endpoint was intraoperative remifentanil consumption. Secondary endpoints were intraoperative hemodynamic instability, pain score, fentanyl consumption and delirium in the post-anesthesia care unit (PACU), and perioperative changes in interleukin-6 and natural killer (NK) cell activity. RESULTS: Seventy-five patients (38, SPI; 37, conventional) were included in the study. The SPI group consumed significantly more remifentanil intraoperatively than the conventional group (mean ± SD, 0.13 ± 0.05 vs. 0.06 ± 0.04 µg/kg/min, P < 0.001). Intraoperative hypertension and tachycardia were more common in the conventional group than in the SPI group. Pain score in the PACU (P = 0.013) and the incidence of delirium in the PACU were significantly lower in the SPI group than the conventional group (5.2% vs. 24.3%, P = 0.02). There was no significant difference in NK cell activity and interleukin-6 level. CONCLUSIONS: In the elderly patients, SPI-guided analgesia provided appropriate analgesia with sufficient intraoperative remifentanil consumption, lower incidence of hypertension/ tachycardia events, and a lower incidence of delirium in the PACU than the conventional analgesia. However, SPI-guided analgesia may not prevent perioperative immune system deterioration. TRIAL REGISTRATION: The randomized controlled trial was retrospectively registered in the UMIN Clinical Trials Registry (trial number: UMIN000048351; date of registration: 12/07/2022).

Establishment of type 2 diabetes mellitus models using streptozotocin after 3 months high-fat diet in Bama minipigs.

In the past twenty years, the number of adults with diabetes has tripled. Most studies have been conducted using rodent models of type 2 diabetes mellitus (T2DM), and the developed drugs have low clinical conversion efficiency. Therefore, it is urgent to establish a more human-like large animal model to explore T2DM pathogenesis and formulate new disease prevention and control strategies. This study was designed to establish and validate a T2DM model using minipigs fed a high-fat or high-cholesterol/high-fat diet and injected with low-dose streptozotocin (STZ). We examined the influence of the STZ injection timing with a diet high in fat (HFD) compared with one high in cholesterol and fat (HCFD) on the atherosclerotic lesions accelerated by T2DM. Male Bama minipigs (n = 24) were randomly divided into five groups. The control group was fed a normal diet for 9 months. The STZ + HFD and STZ + HCFD groups were infused with 90 mg/kg STZ and then fed a high-fat diet or high-cholesterol and high-fat diet for 9 months, respectively. The HFD + STZ and HCFD + STZ groups were fed a high-fat diet or a high-cholesterol and high-fat diet, respectively, for 9 months (after 3 months, these pigs were injected intravenously with 90 mg/kg STZ). During the induction period, animal body weight, BMI, and serum GLU, INS, TG, TC, HDL-C, LDL-C, FFA, ALT, AST, CRE, and BUN were detected monthly intervals. IVGTT and insulin release tests were performed at 3-month intervals. At the end of the test, the coronary artery and abdominal aorta were examined by computed tomography and pathological observations, and the thickness of the basement membrane of the capillary of the retina and kidney glomerulus was measured under a transmission electron microscope. The serum glucose concentrations were normal in all groups except the HFD + STZ and HCFD + STZ groups. Animals fed an HFD for 9 months did not develop apparent atherosclerotic lesions, but atherosclerotic lesions were seen in the animals fed an HCFD. Hyperglycemia accelerated the formation of atherosclerotic lesions on the intimal surface of the abdominal aorta. Low-dose STZ after 3 months of HFD or HCFD successfully established a T2DM model in minipigs. The HFD did not induce apparent atherosclerotic lesions, but these were seen with the HCFD. Hyperglycemia accelerated atherosclerosis in the minipigs.

Immune Checkpoints in Recurrent Pregnancy Loss: New Insights into a Detrimental and Elusive Disorder.

