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Redox Profiling Reveals Clear Differences between Molecular Patterns of Wound Fluids from Acute and Chronic Wounds.

Wound healing is a complex multiphase process which can be hampered by many factors including impaired local circulation, hypoxia, infection … ifferences detected. Nitrotyrosine (the footprint of the potent oxidant peroxynitrite) and poly(ADP-ribose) (the product of the DNA damage sensor enzyme PARP-1) could be detected in wound biopsies. Our data identify multiple signs of redox stress in chronic wounds with notable differences. In chronic wounds, elevations in antioxidant levels/activities ma …

Role of PARP activity in lung cancer-induced cachexia: Effects on muscle oxidative stress, proteolysis, anabolic markers, and phenotype.

Strategies to treat cachexia are still at its infancy. Enhanced muscle protein breakdown and ubiquitin-proteasome system are common features of cachexia associated with chronic conditions including lung cancer (LC). Poly(ADP-ribose) polymerases (PARP), which play a major role in chromatin structure regulation, also underlie maintenance of muscle metabolism and body composition. We hypothesized that protein catabolism, proteolytic markers, muscle fiber phenotype, and muscle anabolism may improve in respiratory and limb muscles of LC-cachectic Parp-1-deficient (Parp-1-/- ) and Parp-2-/- mice. In…

Yinzhilan Formula Ameliorates Healing Delay in Diabetic Ulcer by Inhibiting PARP1 Activation and Regulating Macrophage Polarization.

INTRODUCTION: Yinzhilan formula (YZL) is an effective prescription for diabetic ulcers (DU) with clinical efficacy. This study aimed to explore the mechanism of YZL in ameliorating the healing delay of DU through network pharmacology and experimental validation. METHODS: Network pharmacology integrated with bioinformatics to screen the chemical composition of YZL, as well as its protein targets and disease targets. A mouse model of DU was established, and the efficacy of YZL was evaluated according to ulcer size and histopathological examination. The levels of inflammatory factors were detect

ClickGen: Directed exploration of synthesizable chemical space via modular reactions and reinforcement learning.

Despite the significant potential of generative models, low synthesizability of many generated molecules limits their real-world application … d to conduct wet-lab validation on the ClickGen's proposed molecules for poly adenosine diphosphate-ribose polymerase 1. Due to the guaranteed high synthesizability and model-generated synthetic routes for reference, we successfully produced and tested the bioactivity of these novel compounds in just 20 days, much faster than typically expected time fram …

Efficacy and Safety of Platinum-based Chemotherapy With Bevacizumab Followed by Bevacizumab Maintenance for Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer During PARP Inhibitor Therapy: A Multicenter Retrospective Study.

BACKGROUND/AIM: In recent years, the usefulness of poly ADP-ribose polymerase (PARP) inhibitors as subsequent maintenance therapy with poly ADP-ribose polymerase (PARP) inhibitors has been reported. However, it has been reported shown that platinum-based chemotherapy has a low response rate and short progression-free survival for recurrent platinum-sensitive ovarian cancer during treatment with PARP inhibitor therapy. This retrospective study evaluated platinum-based chemotherapy with bevacizumab (BEV) followed by BEV maintenance in these recurrent patients. PATIENTS AND METHODS: Efficacy and…

Activation of a cytosolic ADP-ribosyltransferase by nitric oxide-generating agents.

Sodium nitroprusside is a vasodilator and an inhibitor of platelet activation. It is thought that these effects are mediated by the spontaneous release of nitric oxide and stimulation of cytosolic guanylate cyclase. We have found that sodium nitroprusside (5-200 microM) greatly increased a cytosolic ADP-ribosyltransferase that ADP-ribosylates a soluble 39-kDa protein. This activity causes the mono-ADP-ribosylation of the 39-kDa protein, since digestion with snake venom phosphodiesterase releases 5'-AMP. This enzyme is present in platelets, brain, heart, intestine, liver, and lung. The effect o

A human MSX1 homeodomain missense mutation causes selective tooth agenesis.

We demonstrate that a mutation in the homeobox gene, MSX1, causes a common developmental anomaly, familial tooth agenesis. Genetic linkage analyses in a family with autosomal dominant agenesis of second premolars and third molars identified a locus on chromosome 4p, where the MSX1 gene resides. Sequence analyses demonstrated an Arg31Pro missense mutation in the homeodomain of MSX1 in all affected family members. Arg 31 is a highly conserved homeodomain residue that interacts with the ribose phosphate backbone of target DNA. We propose that the Arg31 Pro mutatrion comprises MSX1 interactions, a…

Transmission of Lactobacillus jensenii and Lactobacillus acidophilus from mother to child at time of delivery.

