Adomet (S-adenosyl-L-methionine) / Abbott - LARVOL DELTA

Recovery of Severe Acute Hepatic Graft-Versus-Host Disease in A Recently Transplanted Pre-B Cell All (APASL 2024) - "Elevated bilirubins, rather than increase in transaminases, is the best diagnostic marker for Hepatic GVHD. Prompt administration of steroids can help improve the patient's overall survival."

Acute Graft versus Host Disease • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Bone Marrow Transplantation • Gastrointestinal Disorder • Graft versus Host Disease • Hematological Malignancies • Hepatology • Immunology • Infectious Disease • Leukemia • Liver Failure • Oncology • Pneumonia • Respiratory Diseases • Transplantation

High-Density CRISPR Scan Identifies Functional Regions of DOT1L That Mediate Therapeutic Response in MLL-r Leukemia (ASH 2018) - P1; "Furthermore, we identified CRISPR hotspots that coincide with amino acid residues directly contacting the enzymatic substrate S-adenosylmethionine (SAM). Finally, we examined eight clinically observed DOT1L missense mutations in this region (cBioPortal database; 54,510 patients) and foundthree DOT1L-mutant constructs (A591V, G594S and L626P) when expressed in the MLL-AF9 leukemia cells can confer resistance to EPZ5676. These findings suggest the utility of the high-density CRISPR scan for de novoidentification of drug-resistant mutant alleles in the human population, which maydirect future clinical decisions and benefit patients with specific genomic backgrounds."

Acute Myelogenous Leukemia • Biosimilar • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

The results of phase III multicenter open randomized controlled study REM-Chol-III-16 in patients with intrahepatic cholestasis syndrome caused by chronic diffuse liver diseases (PubMed, Ter Arkh) - "Administration of Remaxol as a part of the pathogenetic therapy of patients with intrahepatic cholestasis syndrome who need hepatoprotection is justified."

Journal • P3 data • Cholestasis • Dermatology • Gene Therapies • Hepatology • Pruritus

THE COURSE OF TOXIC HEPATITIS IN LEUKEMIC PATIENTS AT THE STAGE OF SUPPORT THERAPY. (EHOC 2022) - "Each protocol consists of 8 stages of a combination of chemotherapy drugs Metotreksat + 6-Mercaptopurine, which last for 6 weeks and alternate with two-week courses of reinduction - Deksametazon + Vinkristin... Of 51 patients, 42 had toxic hepatitis (82%). It was mild in 12 patients (23.5%), moderate in 26 children (50.9%), and severe in 4 children (7.8%). In the mild form of hepatitis, patients were prescribed intravenous administration of Riboksin + Aevit (orally) for 10-14 days, or alternatively, per os Ursobil + Aevit."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Hepatology • Inflammation • Leukemia • Oncology

Changes in the psychoemotional state under the influence of derivatives of neuroactive amino acids of rats after chronic alcohol intoxication (PubMed, Zh Nevrol Psikhiatr Im S S Korsakova) - "Mefargin, glufimet, phenotropil and heptral restricted anxiety and manifestations of obsessive-compulsive disorder in females subjected to alcoholism (p<0.05). The antidepressant effect was observed in animals treated with phenotropil and heptral after CAI (p<0.05)."

Journal • Preclinical • Mood Disorders • Obsessive-Compulsive Disorder • Psychiatry

Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia (clinicaltrials.gov) - P4; N=150; Recruiting; Sponsor: Tongji Hospital; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Fibrosis • Hematological Disorders • Hepatology • Immunology • Liver Failure • Thrombocytopenia

Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia (clinicaltrials.gov) - P4; N=150; Not yet recruiting; Sponsor: Tongji Hospital

Clinical • New P4 trial • Fibrosis • Hematological Disorders • Hepatology • Immunology • Liver Failure • Thrombocytopenia

[VIRTUAL] NAFLD SUBTYPES WITH IMPAIRED VLDL SECRETION SEGREGATE WITH CARDIOVASCULAR AND CANCER RISK FACTORS (AASLD 2020) - "MAT1A-KO mice have impaired S-adenosylmethionine (SAMe) synthesis and very low-density lipoprotein (VLDL) export... NAFLD subtypes are associated with different NAS values, fibrosis, diabetes, CVD and cancer risks."