Recurrent pregnancy loss (RPL) refers to two or more miscarriages before 20 weeks gestation. Its prevalence is 1-2%; its pathogenesis remains unexplained in more than 50% of cases, in which the cause is thought to be abnormal immune activity during placentation leading to a lack of pregnancy-induced immune tolerance. It is unknown whether immune activity is deranged in the endometrium of women with RPL. We studied the gene expression and the quantitative tissue protein levels of three immune checkpoints (CD276, which enhances cytotoxic T-cell activity, cytotoxic T-lymphocyte-associated antigen-4 [CTL-4], which reduces Th1 cytokine production, and lymphocyte activation gene-3 [LAG-3], which shows suppressive activity on Tregs and CD4+ T-cells) in endometrial samples from 27 women with unexplained RPL and in 29 women with dysfunctional uterine bleeding and previous uneventful pregnancies as controls. RNA isolation, real-time PCR, protein isolation, and ELISA were performed. CD276 gene expression and protein tissue levels were significantly lower in the endometrium of the RPL group than in the controls, whereas both CTL-4 and LAG-3 were significantly higher. This difference suggests defective endometrial immune regulation and overactivation of immune response in women with a history of RPL, at least in relation to controls with dysfunctional uterine bleeding and previous normal reproductive history.

Low Muscle and High Fat Percentages Are Associated with Low Natural Killer Cell Activity: A Cross-Sectional Study.

This study aimed to investigate whether body fat and muscle percentages are associated with natural killer cell activity (NKA). This was a cross-sectional study, conducted on 8058 subjects in a medical center in Korea. The association between the muscle and fat percentage tertiles and a low NKA, defined as an interferon-gamma level lower than 500 pg/mL, was assessed. In both men and women, the muscle mass and muscle percentage were significantly low in participants with a low NKA, whereas the fat percentage, white blood cell count, and C-reactive protein (CRP) level were significantly high in those with a low NKA. Compared with the lowest muscle percentage tertile as a reference, the fully adjusted odd ratios (ORs) (95% confidence intervals (CIs)) for a low NKA were significantly lower in T2 (OR: 0.69; 95% CI: 0.55-0.86) and T3 (OR: 0.74; 95% CI: 0.57-0.95) of men, and T3 (OR: 0.76; 95% CI: 0.59-0.99) of women. Compared with the lowest fat percentage tertile as a reference, the fully adjusted OR was significantly higher in T3 of men (OR: 1.31; 95% CI: 1.01-1.69). A high muscle percentage was significantly inversely associated with a low NKA in men and women, whereas a high fat percentage was significantly associated with a low NKA in men.

The Regulatory Mechanism of Cold Plasma in Relation to Cell Activity and Its Application in Biomedical and Animal Husbandry Practices.

As an innovative technology in biological applications, cold plasma is widely used in oral treatment, tissue regeneration, wound healing, and cancer therapy, etc., because of the adjustable composition and temperature which allow the plasma to react with bio-objects safely. Reactive oxygen species (ROS) produced by cold plasma regulate cell activity in an intensity- and time-dependent manner. A low level of ROS produced by cold plasma treatment within the appropriate intensities and times promotes proliferation of skin-related cells and increases angiogenesis, which aid in the acceleration of the wound healing process, while a high level of ROS produced by cold plasma treatment performed at a high intensity or over a long period of time inhibits the proliferation of endothelial cells, keratinocytes, fibroblasts, and cancer cells. Moreover, cold plasma can regulate stem cell proliferation by changing niche interface and producing nitric oxide directly. However, the molecular mechanism of cold plasma regulating cell activity and its potential application in the field of animal husbandry remain unclear in the literature. Therefore, this paper reviews the effects and possible regulatory mechanisms of cold plasma on the activities of endothelial cells, keratinocytes, fibroblasts, stem cells, and cancer cells to provide a theoretical basis for the application of cold plasma to skin-wound healing and cancer therapy. In addition, cold plasma exposure at a high intensity or an extended time shows excellent performances in killing various microorganisms existing in the environment or on the surface of animal food, and preparing inactivated vaccines, while cold plasma treatment within the appropriate conditions improves chicken growth and reproductive capacity. This paper introduces the potential applications of cold plasma treatment in relation to animal-breeding environments, animal health, their growth and reproduction, and animal food processing and preservation, which are all beneficial to the practice of animal husbandry and guarantee good animal food safety results.

