Therapeutic potential of interleukin-21 in cancer.

Interleukin-21 (IL-21) is an immunostimulatory cytokine which belongs to the common gamma-chain family of cytokines. It plays an import role in the development, differentiation, proliferation, and activation of immune cells, in particular T and natural killer (NK) cells. Since its discovery in 2000, IL-21 has been shown to regulate both adaptive and immune responses associates with key role in antiviral and antitumor responses. Recent advances indicate IL-21 as a promising target for cancer treatment and encouraging results were obtained in preclinical studies which investigated the potency of IL-21 alone or in combination with other therapies, including monoclonal antibodies, checkpoint inhibitory molecules, oncolytic virotherapy, and adoptive cell transfer. Furthermore, IL-21 showed antitumor effects in the treatment of patients with advanced cancer, with minimal side effects in several clinical trials. In the present review, we will outline the recent progress in IL-21 research, highlighting the potential of IL-21 based therapy as single agent or in combination with other drugs to enhance cancer treatment efficiency.

Behaviour testing in two different knockout mouse strains related to chronic inflammation and oxidative stress.

CD36, a fatty acid translocator and NRF2, a transcription factor, are two important players in inflammation and oxidative stress, including in the central nervous system. Both were associated with neurodegeneration as tilting arms of a balance: while activation of CD36 participates in neuroinflammation, activation of NRF2 seems to protect against oxidative stress and neuroinflammation. This study aimed to establish whether tilting the balance one way or the other, by knocking out either of them (NRF2-/- or CD36-/-), would show that one holds higher weight over the other in the cognitive behaviour of mice. We tested both young and old knockout animals in a long-term testing protocol (over one month), using the 8-arm radial maze,. Young NRF2-/- mice exhibited a sustained anxious-like behaviour, which was not recapitulated in old mice nor CD36 -/- mice of either age. Neither knockout strain exhibited cognitive alterations, although CD36 -/- mice showed some improvement over WT littermates. In conclusion, NRF2-/- seems to affect behaviour of mice early in life, and could be considered a vulnerability factor for neurocognition, while CD36 impact on cognitive protection of the aging brain requires more investigation.

Unconventional Therapy with IgY in a Psoriatic Mouse Model Targeting Gut Microbiome.

Psoriasis has a multifactorial pathogenesis and recently it was shown that alterations in the skin and intestinal microbiome are involved in the pathogenesis of psoriasis. Therefore, microbiome restoration becomes a promising preventive/therapy strategy in psoriasis. In our pre-clinical study design using a mice model of induced psoriatic dermatitis (Ps) we have tested the proof-of-concept that IgY raised against pathological human bacteria resistant to antibiotics can alleviate psoriatic lesions and restore deregulated immune cell parameters. Besides clinical evaluation of the mice and histology of the developed psoriatic lesions, cellular immune parameters were monitored. Immune cells populations/subpopulations from peripheral blood and spleen cell suspensions that follow the clinical improvement were assessed using flow cytometry. We have quantified T lymphocytes (CD3ε+) with T-helper (CD4+CD8-) and T-suppressor/cytotoxic (CD8a+CD4-) subsets, B lymphocytes (CD3ε-CD19+) and NK cells (CD3ε-NK1.1+). Improved clinical evolution of the induced Ps along with the restoration of immune cells parameters were obtained when orally IgY was administered. We pin-point that IgY specific compound can be used as a possible pre-biotic-like alternative adjuvant in psoriasis.

Gait Analysis Using Animal Models of Peripheral Nerve and Spinal Cord Injuries.

The present review discusses recent data regarding rodent models of spinal cord and peripheral nerve injuries in terms of gait analysis using the CatWalk system (CW), an automated and exceptionally reliable system for assessing gait abnormalities and motor coordination. CW is a good tool for both studying improvements in the walking of animals after suffering a peripheral nerve and spinal cord lesion and to select the best therapies and procedures after tissue destruction, given that it provides objective and quantifiable data. Most studies using CW for gait analysis that were published in recent years focus on injuries inflicted in the peripheral nerve, spinal cord, and brain. CW has been used in the assessment of rodent motor function through high-resolution videos, whereby specialized software was used to measure several aspects of the animal's gait, and the main characteristics of the automated system are presented here. CW was developed to assess footfall and gait changes, and it can calculate many parameters based on footprints and time. However, given the multitude of parameters, it is necessary to evaluate which are the most important under the employed experimental circumstances. By selecting appropriate animal models and evaluating peripheral nerve and spinal cord lesion regeneration using standardized methods, suggestions for new therapies can be provided, which represents the translation of this methodology into clinical application.

Therapeutic potential of interleukin-15 in cancer (Review).