Clinical • Cardiovascular • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology

Intrahepatic cholestasis induced by α-naphthylisothiocyanate can cause gut-liver axis disorders. (PubMed, Environ Toxicol Pharmacol) - "After treatment with Transmetil, the liver and gut injuries were relieved. These results suggest that intrahepatic cholestasis can cause disorders of the gut-liver axis."

Journal • Cholestasis • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Inflammation • Inflammatory Bowel Disease • Liver Failure

Using cancer-associated variants to dissect functions of SETD8 (AACR 2018) - "...The SET domain of SETD8 is required to catalyze the methylation in substrates using the cofactor S-adenosyl-L-methionine (SAM)...With the technology of Bioorthogonal Profiling of Protein Methylation (BPPM), we have found that SETD8 can methylate cancer-associated transcription factors in a cellular context. Collectively, these findings suggest that native SETD8 can act on cancer driving-associated transcription factors and its mutant maintains this methyltransferase activity but spare H4K20 methylation for cancer malignancy."

Breast Cancer

ME70 - Repair of Endogenous DNA Damage (AACR 2018) - "...However, a large proportion of DNA damage in vivo is generated by simple reactive agents such as water,oxygen, and simple alkylating agents such as S adenosylmethionine ,as well as formaldehyde.Several distinct DNA repair pathways are widely distributed to counteract such damage. They include base excision repair,with a DNA abasic site as a key intermediate, and several types of direct damage reversal employing unexpected cofactors,also used for RNA demethylation. Previously unknown DNA repair enzymes are relevant for slow DNA turnover in response to persistent introduction of altered DNA residues."

Oncology

Targeting methionine metabolism to eradicate cancer stem cells (AACR 2018) - "...Methionine is converted by the enzyme MAT2A to S-adenosylmethionine (SAM), a universal methyl donor that regulates gene expression by DNA and histone methylation... Our findings point to previously unrecognized metabolic vulnerability of CSCs, namely, their intrinsic dependence on methionine and SAM for cell survival. MR induces expression of MAT2A, thereby providing an explanation for the robust synergy between MR and MAT2A inhibition/silencing in supressing CSC survival. Moreover, cycloleucine potentiates the activity of dietary MR in a murine metastatic TNBC model, providing proof-of-principle in vivo evidence for this novel metabolic approach to eradicate CSCs and thereby improve long-term clinical outcomes in poor-prognosis TNBC."

Cancer stem cells • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Triple Negative Breast Cancer

Discovery of PF-06855800, a SAM competitive PRMT5 inhibitor with potent antitumor activity (AACR 2018) - "...PRMT5 utilizes S-adenosylmethionine (SAM) to methylate a number of cytoplasmic and nuclear substrates that are involved in tumorigenesis...Protein structure-based and ligand property-based design were combined to deliver molecules with desirable potency, selectivity and ADME properties. Here we will describe a series of deazapurine nucleoside analogues that culminate in the identification of PF-06855800, a SAM competitive PRMT5 inhibitor with antiproliferative activity in both in vitro and in vivo models."

Oncology

Pharmacologic targeting of DNA methylation blocks breast cancer growth and metastasis (AACR 2018) - "Pioneering works done by us have shown that treatment of various human cell lines (breast, prostate, osteosarcoma) with a methylating agent S-adenosyl methionine (SAM) can block tumor growth and metastasis in vivo. In addition, immunohistochemical analysis of primary tumors revealed that the combination treatment (Decitabine, SAM) reduced the number of Ki67 positive cells as well reduced the expression of angiogenesis marker CD-31. Further studies examining the effects of combined therapy on genome-wide gene expression changes as well as any potential side effects on animal behavior and toxicity will be presented and discussed.Results from this study will provide compelling evidence and rationale for the initiation of clinical trials with SAM alone as a monotherapy and in combination with currently approved epigenetic drugs (Decitabine) to reduce breast cancer-associated morbidity and mortality."