Excellent Dark/Light Dual-Mode Photoresponsive Activities Based on g-C3N4/CMCh/PVA Nanocomposite Hydrogel Using Electron Beam Radiation Method.

Photocatalytic technology for inactivating bacteria in water has received much attention. In this study, we reported a dark-light dual-mode sterilized g-C3N4/chitosan/poly (vinyl alcohol) hydrogel (g-CP) prepared through freeze-thaw cycling and an in situ electron-beam radiation method. The structures and morphologies of g-CP were confirmed using Fourier infrared spectroscopy (FTIR), X-ray diffraction spectroscopy (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), solid ultraviolet diffuse reflectance spectroscopy (UV-vis DRS), and Brunauer-Emmett-Teller (BET). Photocatalytic degradation experiments demonstrated that 1 wt% g-CP degraded rhodamine B (RhB) up to 65.92% in 60 min. At the same time, g-CP had good antimicrobial abilities for Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) within 4 h. The shapes of g-CP were adjustable (such as bar, cylinder, and cube) and had good mechanical properties and biocompatibility. The tensile and compressive modulus of 2 wt% g-CP were 0.093 MPa and 1.61 MPa, respectively. The Cell Counting Kit-8 (CCK-8) test and Hoechst33342/PI double staining were used to prove that g-CP had good biocompatibility. It is expected to be applied to environmental sewage treatment and wound dressing in the future.

[Rheumatological side effects of checkpoint inhibitors and their treatment]. / Rheumatologische Nebenwirkungen von Checkpointinhibitoren und deren Behandlung.

The spectrum of tumors for which checkpoint inhibitor (CI) treatment is used is constantly expanding. The European Medicines Agency has currently approved nine CIs: one anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) CI, one anti-lymphocyte activation gene 3 (LAG-3) CI, four anti-programmed cell death protein 1 (PD-1) CIs and three anti-programmed death ligand 1 (PD-L1) CIs. By blocking immune checkpoints the physiological downregulation of T cell activity against autologous tissue is prevented. This results in an immunologically unregulated activation of T cells directed against malignant cells. Healthy tissue also expresses antigens and thereby continuously activates autologous T cells. Thus, the blockade of immune checkpoints can lead to T cell activity against healthy tissue (immune-related adverse events, irAE). The irAEs can occur in any organ system and approximately 10% of all patients under CI treatment develop rheumatological irAEs, mostly arthralgia and myalgia. The classification criteria of rheumatological diseases do not need to be met to initiate treatment and the primary goal of treatment of irAEs is to enable continuation of CI treatment. Rheumatological irAEs should be recognized and treated quickly. In the treatment of musculoskeletal irAEs, three stages can be defined. In the first stage, nonsteroidal anti-inflammatory drugs or intra-articular as well as systemic glucocorticoids are used. In the second stage, conventional synthetic and in the third stage, biologic disease-modifying antirheumatic drugs are used. The most severe musculoskeletal irAE is myositis with cardiac and/or respiratory involvement and/or myasthenia gravis. In addition to high-dose glucocorticoids, intravenous immunoglobulins or plasma exchange are used in treatment.

Hematopoietic cell transplantation landscape in India.

Hematopoietic cell transplantation (HCT), commonly known as Bone marrow transplantation (BMT), is a medical procedure used to treat various conditions, including blood cancers, genetic disorders, and certain autoimmune diseases. The procedure involves replacing damaged or diseased bone marrow with healthy stem cells to promote the production of new, healthy blood cells. In India, HCT has been performed for several years in specialized medical centers. India has a growing healthcare infrastructure, and many hospitals are equipped to perform these procedures. Though there are studies on HCTs done at individual transplant centers in India, a comprehensive analysis of the current landscape of HCT in the country is lacking. HCT in India has seen major advances both in the quantity and quality of HCT centers. This review article has attempted to cover the gaps of HCT in India, including its status in the Armed Forces HCT centers.

