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Cancer immunity and immunotherapy beyond COVID-19.

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… In the serum, inosine produced by Bifidobacterium pseudolongum and Akkermansia mediated tumor control by activating the cognate adenosine A2A receptor on T cells in the presence of costimulatory signals. … Mager LF Burkhard R Pett N Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy Science 2020 369 1481 1489 10.1126/science.abc3421 32792462 37. …

Targeting ADAR1 Restores Interferon Signaling and Enhances Immunotherapy Response in Multiple Myeloma.

Multiple myeloma (MM) remains an incurable hematological malignancy in which tumor-intrinsic immune evasion limits the efficacy of immunotherapy. Here, we identify the RNA editing enzyme ADAR1 as a key regulator of innate immune suppression in MM. Integrative analyses of bulk and single-cell transcriptomic datasets, together with clinical validation, demonstrated that ADAR1 is upregulated in malignant plasma cells and is associated with adverse clinical outcomes and reduced CD8+ T-cell infiltration. Mechanistically, ADAR1 knockdown increased the association of endogenous dsRNA with melanoma di

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… Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA editing enzyme that catalyzes adenosine-to-inosine (A-to-I) conversion in double-stranded RNA (dsRNA), thereby modulating the recognition of endogenous RNA by innate immune sensors such as melanoma differentiation–associated protein 5 (MDA5) [ 12 … ADAR1 is a central regulator of innate immune homeostasis through adenosine-to-inosine (A-to-I) RNA editing. By editing endogenous double-stranded RNA (dsRNA), ADAR1 prevents inappropriate activation of innate immune sensors, including MDA5 and PKR, thereby maintaining immune tolerance. …

Gut microbiota shapes cancer immunotherapy responses.

The gut microbiota significantly influences cancer immunotherapy efficacy by modulating immune responses, remodeling the tumor microenvironment (TME), and producing key metabolites. Strategies such as FMT, probiotics, and dietary interventions show promise in enhancing responses to ICIs and ACTs while reducing immune-related adverse events (irAEs). This review summarizes clinical and preclinical findings and discusses microbiota-based interventions and future directions for precision immunotherapy.

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… Additionally, inosine interacts with adenosine 2A receptors on T lymphocytes, leading to IL-12 receptor β2 activation and IFN-γ upregulation, further strengthening immune responses 155 . … For instance, Bifidobacterium pseudolongum produces inosine, which activates the T cell adenosine A2A signaling pathway, improving immunotherapeutic efficacy 176 . …

The impact of the gut microbiome on tumor immunotherapy: from mechanism to application strategies.

Immunotherapy is one of the fastest developing areas in the field of oncology. Many immunological treatment strategies for refractory tumors have been approved and marketed. Nevertheless, much clinical and preclinical experimental evidence has shown that the efficacy of immunotherapy in tumor treatment varies markedly among individuals. The commensal microbiome mainly colonizes the intestinal lumen in humans, is affected by a variety of factors and exhibits individual variation. Moreover, the gut is considered the largest immune organ of the body due to its influence on the immune system. In t

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… Some microbiota-derived metabolites, such as SCFAs, inosine, and peptidoglycan, or invasive microbes can activate macrophages (Møs), T cells and B cells in the lamina propria or Peyer’s patches. … Mager Lukas et al. found that inosine produced by Bifidobacterium pseudolongum activates the T-cell-specific A 2A R signaling pathway and stimulates strong antitumor immunity in the tumor and spleen, thereby promoting the efficacy of anti-CTLA-4 antibodies in mouse colon cancer [ 134 ]. …

COVID-19 in 96 Patients With Hematologic Disease: The First Single-center Experience From the Czech Republic.