The immune system is dysfunctional in cancer, and therapeutic approaches designated to restore immunity and increase long-term overall survival are desirable. The role of immunotherapy is to trigger the immune system to recognize and destroy tumor cells. Interleukin-15 (IL-15) is a member of the common gamma-chain (γc) cytokines that promote the differentiation and expansion of T cells, B cells and natural killer (NK) cells, leading to enhanced antitumor responses. This suggests that IL-15 is a promising candidate for anticancer therapy. Renewed interest in cancer immunotherapy has led to an increased number of preclinical studies and clinical trials that have investigated the reliability and potency of IL-15-based agents, not only as single therapy, but also in combination with others. This review provides a description of these studies which show the advantages and disadvantages of IL-15 as an immunotherapeutic agent. We present here the role of IL-15 and pharmacologically improved IL-15 superagonists as a single treatment or in combination with other therapeutic agents.

Oxidative Stress: A Possible Trigger for Pelvic Organ Prolapse.

Pelvic organ prolapse is a frequent health problem in women, encountered worldwide, its physiopathology being still incompletely understood. The integrity of the pelvic-supportive structures is a key element that prevents the prolapse of the pelvic organs. Numerous researchers have underlined the role of connective tissue molecular changes in the pathogenesis of pelvic organ prolapse and have raised the attention upon oxidative stress as an important element involved in its appearance. The advancements made over the years in terms of molecular biology have allowed researchers to investigate how the constituent elements of the pelvic-supportive structures react in conditions of oxidative stress. The purpose of this paper is to underline the importance of oxidative stress in the pathogenesis of pelvic organ prolapse, as well as to highlight the main oxidative stress molecular changes that appear at the level of the pelvic-supportive structures. Sustained mechanical stress is proven to be a key factor in the appearance of pelvic organ prolapse, correlating with increased levels of free radicals production and mitochondrial-induced fibroblasts apoptosis, the rate of cellular apoptosis depending on the intensity of the mechanical stress, and the period of time the mechanical stress is applied. Oxidative stress hinders normal cellular signaling pathways, as well as different important cellular components like proteins, lipids, and cellular DNA, therefore significantly interfering with the process of collagen and elastin synthesis.

The redox biology network in cancer pathophysiology and therapeutics.

The review pinpoints operational concepts related to the redox biology network applied to the pathophysiology and therapeutics of solid tumors. A sophisticated network of intrinsic and extrinsic cues, integrated in the tumor niche, drives tumorigenesis and tumor progression. Critical mutations and distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation and efficient repair mechanisms. Additionally, the complex inter-cellular crosstalk within the tumor niche, mediated by cytokines, redox-sensitive danger signals (HMGB1) and exosomes, under the pressure of multiple stresses (oxidative, inflammatory, metabolic), greatly contributes to the malignant phenotype. The tumor-associated inflammatory stress and its suppressive action on the anti-tumor immune response are highlighted. We further emphasize that ROS may act either as supporter or enemy of cancer cells, depending on the context. Oxidative stress-based therapies, such as radiotherapy and photodynamic therapy, take advantage of the cytotoxic face of ROS for killing tumor cells by a non-physiologically sudden, localized and intense oxidative burst. The type of tumor cell death elicited by these therapies is discussed. Therapy outcome depends on the differential sensitivity to oxidative stress of particular tumor cells, such as cancer stem cells, and therefore co-therapies that transiently down-regulate their intrinsic antioxidant system hold great promise. We draw attention on the consequences of the damage signals delivered by oxidative stress-injured cells to neighboring and distant cells, and emphasize the benefits of therapeutically triggered immunologic cell death in metastatic cancer. An integrative approach should be applied when designing therapeutic strategies in cancer, taking into consideration the mutational, metabolic, inflammatory and oxidative status of tumor cells, cellular heterogeneity and the hypoxia map in the tumor niche, along with the adjoining and systemic effects of oxidative stress-based therapies.

Hematology references for three laboratory mice strains.

The paper contains reference data for the main haematologic indicators from three strains of conventional mice: Balb/c, C57BL/6 and CD1. These data listed include the mean and the standard deviation of the studied values. The animals used were divided by sex (sex ratio 1:1) and age. The study was performed in standard conditions. These strains were chosen as they are widely used for preclinical evaluations. Therefore, our data are expected to be useful for investigators conducting qualitative and quantitative toxicity studies in these mice.

Dynamics of endothelial progenitor cells following sevoflurane preconditioning.

There is relevant evidence concerning the involvement of endothelial progenitor cells in neovascularization and wound healing. In this study we investigated the effects of sevoflurane, a volatile anesthetic with proven cardioprotective virtues, on the mobilization of bone marrow mononuclear cells with endothelial progenitor markers (CD 34+, flk-1 +), an event that may account for the protective effects of delayed anesthetic preconditioning. Male Wistar rats were treated with a mixture of air and sevoflurane (1 MAC) in cycles of 5 minutes, alternating with 5-minutes wash-out periods (the preconditioned group), or ventilated for 30 minutes with room air (control group). Following flow cytometry and immunofluorescence measurements, a considerable increase in circulating CD34+, flk-1 + and CD34+/flk-1 + cells was observed in the preconditioned group beginning at 12 hours after treatment, with a peak value at 24 hours after sevoflurane administration. These cells are a potential source of myocardial regeneration in the context of perioperative or periprocedural ischemia in patients with coronary artery disease.