The presence of Lactobacillus jensenii and Lactobacillus acidophilus has been studied in specimens from the rectum and vagina of the mother, from the mouth of the infant at the time of delivery, and from the mouth and rectum of infants six days of age. L. jensenii could be differentiated from other species of lactobacilli by the following combination of characteristics: production of only D-lactate, hydrolysis of arginine, and fermentation of cellobiose, galactose, and ribose, but not of lactose. L. jensenii and L. acidophilus were common inhabitants of the vagina. In spite of a contamination …

BRCA2 reversion mutation-independent resistance to PARP inhibition through impaired DNA prereplication complex function.

Recent approvals of polymeric adenosine diphosphate ribose (poly(ADP-ribose) polymerase inhibitors (PARPi) for BRCA-mutant metastatic castration resistant prostate cancer necessitate an understanding of the factors that shape sensitivity and resistance. Reversion mutations that restore homologous recombination (HR) repair are detected in ~50 to 80% of BRCA-mutant patients who respond but subsequently relapse, but there is currently little insight into why only ~50% of BRCA-mutant patients display upfront resistance. To address this question, we performed a genome-wide CRISPR screen to identify…

The Molecular Basis of COVID-19 Pathogenesis, Conventional and Nanomedicine Therapy.

In late 2019, a new member of the Coronaviridae family, officially designated as "severe acute respiratory syndrome coronavirus 2" (SARS-CoV … with an oxidative/nitrosative burst. The DNA damage induced by oxidative stress activates poly ADP-ribose polymerase-1 (PARP-1), viral macrodomain of non-structural protein 3, poly (ADP-ribose) glycohydrolase (PARG), and transient receptor potential melastatin type 2 (TRPM2) channel in a sequential manner which results in cell apoptosis or necrosis. In …

CD38 in the nucleus accumbens and oxytocin are related to paternal behavior in mice.

BACKGROUND: Mammalian sires participate in infant care. We previously demonstrated that sires of a strain of nonmonogamous laboratory mice initiate parental retrieval behavior in response to olfactory and auditory signals from the dam during isolation in a new environment. This behavior is rapidly lost in the absence of such signals when the sires are caged alone. The neural circuitry and hormones that control paternal behavior are not well-understood. CD38, a membrane glycoprotein, catalyzes synthesis of cyclic ADP-ribose and facilitates oxytocin (OT) secretion due to cyclic ADP-ribose-depend…

Protein nitration and poly-ADP-ribosylation in brain after rapid exsanguination cardiac arrest in a rat model of emergency preservation and resuscitation.

BACKGROUND: Emergency preservation and resuscitation (EPR) of 60 min in rats is achievable with favorable outcome, while 75 min is associated with substantial mortality and impaired neurological outcome in survivors. We hypothesized that 75 min but not 60 min of EPR would be associated with activation of two potential secondary injury cascades in brain as reflected by protein nitration and poly (ADP-ribose) polymerase (PARP) activation. METHODS: Rats were rapidly exsanguinated over 5 min. After 1 min of cardiac arrest (CA), rats were cooled to a target tympanic temperature of 15 degrees C. Af…

Abnormal regulation of DNA replication and increased lethality in ataxia telangiectasia cells exposed to carcinogenic agents.

The effect of different carcinogenic agents on the rate of semiconservative DNA replication in normal and ataxia telangiectasis (AT) cells w … on AT and normal cells was not affected by nicotinamide, an inhibitor of poly(adenosine diphosphate ribose) synthesis. These data indicate that the diminished inhibition of DNA replication in carcinogen-treated AT cells (a) is a general characteristic of all AT cell strains, (b) correlates with AT cellular hypersensitivity, (c) is not directly caused by …

Role of Genetics in Gynecologic Malignancies.

Advances in cancer genomics have transformed the prevention, classification, and management of gynecologic malignancies. Germline and somati … rial cancer, refine prognosis and treatment intensity. Biomarker-driven therapies-such as poly (ADP-ribose) polymerase inhibitors, immune checkpoint inhibitors, and HER2-directed agents-have become integral across disease stages.

Diagnosis and Management of Skin Toxicities in Systemic Treatment of Genitourinary Cancers.

