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Molecular Context of ADP-ribosylation in Schistosomes for Drug Discovery and Vaccine Development.

Schistosome infection is regarded as one of the most important and neglected tropical diseases associated with poor sanitation. Like other living organisms, schistosomes employ multiple biological processes, of which some are regulated by a post-translational modification called Adenosine Diphosphate-ribosylation (ADP-ribosylation), catalyzed by ADP-ribosyltransferases. ADP-ribosylation is the addition of ADP-ribose moieties from Nicotinamide Adenine Dinucleotide (NAD+) to various targets, which include proteins and nucleotides. It is crucial in biological processes such as DNA repair, apoptos

Antitumor efficacy of lidamycin against human multiple myeloma RPMI 8226 cells and the xenograft in nonobese diabetic/severe combined immunodeficiency mice.

AIMS: The aim of this study is to explore the antitumor efficacy of lidamycin (LDM) against human multiple myelomas (MM). MATERIALS AND METHODS: Human MM RPMI 8226 cells and the xenograft model in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice were used to examine the antitumor activity of LDM. RESULTS: Notably, LDM markedly suppressed the growth of human MM RPMI 8226 xenograft in NOD/SCID mice. In vitro, there was a significant reduction in cell proliferation after treatment with LDM. The overall growth inhibition correlated with the increase of apoptotic cells. The apopt

Triple negative breast cancer: a brief review of its characteristics and treatment options.

Triple negative breast cancer (TNBC), an aggressive variant of breast cancer, is characterized by lack of expression of the estrogen (ER) an … otherapy. Potential future therapies for TNBC include targeted molecular strategies including poly (adenosine diphosphate ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents. Further research aimed at identifying unique genetic characteristics of TNBC may allow development of other targeted molecular chemotherapy treatmen …

Resveratrol attenuates hydrogen peroxide- and ADP-ribose-associated calcium dysregulation, oxidative stress, and apoptosis in TRPM2-transfected Chinese hamster ovary (CHO)-K1 cells.

Oxidative stress can couple reactive oxygen species generation to dysregulated intracellular calcium signaling and apoptosis. This study investigated whether resveratrol modified hydrogen peroxide (H₂O₂)- and adenosine diphosphate ribose (ADPR)-associated cellular injury in transient receptor potential melastatin 2 (TRPM2)-transfected Chinese hamster ovary (CHO)-K1 cells. Cells were assigned to control, resveratrol, H₂O₂, ADPR, H₂O₂ plus resveratrol, and ADPR plus resveratrol groups. H₂O₂ and ADPR increased the integrated Ca²⁺ response, apoptosis, JC-1 fluorescence, caspase activities, intrace…

Bacterial defense via RES-mediated NAD+ depletion is countered by phage phosphatases.

Many bacterial defense systems restrict phage infection by breaking down the molecule nicotinamide (Nam) adenine dinucleotide (NAD+) into adenosine diphosphate ribose (ADPR) and Nam. To counter NAD+ depletion-mediated defense, phages evolved NAD+ reconstitution pathway 1 (NARP1), which uses ADPR and Nam to rebuild NAD+. Here, we report a bacterial defense system called aRES, involving RES-domain proteins that are triggered by a phage DNA polymerase to degrade NAD+ into Nam and ADPR-1″-phosphate (ADPR-1P). This molecule cannot serve as a substrate for NARP1; therefore, NAD+ depletion by aRES de…

Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.

Recent clinical trials have explored the combination of androgen receptor (AR) pathway inhibitors and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors as a potential treatment for castration-resistant prostate cancer. This combination treatment is based on the premise that AR directly regulates expression of DNA repair genes, leading to synergy between PARP and AR inhibition. Despite some promising preclinical evidence, this combination therapy has shown limited efficacy in patients with homologous recombination (HR)-proficient tumors. To investigate this discrepancy between pr

Bacterial TIR-based immune systems sense phage capsids to initiate defense.

Thoeris systems use proteins with Toll/interleukin-1 receptor domains to protect prokaryotes from phage infection through the synthesis of a cyclic adenosine diphosphate ribose signalling molecule, which activates an effector that depletes the host of the essential metabolite NAD+ to limit viral propagation. How infection is recognized during Thoeris immunity is not known. Here we investigate the staphylococcal Thoeris defense system, ThsA-B1-B2, and found that, upon infection, the major capsid proteins of Siphoviridae phages from serogroup B, but not A, form a complex with ThsB1 and ThsB2 to …

Optimizing treatment for metastatic castration-resistant prostate cancer: Food and Drug Administration-approved therapies, emerging strategies, and biomarker-driven approaches.

