Autophagy, Inflammation, and Immune Dysfunction in the Pathogenesis of Pancreatitis

Neuroinflammation refers to a highly complicated reaction of the central nervous system (CNS) to certain stimuli such as trauma, infection, and neurodegenerative diseases. This is a cellular immune response whereby glial cells are activated, inflammatory mediators are liberated and reactive oxygen and nitrogen species are synthesized. Neuroinflammation is a key process that helps protect the brain from pathogens, but inappropriate, or protracted inflammation yields pathological states such as Parkinson’s disease, Alzheimer’s, Multiple Sclerosis, and other neurodegenerative disorders that showcase various pathways of neurodegeneration distributed in various parts of the CNS. This review reveals the major neuroinflammatory signaling pathways associated with neurodegeneration. Additionally, it explores promising therapeutic avenues, such as stem cell therapy, genetic intervention, and nanoparticles, aiming to regulate neuroinflammation and potentially impede or decelerate the advancement of these conditions. A comprehensive understanding of the intricate connection between neuroinflammation and these diseases is pivotal for the development of future treatment strategies that can alleviate the burden imposed by these devastating disorders.

The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets

Mesenchymal stem cells (MSCs) can serve as a vehicle for gene therapy. Angiopoietin-1 (ANGPT1) plays an important role in the regulation of endothelial cell survival, vascular stabilization, and angiogenesis. We hypothesized that ANGPT1 gene-modified MSCs might be a potential therapeutic approach for severe acute pancreatitis (SAP) in rats. Human umbilical cord-derived MSCs with or without transfection with lentiviral vectors containing the ANGPT1 gene were delivered through the tail vein of rats 12 h after induction of SAP. Administration of MSCs alone significantly reduced pancreatic injury and inflammation, as reflected by reductions in pancreatitis severity scores and serum amylase and lipase levels as well as reducing the serum levels of proinflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6). Furthermore, administration of ANGPT1-transfected MSCs resulted in not only further reductions in pancreatic injury and serum levels of proinflammatory cytokines, but also promotion of pancreatic angiogenesis. These results suggest that MSCs and ANGPT1 have a synergistic role in the treatment of SAP. ANGPT1 gene-modified MSCs may be developed as a potential novel therapy strategy for the treatment of SAP.

Angiopoietin-1 gene-modified human mesenchymal stem cells promote angiogenesis and reduce acute pancreatitis in rats

Antagonist of fractalkine (CX3CL1) delays the initiation and ameliorates the progression of lupus nephritis in MRL/lpr mice

It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3(rd) d to the 14(th) d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis.

Immunomodulatory therapies for acute pancreatitis.

For decades, it has been widely believed that the blood–brain barrier (BBB) provides an immune privileged environment in the central nervous system (CNS) by blocking peripheral immune cells and humoral immune factors. This view has been revised in recent years, with increasing evidence revealing that the peripheral immune system plays a critical role in regulating CNS homeostasis and disease. Neurodegenerative diseases are characterized by progressive dysfunction and the loss of neurons in the CNS. An increasing number of studies have focused on the role of the connection between the peripheral immune system and the CNS in neurodegenerative diseases. On the one hand, peripherally released cytokines can cross the BBB, cause direct neurotoxicity and contribute to the activation of microglia and astrocytes. On the other hand, peripheral immune cells can also infiltrate the brain and participate in the progression of neuroinflammatory and neurodegenerative diseases. Neurodegenerative diseases have a high morbidity and disability rate, yet there are no effective therapies to stop or reverse their progression. In recent years, neuroinflammation has received much attention as a therapeutic target for many neurodegenerative diseases. In this review, we highlight the emerging role of the peripheral and central immune systems in neurodegenerative diseases, as well as their interactions. A better understanding of the emerging role of the immune systems may improve therapeutic strategies for neurodegenerative diseases.

https://www.frontiersin.org/articles/10.3389/fnagi.2022.872134/pdf

The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases

Fractalkine (FKN), a chemokine that acts as both an adhesion molecule and a chemoattractant, is expressed in many inflammatory diseases Chemokines play a crucial role in severe acute pancreatitis (SAP) This study used adenovirus-mediated siRNA to target FKN overexpression and assessed its ability to suppress inflammation development in a SAP rat model Adenovirus-mediated FKN siRNA was transfected into cerulein-stimulated AR42J cells The growth of cerulein-stimulated AR42J cells was determined by colony formation and MTT assays The inhibitory effect of the FKN siRNA was studied in a SAP rat model in vivo and detected by ELISA, RT-PCR, western blot analysis and immunohistochemistry FKN, IL-8 and TNF-α were found to be overexpressed in cerulein-stimulated AR42J cells by ELISA and western blot analysis (P<005) The animal experiments confirmed that FKN siRNA could inhibit inflammation development in SAP The values of serum FKN, TNF-α and IL-8 levels were decreased after FKN siRNA treatment (P<005) Furthermore, western blotting and RT-PCR analysis showed that FKN protein and mRNA levels were decreased after injection with FKN siRNA (P<005) Immunohistochemistry also showed that inflammation was decreased after injection with FKN-siRNA in the SAP rat model Treatment with siRNA can inhibit FKN overexpression and also suppresses inflammation development in a SAP rat model More importantly, this study indicated that FKN, which is overexpressed in the SAP rat model, may serve as a novel and effective therapeutic target for SAP

/pdf/sirna-based-targeting-of-fractalkine-overexpression-4mzcvs1i4m.pdf

siRNA-based targeting of fractalkine overexpression suppresses inflammation development in a severe acute pancreatitis rat model

Appendiceal mucinous neoplasms: a case report and review of literature.

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The Emerging Role of Central and Peripheral Immune Systems in Neurodegenerative Diseases

siRNA-based targeting of fractalkine overexpression suppresses inflammation development in a severe acute pancreatitis rat model

Appendiceal mucinous neoplasms: a case report and review of literature.