BackgroundCoronavirus disease 2019 (COVID-19) represents an important infectious complication associated with high mortality rates in patients with hematologic diseases. There have not been published any epidemiologic studies from Czech Republic so far.Patients and methodsThis study is the first analysis of patients with hematologic malignancies and bone marrow failure syndromes treated at single hematology center in the Czech Republic between March 1 and December 31, 2020, in whom COVID-19 infection was confirmed.ResultsThe sample comprised 96 patients aged 26 to 84 years (median, 66.0 years)

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… Patients staying in the center's COVID care unit were treated in accordance with the World Health Organization (WHO) guidance for clinical management of COVID-19. 8 , 9 Depending on the severity of their condition, COVID-19 patients were treated with corticosteroids, remdesivir, convalescent plasma, inosine … Five patients (5.2%) were given inosin pranobex. The other patients either did not receive this therapy or such information could not be obtained from their medical records. …

Current strategies for armoring chimeric antigen receptor T-cells to overcome barriers of the solid tumor microenvironment.

Chimeric antigen receptor (CAR) T-cell therapy is a transformative immunotherapeutic approach, yet its application in solid tumors is hindered by the immunosuppressive tumor microenvironment (TME). The TME restricts T-cell trafficking, impairs effector functions, and promotes exhaustion through soluble factors, metabolic stress, and suppressive cell populations. Recent efforts to enhance CAR T-cell efficacy have focused on armoring strategies that 'reprogram' and 'boost' T-cell responses within the TME. These include engineered expression of dominant-negative receptors or cytokine-releasing co

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… Adenosine deaminase (ADA) is an enzyme that catabolizes adenosine into inosine, thereby preventing accumulation of adenosine. … To avoid supplying inosine to tumor cells, they engineered ADA-secreting CAR T-cells with the secreted ADA anchored to the CAR T-cell. …

The Gut-Bone Marrow Axis: Deciphering the Mechanistic Impact of Microbial Metabolites on Hematopoietic Homeostasis and Disorders.

The gut microbiota is increasingly recognized as a dynamic endocrine-like microbial network that exerts systemic effects far beyond the gastrointestinal tract. Emerging evidence supports the existence of a "gut-bone marrow axis" through which gut-derived signals orchestrate hematopoietic homeostasis. However, shifting from correlative observations to causal mechanisms remains a major challenge in defining precise microbial impacts on hematopoietic outcomes. In this review, we systematically synthesize current knowledge on the molecular mechanisms by which microbial products-specifically short-

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… Inosine, a key intermediate in purine metabolism, promotes uric acid production when its concentration increases. However, certain Lactobacilli , such as DM9218 , can degrade inosine by expressing inosine hydrolase, thereby reducing hepatic precursors of uric acid synthesis [ 71 ]. … Lactobacillus brevis DM9218 ameliorates fructose-induced hyperuricemia through inosine degradation and manipulation of intestinal dysbiosis. Nutrition. 2019;62:63–73. doi: 10.1016/j.nut.2018.11.018. 70. Ghosh S., Whitley C.S., Haribabu B., Jala V.R. …

CD200 является мощным новым фактором роста в Мультимиломе, зависящим от сигнала рецептора IGF1.

CD200 — это иммунный контрольно-пропускной пункт, безошибочно выраженный в 70% недавно диагностированных пациентов с множественной миеломой (ММ) и связанный с плохим исходом. Выражение CD200 клетками опухоли препятствует иммунной реакции через взаимодействие с CD200R и участвует в устойчивости к иммунной терапии. Однако его роль в опухоли остается слабой. В этом исследовании мы показываем, что клетки MM, перевыражающие CD200, представляют собой значительное пролиферативное преимущество в свободных культурных сыворотках, средних и клоногенных анализах. Преимущество роста клеток, опосредованное

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… shock protein 90 kDa alpha (cytosolic), class B member 1 183.5 IF2G_HUMAN eukaryotic translation initiation factor 2, subunit 3 gamma, 52kDa 62.5 IGHG2_HUMAN immunoglobulin heavy constant gamma 2 (G2m marker) 324.4 IGHG4_HUMAN immunoglobulin heavy constant gamma 4 (G4m marker) 571.6 IMDH2_HUMAN IMP (inosine … shock protein 90 kDa alpha (cytosolic), class B member 1 183.5 IF2G_HUMAN eukaryotic translation initiation factor 2, subunit 3 gamma, 52kDa 62.5 IGHG2_HUMAN immunoglobulin heavy constant gamma 2 (G2m marker) 324.4 IGHG4_HUMAN immunoglobulin heavy constant gamma 4 (G4m marker) 571.6 IMDH2_HUMAN IMP (inosine …

Genetic and Plasma Proteomic Approaches to Identify Therapeutic Targets for Graves' Disease and Graves' Ophthalmopathy.