IO Biomarker • Breast Cancer • Sarcoma

Metabolic vulnerabilities of mesenchymal-like EGFR-mutant NSCLC cells with acquired resistance to tyrosine kinase inhibitors (AACR 2018) - "...However, in the context of NSCLC, there are no comprehensive studies linking epigenomic and metabolic reprogramming during EMT and the acquisition of drug resistance.One-carbon metabolic pathway is composed of the folate and methionine cycle, generating S-adenosylmethionine (SAM), which is the universal methyl donor for methylation reactions, including histone and DNA methylation...This new cancer vulnerability of TKI-resistant, mesenchymal-like NSCLC cells is druggable using NAD depleting agents such as daporinad, a NAMPT inhibitor in phase II clinical trials for the treatment of B-cell chronic lymphocytic leukemia, cutaneous T-cell lymphoma and melanoma. Additionally, the quantitative measurement of the metabolite signature of the nicotinamide pathway in liquid biopsies may correlate with poor prognosis of TKI-treated patients, and emerges as a potential biomarker of TKI response and tumor progression in NSCLC patients. Based on these evidences and tools

Preclinical • Chronic Lymphocytic Leukemia • Cutaneous T-cell Lymphoma • Indolent Lymphoma • Melanoma • Non Small Cell Lung Cancer

Development of Improved Mumps Vaccine Candidates by Mutating Viral mRNA Cap Methyltransferase Sites in the Large Polymerase Protein. (PubMed, Virol Sin) - "We generated a panel of eight recombinant MuVs (rMuVs) carrying mutations in the MTase catalytic site or S-adenosylmethionine (SAM) binding site in the large (L) polymerase protein...Importantly, cotton rats vaccinated with these seven rMuV mutants produced high levels of serum neutralizing antibodies and were completely protected against challenge with a wild-type MuV strain (genotype F). Therefore, our results demonstrate that alteration in the MTase catalytic site or SAM binding site in MuV L protein improves the safety or the immunogenicity of the MuV vaccine and thus mRNA cap MTase may be an effective target for the development of new vaccine candidates for MuV."

Journal • Infectious Disease

Licochalcone A is a Natural Selective Inhibitor of Arginine Methyltransferase 6. (PubMed, Biochem J) - "We demonstrated that licochalcone A is a non-S-adenosyl L-methionine (SAM) binding site competitive inhibitor of PRMT6...Licochalcone A exhibited cytotoxicity towards human MCF-7 breast cancer cells, but not MCF-10A human breast epithelial cells, by upregulating p53 expression and blocking cell cycle progression at G2/M, followed by apoptosis. Thus, licochalcone A has potential for further development as a therapeutic agent against breast cancer."

Journal • Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER

Carnosine Alleviates Diabetic nephropathy by Targeting GNMT, a Key Enzyme Mediating renal inflammation and fibrosis. (PubMed, Clin Sci (Lond)) - "Importantly, we found that GNMT, a multiple functional protein that regulates the cellular pool of methyl groups by controlling the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH), was down-regulated significantly in the serum of Type 1 DM patients and renal tissues of DN mice...Conversely, the inhibition of GNMT expression abolished the protective effects of carnosine. In conclusion, carnosine might serve as a promising therapeutic agent for DN and GNMT might be a potential therapeutic target for DN."