Metastatic castration-resistant prostate cancer (mCRPC) remains a lethal stage of disease progression despite substantial therapeutic advancements. Driven largely by androgen receptor (AR) signaling, prostate cancer eventually develops resistance to AR-directed therapies, necessitating alternative strategies. In recent years, several novel agents have received US Food and Drug Administration approval for mCRPC, including next-generation AR-signaling inhibitors, poly(adenosine diphosphate-ribose) polymerase inhibitors, targeted radioligand therapy, and immunotherapy. Although these treatments h

Потенциальные цели микроглии в лечении нейродегенеративных заболеваний: механизм и терапевтические последствия.

В случае различных нейродегенеративных расстройств активируются микроглиальные клетки. Кроме того, дисфункциональная и гиперактивированная микроглия инициирует митохондриальную автофагию, окислительный стресс и патологическое накопление белка, заканчивающееся нейроинфламмацией, которая усугубляет повреждения допаминергических нейронов и вносит значительный вклад в патологию нейродегенеративного расстройства. Микроглиальная чрезмерная активация тесно связана с секрецией провоспалительных цитокинов, фагоцитозом травмированных нейронов и модуляцией нейротоксичной среды. В этом обзоре резюмируется

Совпадение в аннотации оригинала
For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mi … s novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenera …

Meningitis-associated central nervous system complications are mediated by the activation of poly(ADP-ribose) polymerase.

The present study assessed the role of PARP [poly(adenosine diphosphate-ribose) polymerase] activation in experimental pneumococcal meningitis. Mice with a targeted disruption of the PARP 1 gene were protected against meningitis-associated central nervous system complications including blood-brain barrier breaching and increase in intracranial pressure. This beneficial effect was paralleled by a significant reduction in meningeal inflammation, as evidenced by significantly lower cerebrospinal fluid leukocyte counts and interleukin-1beta, -6, and tumor necrosis factor-alpha concentrations in th

Inducible nitric oxide synthase-knockout mice exhibit resistance to pleurisy and lung injury caused by carrageenan.

In the present study, we investigated the role of inducible (or type 2) nitric oxide synthase (iNOS) in the development of acute inflammation by comparing the responses in wild-type mice (WT) and mice lacking (knockout [KO]). When compared with carrageenan-treated iNOS-WT mice, iNOS-KO mice that had received carrageenan exhibited a reduced degree of pleural exudation and polymorphonuclear cell migration. Lung myeloperoxidase (MPO) activity and lipid peroxidation were significantly reduced in iNOS-KO mice in comparison with iNOSWT mice. Immunohistochemical analysis for nitrotyrosine revealed po

Kynurenine-PARP-1 Link Mediated by MicroRNA 210 May Be Dysregulated in Pulmonary Hypertension.

BACKGROUND: Dysregulation of microRNAs is associated with pulmonary hyperten-sion. The present study aimed to determine the alterations in microRNA and microRNA expressions and their role in signaling pathways and investigate the relationship with serum levels of apelin, kynurenine, and endocan in pulmonary hypertension. METHODS: The study design was prospective and single-centered. The study included 32 consecutive treatment-naive patients with precapillary pulmonary hypertension and 55 age and sex-matched healthy controls. All subjects underwent right heart catheter-ization. mRNA expression

The calcium channel blocker diltiazem ameliorates parthanatos in juvenile neuronal ceroid lipofuscinosis.

Accumulation of pre-mutagenic 8-oxoguanine and impaired DNA repair can lead to poly(ADP-ribose) (PAR) accumulation and parthanatos in Alzheimer's disease, the leading cause of age-dependent dementia. However, the occurrence of parthanatos has not been well established in other types of dementia, including juvenile neuronal ceroid lipofuscinosis (JNCL), a major form of juvenile dementia. In this study, we investigated parthanatos-associated pathology in JNCL using patient-derived lymphoblasts (PDLs). Quantitative immunofluorescence microscopy revealed increased accumulation of 8-oxoguanine and

Involvement of ryanodine receptors in EPYLRFamide-mediated reduction of acetylcholine-induced inward currents in helix lucorum identified neurones.

