Immunoregulatory effect of mesenchymal stem cell via mitochondria signaling pathways in allergic asthma

Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied.After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, −5, −13, −25, –33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done.BALf's eosinophils, the levels of IL-4, −5, −13, −25, –33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4.MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology.     

Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth,metastasis and sorafenib resistance through STAT3 activation

The pro-inflammatory and pro-fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl₄ gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non-invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti-apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I-201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up-regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.     

Beyond NF-κB activation: nuclear functions of IκB kinase α

IκB kinase (IKK) complex, the master kinase for NF-κB activation, contains two kinase subunits, IKKα and IKKβ. In addition to mediating NF-κB signaling by phosphorylating IκB proteins during inflammatory and immune responses, the activation of the IKK complex also responds to various stimuli to regulate diverse functions independently of NF-κB. Although these two kinases share structural and biochemical similarities, different sub-cellular localization and phosphorylation targets between IKKα and IKKβ account for their distinct physiological and pathological roles. While IKKβ is predominantly cytoplasmic, IKKα has been found to shuttle between the cytoplasm and the nucleus. The nuclear-specific roles of IKKα have brought increasing complexity to its biological function. This review highlights major advances in the studies of the nuclear functions of IKKα and the mechanisms of IKKα nuclear translocation. Understanding the nuclear activity is essential for targeting IKKα for therapeutics.     

A study on thermal damage during hyperthermia treatment based on DPL model for multilayer tissues using finite element Legendre wavelet Galerkin approach

Hyperthermia is a process that uses heat from the spatial heat source to kill cancerous cells without damaging the surrounding healthy tissues. Efficacy of hyperthermia technique is related to achieve temperature at the infected cells during the treatment process. A mathematical model on heat transfer in multilayer tissues in finite domain is proposed to predict the control temperature profile at hyperthermia position. The treatment technique uses dual-phase-lag model of heat transfer in multilayer tissues with modified Gaussian distribution heat source subjected to the most generalized boundary condition and interface at the adjacent layers. The complete dual-phase-lag model of bioheat transfer is solved using finite element Legendre wavelet Galerkin approach. The present solution has been verified with exact solution in a specific case and provides a good accuracy. The effect of the variability of different parameters such as lagging times, external heat source, metabolic heat source and the most generalized boundary condition on temperature profile in multilayer tissues is analyzed and also discussed the effective approach of hyperthermia treatment. Furthermore, we studied the modified thermal damage model with regeneration of healthy tissues as well. For viewpoint of thermal damage, the least thermal damage has been observed in boundary condition of second kind. The article concludes with a discussion of better opportunities for future clinical application of hyperthermia treatment.     

INHIBITION OF EHRLICH TUMOR GROWTH IN MICE BY ELECTRIC INTERFERENCE THERAPY (IN VIVO STUDIES)

A study of solid tumor growth retardation by employing extremely low frequency (ELF) electric fields has been carried out. ELF electric fields were generated in tumor tissue in mice by the interference of two high frequency sinusoidal waves with the beat frequency centered at the tumor core. The results indicated a pronounced decrease in tumor growth rate in animals exposed to a 5-Hz interferential frequency for 1 hr daily. The 1 hr/day treatment produced a greater retardation effect than the 1 hr/week treatment. This indicates that treatment duration at the applied field frequency appears to play an important role in tumor growth delay. The dielectric properties of the tumor cells showed higher permittivity and conductivity values than homologous normal tissue. The permittivity of tumor cells treated daily with 5 Hz reaches nearly the same value as control tissue. Moreover, histological studies show that tumor tissues treated daily with the same frequency undergo partial regression and shrinkage of the aggregates of neoplastic cells leaving very little of them. We conclude that this new interferential technique is promising for tumor treatment in which a resonating electric field affects cell-to-cell communication.     

The role of cytokines in the pathogenesis of cutaneous lupus erythematosus

Cutaneous lupus erythematosus (CLE) is an inflammatory disease with a broad range of cutaneous manifestations that may be accompanied by systemic symptoms. The pathogenesis of CLE is complex, multifactorial and incompletely defined. Below we review the current understanding of the cytokines involved in these processes. Ultraviolet (UV) light plays a central role in the pathogenesis of CLE, triggering keratinocyte apoptosis, transport of nucleoprotein autoantigens to the keratinocyte cell surface and the release of inflammatory cytokines (including interferons (IFNs), tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, IL-10 and IL-17). Increased IFN, particularly type I IFN, is central to the development of CLE lesions. In CLE, type I IFN is produced in response to nuclear antigens, immune complexes and UV light. Type I IFN increases leukocyte recruitment to the skin via inflammatory cytokines, chemokines, and adhesion molecules, thereby inducing a cycle of cutaneous inflammation. Increased TNFα in CLE may also cause inflammation. However, decreasing TNFα with an anti-TNFα agent can induce CLE-like lesions. TNFα regulates B cells, increases the production of inflammatory molecules and inhibits the production of IFN-α. An increase in the inflammatory cytokines IL-1, IL-6, IL-10, IL-17 and IL-18 and a decrease in the anti-inflammatory cytokine IL-12 also act to amplify inflammation in CLE. Specific gene mutations may increase the levels of these inflammatory cytokines in some CLE patients. New drugs targeting various aspects of these cytokine pathways are being developed to treat CLE and systemic lupus erythematosus (SLE).     

Immune modulation by interleukin-12 in tumor-bearing mice receiving vitamin D3 treatments to block induction of immunosuppressive granulocyte/macrophage progenitor cells

 Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D₃ eliminated natural suppressor activity. In mice that were first treated with vitamin D₃ and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus IL-2. In addition, spleen and lymph node cells from vitamin-D₃/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon γ (IFNγ), although IL-2 production was not stimulated. A prominent effect of the combined vitamin-D₃/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show that, after treatment of tumor bearers with vitamin D₃ to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFNγ production and cytolysis by regional lymph node cells of autologous tumor. Received: 15 December 1995 / Accepted: 22 March 1996     

NK cells: An attractive candidate for cancer therapy

Natural killer (NK) cells have significant capability in tumor immune-surveillance. The ability of lyse transformed cells immediately in an antigen-independent manner make them an attractive candidate for cancer cell therapy. Despite employment of NK cells in cancer immunotherapy, clinical trials are faced with serious limitations such as trouble with the penetration of NK cells in tumor sites, limited in vivo persistence, and tumor microenvironment interference. Taken together, the NK-cell cancer therapy is still infant scenario that has a long way to be translated in clinic. Current article first reviews characteristic features of NK lymphocytes. Then, it discusses about important disruptive barriers and motivator in the developmental stages of NK cells like as tumor microenvironment. Finally, some revolutionary approaches are highlighted utilizing of NK cells in cancer therapy.     

Targeting respiratory complex I to prevent the Warburg effect

In the last 10 years, studies of energetic metabolism in different tumors clearly indicate that the definition of Warburg effect, i.e. the glycolytic shift cells undergo upon transformation, ought to be revisited considering the metabolic plasticity of cancer cells. In fact, recent findings show that the shift from glycolysis to re-established oxidative metabolism is required for certain steps of tumor progression, suggesting that mitochondrial function and, in particular, respiratory complex I are crucial for metabolic and hypoxic adaptation. Based on these evidences, complex I can be considered a lethality target for potential anticancer strategies. In conclusion, in this mini review we summarize and discuss why it is not paradoxical to develop pharmacological and genome editing approaches to target complex I as novel adjuvant therapies for cancer treatment.This article is part of a Directed Issue entitled: Energy Metabolism Disorders and Therapies.