Inosine, gut microbiota, and cancer immunometabolism.

This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in cancer immunometabolism. The immune system plays a paradoxical role in cancer treatment. Antitumor immunity depends on the T-cell priming against tumor antigens, whereas inflammatory mediators trigger the protumor signaling in the tumor microenvironment. Studies link the microbiome with metabolism and immunity-two main factors implicated in carcinogenesis. Gut microbiota has been shown to affect both antitumor immunity and protumor immune signaling. There is mounting evidence that the human microbiome can play a role in the immunotherapeutic effects, both response and resistance. Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conservative enzyme widely expressed in mammals. Cell signaling pathways use molecular inosine, a crucial secondary metabolite in purine metabolism and a molecular messenger. Recent research has identified inosine as a critical regulator of immune checkpoint inhibition (ICI) therapeutic response in various tumor types. Some bacterial species were found to produce inosine or its metabolite hypoxanthine and induce T-helper 1 differentiation and effector functions via the inosine-A2AR-cAMP-PKA pathway upon ICI therapy. Also, inosine acts as a substitute carbon source for T-cell metabolism in glucose-restricted environments, i.e., the tumor microenvironment, assisting T-cell proliferation and differentiation while enhancing sensitivity to ICI, reinforcing the notion that inosine metabolism might contribute to antitumor immunity. Also, inosine is a potent agonist of the adenosine receptor, A2AR, and A2AR signaling can affect T-cell responses and antitumor immunity, making the inosine-A2AR pathway blockage a candidate for cancer treatment. Further research is required to investigate inosine as a cancer immunometabolism therapy.

Therapeutic potential of ADAM10 modulation in Alzheimer's disease: a review of the current evidence.

Alzheimer's disease (AD), the most common neurodegenerative disease worldwide, is caused by loss of neurons and synapses in central nervous system. Several causes for neuronal death in AD have been introduced, the most important of which are extracellular amyloid ß (Aß) accumulation and aggregated tau proteins. Increasing evidence suggest that targeting the process of Aß production to reduce its deposition can serve as a therapeutic option for AD management. In this regard, therapeutic interventions shown that a disintegrin and metalloproteinase domain-containing protein (ADAM) 10, involved in non-amyloidogenic pathway of amyloid precursor protein processing, is known to be a suitable candidate. Therefore, this review aims to examine the molecular properties of ADAM10, its role in AD, and introduce it as a therapeutic target to reduce the progression of the disease. Video abstract.

Dynamic Antibody Response: a Biomarker for COVID-19.

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is the cause of the third pneumonia-like outbreak of coronaviruses in humans during the 21st century. The status of the host immune system is a critical factor that affects the severity and outcomes of COVID-19. In particular, antibody responses are an indicator of the anti-viral defense; so, a delayed or inappropriate induction of these responses would correlate with a defect in the viral clearance. METHODS: This is a rapid synthesis of literature investigating antibody responses in patients with the severe acute respiratory syndrome (SARS) and COVID-19. RESULTS: Lessons learned from severe acute respiratory syndrome (SARS), along with the direct evidence of antibody responses in COVID-19, pose the potentials of dynamic antibody responses for screening and prognostic purposes in COVID-19. Also, neutralizing antibodies extracted from recovered patients and monoclonal antibodies targeting cytokines offer therapeutic support for COVID-19. CONCLUSIONS: Altogether, the dynamics of antibody responses help to determine the effectiveness of treatments for COVID-19. Of note, it might be helpful for the evaluation of the efficacy of immunotherapy and vaccination - the dreams for the future of COVID-19. Further studies are necessary to investigate the possibility and efficacy of antibody extraction from animal subjects. Finally, numerous factors affect antibody response such as race, nutrition status, and virus mutations in viral infections, which need to be considered in the context of COVID-19.

BDNF and its signaling in cancer.

PURPOSE: Brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophic factors that can potentially increase cancer cell growth, survival, proliferation, anoikis, and migration by tyrosine kinase receptors TrkB and the p75NTR death receptor. The activation of BDNF/TrkB pathways leads to several downstream signaling pathways, including PI3K/Akt, Jak/STAT, PLCγ, Ras-Raf-MEK-ERK, NF-kB, and transactivation of EGFR. The current review aimed to provide an overview of the role of BDNF and its signaling in cancer. METHODS: We searched a major medical database, PubMed, to identify eligible studies for a narrative synthesis. RESULTS: Pathological examinations demonstrate BDNF overexpression in human cancer, notably involving the prostate, lung, breast, and underlying tissues, associated with a higher death rate and poor prognosis. Therefore, measurement of BDNF, either for identifying the disease or predicting response to therapy, can be helpful in cancer patients. Expression profiling studies have recognized the role of microRNAs (miR) in modulating BDNF/TrkB pathways, such as miR-101, miR-107, miR-134, miR-147, miR-191, miR-200a/c, miR-204, miR-206, miR-210, miR-214, miR-382, miR-496, miR-497, miR-744, and miR-10a-5p, providing a potential biological mechanism by which targeted therapies may correlate with decreased BDNF expression in cancers. Clinical studies investigating the use of agents targeting BDNF receptors and related signaling pathways and interfering with the related oncogenic effect, including Entrectinib, Larotrectinib, Cabozantinib, Repotrectinib, Lestaurtinib, and Selitrectinib, are in progress. CONCLUSION: The aberrant signaling of BDNF is implicated in various cancers. Well-designed clinical trials are needed to clarify the BDNF role in cancer progression and target it as a therapeutic method.