The effects of several modulators of ryanodine receptors (RYRs) on the reduction of acetylcholine induced inward current (ACh-current) evoke … e. Adenosine (1 mM), alpha,beta-methylene ATP (0.1 mM), the nonhydrolisable ATP analogue and cyclic adenosine diphosphate ribose (0.1 mM) (agonists of RYRs) potentiate the modulatory effect of EPYLRFamide. Ruthenium red (1 mM), antagonist of RYRs and caffeine (1 mM), agonist of RYRs do not change the modulatory effect of EPYLRFamide. These data suggest that intracellular Ca(2 …

Attitudes and training needs of oncologists and surgeons in mainstreaming breast cancer genetic counseling in a low-to-middle income Asian country.

With the advent of poly-ADP-ribose polymerase inhibitor (PARPi) therapies, the focus of genetic testing for breast, ovarian, and other cancers has shifted from risk management to treatment decision-making in high-resource settings. Due to the shortage of genetic counselors worldwide, alternative ways of delivering genetic counseling have been explored, including training nongenetics healthcare professionals (NGHPs) to provide genetic counseling. However, little is known about the feasibility of adopting such models in healthcare settings with insufficient specialists, where population health l

Melatonin limits lung injury in bleomycin treated mice.

Melatonin is the principal secretory product of the pineal gland and its role as an immuno-modulator is well established. Recent evidence shows that melatonin is a scavenger of oxyradicals and peroxynitrite and exerts protective effects in septic shock, hemorrhagic shock and inflammation. The aim of this study was to investigate the effect of melatonin on the lung injury caused by bleomycin (BLM) administration. Mice subjected to intratracheal administration of BLM developed significant lung injury characterized by a marked neutrophil infiltration [assessed by myeloperoxidase (MPO) activity] a

Mono ADP-ribosylation of transducin catalyzed by rod outer segment extract.

Transducin is the retinal rod outer segment (ROS)-specific G protein coupling the photoexcited rhodopsin to cyclic GMP-phosphodiesterase. The alpha subunit of transducin is known to be ADP-ribosylated by bacterial toxins. We investigated the possibility that transducin is modified in vitro by an endogenous ADP-ribosyltransferase activity. By using either ROS, cytosolic extract of ROS or purified transducin in the presence of [alpha-32P]nicotinamide adenine dinucleotide (NAD+), the alpha and beta subunits of transducin were found to be radiolabeled. The labeling was decreased by snake venom pho

ADP-ribosylation in cultured cells treated with Clostridium difficile toxin B.

In cultured fibroblasts intoxicated with Clostridium difficile toxin B, a radioactive moiety was transferred from [14C-adenosine]NAD, but not from [14C-nicotinamide] NAD, into a cellular protein (MW 90,000). No labeling was detected in toxin-treated cultures not yet showing any toxin-induced cytopathogenic effect, whereas maximal labeling was obtained in cultures with about half of the cells showing a cytopathogenic effect. The radioactivity was removed from the substrate by treatment with snake venom phosphodiesterase. The results suggest that ADP-ribosylation of a cellular protein occurs in

Poly(ADP-ribosylation) of histones in intact human keratinocytes.

The poly(ADP-ribosylation) of chromosomal proteins is an epigenetic consequence of clastogenic DNA damaging agents which affects chromatin structure and function. We studied the poly(ADP-ribosylation) of the major classes of histones in response to DNA breakage induced by an extracellular burst of active oxygen (AO) or the alkylating agent N-methyl-N'-nitrosoguandine (MNNG) in the immortalized human keratinocytes HaCa T using a combination of affinity chromatography on phenylboronate resin and immunoblotting with polyclonal antibodies against histones H1, H2B, H2A, H3, and H4. The following fi

Reversible RNA ADP-ribosylation on uracil bases.

ADP-ribosylation is a conserved modification that uses NAD+ as a co-substrate to regulate essential cellular processes, such as genome stability and transcription, with Poly(ADP-ribose) Polymerases (PARPs) serving as the major catalyzing enzymes in humans. Historically defined as a protein post-translational modification, ADP-ribosylation on nucleic acids has been increasingly recognized in recent years, particularly in bacterial systems, but remains poorly understood in higher organisms. Here, we identify human PARP10 as a candidate enzyme that ADP-ribosylates nucleic acid bases, showing appa