Journal • Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Fibrosis • Immunology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease

Identification of naphthyridine and quinoline derivatives as potential Nsp16-Nsp10 inhibitors: a pharmacoinformatics study. (PubMed, J Biomol Struct Dyn) - "Fourteen out of fifty-eight compounds were exhibited binding affinity higher than co-crystal bound ligand s-adenosylmethionine (SAM) toward Nsp16-Nsp10...Hence, from the pharmacoinformatics assessment, it can be concluded that both heterocyclic compounds might be crucial for SARS-CoV-2 inhibition, subjected to experimental validation. Communicated by Ramaswamy H. Sarma."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Biotransformation of halophenols into earthy-musty haloanisoles: Investigation of dominant bacterial contributors in drinking water distribution systems. (PubMed, J Hazard Mater) - "All bacteria could use S-adenosyl methionine as methyl donor. Potential taste and odor (T & O) risks of five HAs in DWDS followed an order of 2,4,6-TBA > 2,4,6-TCA > 2,3,6-TCA > 2,4-DCA > 2-MCA. The recommended 2,4,6-TCP criteria for T & O control is 0.003-0.07 mg/L."

Journal

Mechanistic Insights into the Allosteric Regulation of the Clr4 Protein Lysine Methyltransferase by Autoinhibition and Automethylation. (PubMed, Int J Mol Sci) - "Due to enzyme activation by automethylation, we observed a sigmoidal dependence of Clr4 activity on the AdoMet concentration, with stimulation at high AdoMet levels...This process could connect epigenome modifications with the metabolic state of cells. As other human protein lysine methyltransferases (for example, PRC2) also use automethylation/autoinhibition mechanisms, our results may provide a model to describe their regulation as well."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Therapeutic Potential of the Natural Compound S-Adenosylmethionine as a Chemoprotective Synergistic Agent in Breast, and Head and Neck Cancer Treatment: Current Status of Research. (PubMed, Int J Mol Sci) - "In this regard, combination therapy with natural compounds, such as AdoMet, a molecule with pleiotropic effects on multiple cellular processes, is emerging as a suitable strategy to achieve synergistic anticancer efficacy. In this context, the analysis of studies conducted in the literature highlighted AdoMet as one of the most effective and promising chemosensitizing agents to be taken into consideration for inclusion in emerging antitumor therapeutic modalities such as nanotechnologies."

Journal • Review • Breast Cancer • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

From Synthetic to Biological Fe S Complexes: Redox Properties Correlated to Function of Radical S-Adenosylmethionine Enzymes. (PubMed, Chempluschem) - "7-9 kcal mol ) and hence more feasible in both enzymes as compared to the identical process in water. Furthermore, our calculations indicate that the enzyme-bound 5'-deoxyadenosyl radical has a significantly lower reduction potential than in referential aqueous solution, which may help the enzymes to suppress potential side redox reactions and simultaneously elevate its proton-philic character, which may, in turn, promote the radical hydrogen-atom abstraction ability."

Journal

Structure and Biochemical Characteristic of the Methyltransferase (MTase) Domain of RNA Capping Enzyme from African Swine Fever Virus. (PubMed, J Virol) - "Here we report the crystal structure of pNP868R methyltransferase (MTase) domain (referred as pNP868R) in complex with S-adenosyl-L-methionine (AdoMet)...Notably, both the conformation and the role in MTase activities of the N-terminal extension are distinct from those of previously characterized poxvirus MTase domain. Our structure-function studies provide the basis for potential anti-ASFV inhibitor design targeting the critical enzyme."

Journal • Hematological Disorders • Infectious Disease

Non-targeted metabolomics of quinoa seed filling period based on liquid chromatography-mass spectrometry. (PubMed, Food Res Int) - "The two filling periods of yellow, white, black, and red quinoa grains resulted in significant differences in the metabolites, particularly in L-methionine, S-adenosyl-L-homocysteine, S-adenosyl-L-methionine, pyruvate, fumarate, and oxaloacetate...The relative difference in the metabolites was largest when the yellow quinoa grain was compared with the other quinoa varieties and smallest when the red and black varieties were compare. The results of this study provide a basis for the reproduction and identification of new quinoa varieties, as well as for screening potential quality control target genes by combining genomics and transcriptomics."

Journal