Role of Maternal Immune Factors in Neuroimmunology of Brain Development.

Inflammation during pregnancy may occur due to various factors. This condition, in which maternal immune system activation occurs, can affect fetal brain development and be related to neurodevelopmental diseases. MIA interacts with the fetus's brain development through maternal antibodies, cytokines, chemokines, and microglial cells. Antibodies are associated with the development of the nervous system by two mechanisms: direct binding to brain inflammatory factors and binding to brain antigens. Cytokines and chemokines have an active presence in inflammatory processes. Additionally, glial cells, defenders of the nervous system, play an essential role in synaptic modulation and neurogenesis. Maternal infections during pregnancy are the most critical factors related to MIA; however, several studies show the relation between these infections and neurodevelopmental diseases. Infection with specific viruses, such as Zika, cytomegalovirus, influenza A, and SARS-CoV-2, has revealed effects on neurodevelopment and the onset of diseases such as schizophrenia and autism. We review the relationship between maternal infections during pregnancy and their impact on neurodevelopmental processes.

T helper type (Th1/Th2) responses to SARS-CoV-2 and influenza A (H1N1) virus: From cytokines produced to immune responses.

Cytokines produced by T helper cells (Th cells) have essential roles in the body's defense against viruses. Type 1 T helper (Th1) cells are essential for the host defense toward intracellular pathogens while T helper type 2 (Th2) cells are considered to be critical for the helminthic parasites' elimination swine-origin influenza A (H1N1) virus, a disease led to an epidemic in 2009 and rapidly spread globally via human-to-human transmission. Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a global pandemic in 2020 and is a serious threat to the public health. Pulmonary immunopathology is the leading cause of death during influenza and SARS-CoV-2 epidemics and pandemics. Influenza and SARS-CoV-2 cause high levels of cytokines in the lung. Both inadequate levels and high levels of specific cytokines can have side effects. In this literature review article, we want to compare the Th1 and Th2 cells responses in SARS-CoV-2 and H1N1.

Investigation of the Molecular Mechanism of Coagulopathy in Severe and Critical Patients With COVID-19.

Coagulopathy is a frequently reported finding in the pathology of coronavirus disease 2019 (COVID-19); however, the molecular mechanism, the involved coagulation factors, and the role of regulatory proteins in homeostasis are not fully investigated. We explored the dynamic changes of nine coagulation tests in patients and controls to propose a molecular mechanism for COVID-19-associated coagulopathy. Coagulation tests including prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen (FIB), lupus anticoagulant (LAC), proteins C and S, antithrombin III (ATIII), D-dimer, and fibrin degradation products (FDPs) were performed on plasma collected from 105 individuals (35 critical patients, 35 severe patients, and 35 healthy controls). There was a statically significant difference when the results of the critical (CRT) and/or severe (SVR) group for the following tests were compared to the control (CRL) group: PTCRT (15.014) and PTSVR (13.846) (PTCRL = 13.383, p < 0.001), PTTCRT (42.923) and PTTSVR (37.8) (PTTCRL = 36.494, p < 0.001), LACCRT (49.414) and LACSVR (47.046) (LACCRL = 40.763, p < 0.001), FIBCRT (537.66) and FIBSVR (480.29) (FIBCRL = 283.57, p < 0.001), ProCCRT (85.57%) and ProCSVR (99.34%) (ProCCRL = 94.31%, p = 0.04), ProSCRT (62.91%) and ProSSVR (65.06%) (ProSCRL = 75.03%, p < 0.001), D-dimer (p < 0.0001, χ2 = 34.812), and FDP (p < 0.002, χ2 = 15.205). No significant association was found in the ATIII results in groups (ATIIICRT = 95.71% and ATIIISVR = 99.63%; ATIIICRL = 98.74%, p = 0.321). D-dimer, FIB, PT, PTT, LAC, protein S, FDP, and protein C (ordered according to p-values) have significance in the prognosis of patients. Disruptions in homeostasis in protein C (and S), VIII/VIIIa and V/Va axes, probably play a role in COVID-19-associated coagulopathy.