Prognostic value of natural killer cell activity for patients with HER2 + advanced gastric cancer treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab.

BACKGROUND: We aimed to evaluate the prognostic value of natural killer (NK) cell activity for patients with HER2 + advanced gastric cancer (AGC) treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab. METHODS: Forty-one patients with HER2 + AGC who received fluoropyrimidine-platinum doublet plus trastuzumab as first-line treatment were prospectively enrolled. NK cell activity was evaluated using the NK Vue®. RESULTS: The median age was 63.5 years, and 31 patients (75.6%) were male. Patients with low baseline NK cell activity (≤ median, n = 21) were associated worse progression-free survival (PFS) and overall survival (OS) compared with patients with high baseline NK cell activity (> median, n = 20) with a median PFS of 4.21 vs. 9.53 months (P < 0.001), and median OS of 8.15 months vs. 17.82 months (P = 0.025), respectively. In the multivariate analysis, low baseline NK cell activity was independently associated with poor PFS (HR 4.35, P = 0.007). NK cell activity recovered to a normal range in nine patients (47.4%) with a low baseline NK cell activity (n = 19) after two cycles of treatment. The median PFS and OS among patients with recovered NK cell activity were significantly better than that among patients with persistently low NK cell activity (PFS, P = 0.038; OS, P = 0.003). CONCLUSION: Our results demonstrated the prognostic value of baseline NK cell activity for patients with HER2 + AGC treated with fluoropyrimidine-platinum doublet plus trastuzumab. The association between treatment outcomes and dynamic changes in NK cell activity suggests that NK cell treatment may improve treatment outcomes, especially for patients with low baseline NK cell activity.

Elastin turnover in ocular diseases: A special focus on age-related macular degeneration.

The extracellular matrix (ECM) and its turnover play a crucial role in the pathogenesis of several inflammatory diseases, including age-related macular degeneration (AMD). Elastin, a critical protein component of the ECM, not only provides structural and mechanical support to tissues, but also mediates several intracellular and extracellular molecular signaling pathways. Abnormal turnover of elastin has pathological implications. In the eye elastin is a major structural component of Bruch's membrane (BrM), a critical ECM structure separating the retinal pigment epithelium (RPE) from the choriocapillaris. Reduced integrity of macular BrM elastin, increased serum levels of elastin-derived peptides (EDPs), and elevated elastin antibodies have been reported in AMD. Existing reports suggest that elastases, the elastin-degrading enzymes secreted by RPE, infiltrating macrophages or neutrophils could be involved in BrM elastin degradation, thus contributing to AMD pathogenesis. EDPs derived from elastin degradation can increase inflammatory and angiogenic responses in tissues, and the elastin antibodies are shown to play roles in immune cell activity and complement activation. This review summarizes our current understanding on the elastases/elastin fragments-mediated mechanisms of AMD pathogenesis.

Orexin A Suppresses the Expression of Exosomal PD-L1 in Colon Cancer and Promotes T Cell Activity by Inhibiting JAK2/STAT3 Signaling Pathway.