BackgroundThe blood proteome is a major source of biomarkers and therapeutic targets. We aimed to identify the causal proteins and potential targets for Graves' disease (GD) and Graves' ophthalmopathy (GO) via systematic genetic analyses.MethodsGenome-wide association studies (GWASs) on the UK Biobank- Pharma Proteomics Project (UKB-PPP) collected 2923 Olink proteins from 54,219 participants. We conducted a proteome-wide Mendelian randomization (MR) study with cis-pQTLs to identify candidate proteins for GD and GO risk. Colocalization analysis and the Heidi test were used to examine whether th

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… GMPR is a key enzyme in the nucleotide anabolic pathway that converts guanosine monophosphate (GMP) to inosine monophosphate (IMP). … Potential of Onchocerca ochengi inosine-5′-monophosphate dehydrogenase (IMPDH) and guanosine-5′-monophosphate oxidoreductase (GMPR) as druggable and vaccine candidates: immunoinformatics screening. J Biomol Struct Dyn . 2023;41(24):14832–14848. doi: 10.1080/07391102.2023.2184171 45. …

Transplant oncology and anti-cancer immunosuppressants.

Organ transplantation is a life-saving intervention that enhances the quality of life for patients with end-stage organ failure. However, long-term immunosuppressive therapy is required to prevent allogeneic graft rejection, which inadvertently elevates the risk of post-transplant malignancies, especially for liver transplant recipients with a prior history of liver cancer. In response, the emerging field of transplant oncology integrates principles from oncology and immunology to improve outcomes for patients at high risk of tumor occurrence or recurrence following transplantation. Therefore,

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… Mycophenolic acid and its derivatives Mycophenolic acid (MPA), an antibiotic derived from Penicillium stoloniferum and similar fungal strains, inhibits the proliferation and function of T and B lymphocytes by targeting inosine monophosphate dehydrogenase, the rate-limiting enzyme in the de novo synthesis … Phase I clinical trial of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil (cellcept) in advanced multiple myeloma patients. Clin Cancer Res. (2004) 10:8301–08. doi: 10.1158/1078-0432.CCR-04-0747 45. …

Clinical antitumor application and pharmacological mechanisms of Dahuang Zhechong Pill.

Cancer still has elevated morbidity and mortality, which undoubtedly impacts the life quality of affected individuals. Remarkable advances have been made in cancer therapy, although the toxicities of traditional therapies remain an obvious challenge. Dahuang Zhechong Pill (DHZCP), developed by Zhongjing Zhang in the Synopsis of the Golden Chamber, represents an effective anticancer traditional Chinese medicine (TCM). In this review, it was found that DHZCP is therapeutically utilized in liver, lung, gastric, pancreatic and other cancers in clinic. Pharmacological evidence showed that its anti-

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… tyrosine C 9 H 11 NO 3 Y 16 Kaempferol C 15 H 10 O 6 Y 86 DL -Lysine C 6 H 14 N 2 O 2 Y 17 Campesterol C 28 H 48 O Y 87 Uracil C 4 H 4 N 2 O 2 Y 18 Oleic acid C 18 H 34 O 2 Y 88 Uridine C 9 H 12 N 2 O 6 Y 19 Linoleic acid C 18 H 32 O 2 Y 89 Hypoxanthine C 5 H 4 N 4 O Y 20 Heptanoic Acid C 7 H 14 O 2 Y 90 Inosine … H 14 N 2 O 2 | Y 17 | Campesterol | C 28 H 48 O | Y | 87 | | Uracil | C 4 H 4 N 2 O 2 | Y 18 | Oleic acid | C 18 H 34 O 2 | Y | 88 | | Uridine | C 9 H 12 N 2 O 6 | Y 19 | Linoleic acid | C 18 H 32 O 2 | Y | 89 | | Hypoxanthine | C 5 H 4 N 4 O | Y 20 | Heptanoic Acid | C 7 H 14 O 2 | Y | 90 | | Inosine …

Синдром Нейро-Бехчета: доклад по делу.