The landscape of available therapeutic options for treatment of genitourinary (GU) cancers is expanding dramatically. Many of these treatments have distinct, sometimes severe, skin toxicities including morbilliform, bullous, pustular, lichenoid, eczematous, psoriasiform, and palmoplantar eruptions. Pruritus and skin pigmentation changes have also been noted. This review aims to synthesize dermatologic events observed with antibody drug conjugates, poly (ADP-ribose) polymerase (PARP) inhibitors, androgen receptor pathway inhibitors, tyrosine kinase inhibitors, immune checkpoint inhibitors, and …

Quantification of DNA Damage in Heart Tissue as a Novel Prediction Tool for Therapeutic Prognosis of Patients With Dilated Cardiomyopathy.

This study evaluated myocardial nuclear staining for the DNA damage markers poly(ADP-ribose) (PAR) and γ-H2A.X in 58 patients with dilated cardiomyopathy. Patients with left ventricular reverse remodeling (LVRR) showed a significantly smaller proportion of PAR-positive nuclei and γ-H2A.X-positive nuclei in biopsy specimens compared with those without LVRR. Propensity analysis showed that the proportion of both PAR-positive and γ-H2A.X-positive nuclei were independent prognostic factors for LVRR. In conclusion, we showed the utility of DNA damage-marker staining to predict the probability of LV…

Role of the calcium store in uterine contractility.

This article assesses the nature of the sarcoplasmic reticulum (SR) in uterine smooth muscle. Modern imagining techniques have revealed new information about the location and density of Ca storage and release. Release mechanisms, including IP(3) and Ca itself, via ryanodine receptors (RyR), as well as possible roles for cyclic ADP ribose, and the contribution of the SR to relaxation are detailed. The role of the SR Ca-ATPase in both decay of the Ca transient and maintaining Ca homeostasis is reviewed. Recent data on the role of local Ca signals from the SR in contributing to membrane excitabil…

Optimized Detection of Acidic ADP-Ribosylation by PARP14 in Vitro Using Multi-Modal Mass Spectrometry Reveals Putative Autoregulatory Patches.

ADP-ribosylation is a highly dynamic process that is increasingly linked to a diverse set of cellular functions and pathophysiological outcomes. The modification of target substrates (e.g., proteins, DNA, RNA) involves ligation to an array of different chemical moieties. Recent work has shown that the ester bonds formed between ribose and aspartate (Asp)/glutamate (Glu) residues are particularly labile. A common strategy to overcome this lability is the replacement of the ADP-ribose (ADPr) by hydroxylamine. Attachment of hydroxamic acid (HA) permanently shifts the mass of labeled Asp/Glu resid…

Targeting Parthanatos in Ischemic Stroke.

Parthanatos is a cell death signaling pathway in which excessive oxidative damage to DNA leads to over-activation of poly(ADP-ribose) polymerase (PARP). PARP then generates the formation of large poly(ADP-ribose) polymers that induce the release of apoptosis-inducing factor from the outer mitochondrial membrane. In the cytosol, apoptosis-inducing factor forms a complex with macrophage migration inhibitory factor that translocates into the nucleus where it degrades DNA and produces cell death. In a review of the literature, we identified 24 publications from 13 laboratories that support a role …

Флавивирусная политрансфераза РНК: структура, функция и ингибиция.

Многие флавивирусы являются значительными человеческими патогенами. Плюс-стренд геном РНК флавивируса содержит 5-футовую конструкцию верхнего предела 1 (m(7)GpppAmG). Флавивирус кодирует одну метилтрансферазу (MTase), расположенную на N-терминальной части NS5 в зависимости от RNA полимеразы (RdRp). В этой связи мы рассматриваем последние достижения в нашем понимании механизмов пальца и последствий для развития наркотиков. NS5 MTase катализирует как гунанин N7 и рибоза 2-OH метилации во время формирования вирусных колпаков. Репрезентативный флавирус MTases, от денге, желтой лихорадки и вируса З

Совпадение в аннотации оригинала
Many flaviviruses are significant human pathogens. The plus-strand RNA genome of a flavivirus contains a 5' terminal cap 1 structure (m(7)Gp … ng machinery and the implications for drug development. The NS5 MTase catalyzes both guanine N7 and ribose 2'-OH methylations during viral cap formation. Representative flavivirus MTases, from dengue, yellow fever, and West Nile virus (WNV), sequentially generate GpppA → m(7)GpppA → m(7)GpppAm. Despite the existence of two distinct methylation activities …