BACKGROUND: Colon cancer, ranked third in cancer related mortality, is the most common malignant cancer of digestive tract. Though immune checkpoint inhibitors show promising efficacy in colon cancer, a rather high unresponsive rate and recurrence rate requires further elucidation of the underlying regulatory mechanism of cancer-related immunity. AIMS: To study the regulatory function of Orexin A in the expression of exosomal PD-L1 and T cell activity. METHODS: Orthotopic colon cancer transplantation mice model were established to study the cancer growth and immune infiltration between Orexin A treated group and untreated group. In vitro studies using mouse CT-26 and human HCT-116 colon cancer cell model studied the effect of Orexin A on cellular and exosomal PD-L1 expression. Co-culturing Jurkat cells with exosomes delivered by cancer cells treated with Orexin A, PD-L1 knockdown and PBS studied different effects on T cell. Comparing Orexin A with WP1066, a JAK2/STAT3 inhibitor verified the mechanism of these changes. RESULTS: The growth rate of orthotopic transplanted colon cancer was slower in Orexin A treated group, with lower PD-L1 expression and higher immune infiltration. Orexin A could inhibit cellular and exosomal PD-L1 expression. The decreased expression of PD-L1 in exosomes could promote the activity of Jurkat cells secreting higher level of IFN-γ and IL-2. Orexin A showed a similar effect like WP1066 which proved JAK2/STAT3 signaling pathway was its downstream signaling pathway. CONCLUSIONS: Orexin A could suppress the expression of exosomal PD-L1 in colon cancer cells and promote T cells activity by inhibiting JAK2/STAT3 signaling pathway.

Poly(ethylene-Co-vinyl Alcohol)/Titanium Dioxide Nanocomposite: Preparation and Characterization of Properties for Potential Use in Bone Tissue Engineering.

A series of poly(ethylene-co-vinyl alcohol)/titanium dioxide (PEVAL/TiO2) nanocomposites containing 1, 2, 3, 4 and 5 wt% TiO2 were prepared by the solvent casting method. These prepared hybrid materials were characterized by Fourier-transform infrared (FT-IR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and scanning electron microscopy (SEM). The pores and their interconnections inside these nanocomposites were created using naphthalene microparticles used as a porogen after having been extracted by sublimation under a high vacuum at temperatures slightly below the glass transition temperature. A cellular activity test of these hybrid materials was performed on human gingival fibroblast cells (HGFs) in accordance with ISO 10993-5 and ISO 10993-12 standards. The bioviability (cell viability) of HGFs was evaluated after 1, 4 and 7 days using Alamar Blue®. The results were increased cell activity throughout the different culture times and a significant increase in cell activity in all samples from Day 1 to Day 7, and all systems tested showed significantly higher cell viability than the control group on Day 7 (p < 0.002). The adhesion of HGFs to the scaffolds studied by SEM showed that HGFs were successfully cultured on all types of scaffolds.

Modulatory effect of resveratrol and melatonin on natural killer cell activity and adrenomedullin in diabetic rats.

BACKGROUND: Epidemiological evidence suggests that diabetes poses a high risk for many chronic diseases, especially cardiovascular diseases, and cancer by stimulating many inflammatory and immunological pathogenic mediators and affecting natural killer (NK)-cell activity. In this study, the effects of melatonin and resveratrol on IL-6, TNF-alpha, oxidant/antioxidant capacity, NK-cell activity, and mid-regional proadrenomedullin (MR-proADM) levels of diabetic rats were investigated. METHODS: In the study, 28 Sprague Dawley rats were randomly divided into the control group (group I) and 3 streptozotocininduced diabetes mellitus (DM) groups (group II, III, and IV), each group consisting of 7 rats. Five mg/kg/day melatonin to group III and 5 mg/kg/day resveratrol (intraperitoneal) to group IV was given. At the end of 3 weeks, NK-cell activity, total antioxidant/oxidant capacity, MR-proADM, IL-6, and TNF-alpha levels were measured in intracardiac blood taken under anesthesia. RESULTS: NK-cell activity of group II was found lower than group I, group III, and group IV (7.4 ± 2.0 vs. 22.5 ± 11.9, 30.6 ± 22.5 and 20.4 ± 9.1 pg/mL; p = 0.0018, respectively). The difference was more prominent in diabetic rats receiving melatonin (p < 0.01). TNF-alpha levels of group II were higher than the group I (p < 0.05). The MR-proADM levels of group II were found to be lower than the group I and group III (6.4 ± 3.6 vs. 14.4 ± 3.2 and 14.0 ± 4.2 ng/L; p < 0.05, respectively). In addition, NK-cell activity was moderately correlated with MR-proADM (r = 0.5618, p = 0.0019).