Синдром Бехчета является системным васкулитом, характеризующимся повторяющимися оральными и генитальными язвами, увеитизмом и часто связанным с множественными системами органов. Неврологическое участие является редким осложнением синдрома Бехчета и связано со значительной заболеваемостью и смертностью. Синдром Neuro-Behchet (NBS) представляет собой сочетание неврологических проявлений у пациента с синдромом Бехчета, включая расстройства движения, миэлопатический синдром, внутричерепную гипертонию и многократную склероз-подобную презентацию. Диагноз NBS может быть проблематичным из-за широкого

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… Mycophenolate mofetil, a prodrug of mycophenolic acid, is an inhibitor of inosine-5’-monophosphate dehydrogenase, which can be used to treat NBS. There has been a case series of four patients reporting efficacy of mycophenolate mofetil 2 g/day without relapse within three to seven years [ 10 ]. …

Immune mechanisms and immunomodulatory therapies in steroid-resistant nephrotic syndrome.

Steroid-resistant nephrotic syndrome (SRNS) is a complex and refractory kidney disease generally causing chronic kidney dysfunction, characterized by persistent proteinuria despite prolonged corticosteroid therapy. This review comprehensively explores the mechanisms of immunity driving SRNS, mainly focusing on the complex function network within immune cells, pro-inflammatory cytokines, and podocyte injury. Current immunosuppressive therapies show limited efficacy, prompting exploration of precision immunomodulatory strategies. Emerging approaches include IL-17 or low-dose IL-12 modulation, pr

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… NF-κB: nuclear factor-kappa B, SRNS: steroid-resistant nephrotic syndrome, NFAT: nuclear factor of activated T cells, IMPDH: inosine monophosphate dehydrogenase, MMF: Mycophenolate Mofetil, MPA: mycophenolic acid. … Mycophenolate mofetil Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase (IMPDH) in lymphocytes, offering a nephrotoxicity-free alternative for patients intolerant to CNIs. …

Influence of gut microbial metabolites on tumor immunotherapy: mechanisms and potential natural products.

In recent years, tumor immunotherapy has made significant breakthroughs in the treatment of malignant tumors. However, individual differences in efficacy have been observed in clinical practice. There is increasing evidence that gut microbial metabolites influence the efficacy of distal tumor immunotherapy via the gut-liver axis, the gut-brain axis and the gut-breast axis, a process that may involve modulating the expression of immune cells and cytokines in the tumor microenvironment (TME). In this review, we systematically explore the relationship between gut microbial metabolites and tumor i

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… Inosine is mainly derived from endogenous purine nucleosides formed from the deamination metabolism of the adenine portion of nucleic acid by intestinal microorganisms and has the function of regulating the intestinal microbiota and protecting the intestinal mucosal barrier ( 40 ). … Studies have shown that hyaluronic acid conjugates of butyrate can significantly inhibit cell proliferation in pancreatic cancer cell cultures ( 129 ).Another study showed that inosine improved the efficacy of monoclonal antibodies against CTLA-4 and against PD-L1 in mouse models of bladder and small …

Genetic and Epigenetic Regulation of the Innate Immune Response to Gout.

Gout is a disease caused by uric acid (UA) accumulation in the joints, causing inflammation. Two UA forms - monosodium urate (MSU) and solub … 3: interleukin 23; IL23R: interleukin 23 receptor; IL-33: interleukin 33; IL-6: interleukin 6; IMP: inosine monophosphate; INSIG1: insulin-induced gene 1; JNK1: c-jun n-terminal kinase 1; lncRNA: long non-coding ribonucleic acid; LRR: leucine-rich repeats; miR: mature non-coding microRNAs measuring from 20 to 24 nucleotides, animal origin; miR-1: miR foll …

IgA Vasculitis (Henoch-Schönlein Purpura): An Update on Treatment.

Objective: IgA vasculitis (IgAV), previously named as Henoch-Schönlein purpura, is the most frequent systemic vasculitis in children. In adults, IgAV is less common although it is associated with more severe disease. In fact, the frequency of glomerulonephritis (referred to as IgAV nephritis) in adults is higher than in children and tends to present more severely, with around 10-30% of those affected eventually progressing to end-stage renal disease. In this review, we describe the pathophysiology, main clinical features, diagnosis of the disease, and latest clinical data regarding IgAV therap

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… Mycophenolate Mofetil The mechanism of action of mycophenolate mofetil (MMF) has been linked to the inhibition of type I and II inosine monophosphate dehydrogenase, which inhibits the proliferation of B and T lymphocytes reversibly, since the de novo synthesis of DNA and guanosine nucleotide is prevented … Mizoribine Mizoribine (MZB) is an imidazole nucleoside that reduces B- and T-cell proliferation and DNA synthesis through its inhibitory action on inosine monophosphate dehydrogenase and guanosine monophosphate synthetase [ 88 ] ( Table 2 ). …

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

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… The process can be divided into two stages (Figure 1 ): first, the synthesis of inosine monophosphate (IMP), followed by the conversion of IMP into adenosine monophosphate [ 34 ] and guanosine monophosphate (GMP) [ 35 ]. Synthesis of IMP (Figure 1 ). …

Exploring viral mimicry combined with epigenetics and tumor immunity: new perspectives in cancer therapy.

Viral mimicry refers to an active antiviral response triggered by the activation of endogenous retroviruses (ERVs), usually manifested by the formation of double-stranded RNA (dsRNA) and activation of the cellular interferon response, which activates the immune system and produces anti-tumor effects. Epigenetic studies have shown that epigenetic modifications (e.g. DNA methylation, histone modifications, etc.) play a crucial role in tumorigenesis, progression, and treatment resistance. Particularly, alterations in DNA methylation may be closely associated with the suppression of ERVs expressio

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… However, an adenosine deaminase that acts on RNA (ADAR) prevents MDA5 from sensing endogenous dsRNA as nonself by catalyzing adenosine-to-inosine (A-to-I) editing of dsRNA 100 . … In detail, ADAR is a group of enzymes that bind dsRNA to homodimers and catalyze the hydrolytic deamination of adenosine nucleotides to form inosine 101 , 102 . Humans have three ADAR proteins: ADAR1, ADAR2, and ADAR3 103 - 105 . …

Combination strategies of gut microbiota in cancer therapy through metabolic reprogramming and immune remodeling.

Over the past decade, there has been a qualitative improvement in the understanding of gut microbiota in cancer development and treatment. Gut microbiota regulates metabolic reprogramming that occurs in the competition between tumor cells and immune cells for essential nutrients in the tumor microenvironment (TME). Besides, gut microbiota dysbiosis is one of the key factors leading to the formation of aging environment, which has many similarities with the TME. Accumulating research findings have demonstrated that gut microbiota enhances the efficacy of cancer therapies by activating the immun

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… LGG activates cGAS/STING pathway in DCs, promoting CD8 + T cell and NK cell activation; Inosine binds to A2 AR on T cells, promoting the activation of TH1 cells; C. cateniformis reduces the expression of PD-L2 in DCs; B. breve and E. hirae share antigenic similarities with tumors, enhancing the cross-reactive … Mager et al. found that the inosine from Bifidobacterium pseudolongum activates the adenosine A 2 A receptor specifically on T cells, promoting the activation of TH1 cells as well [ 71 ]. …

Invited Lectures : Overviews Purinergic signalling: past, present and future.

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