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Chronic Intake of Green Propolis Negatively Affecting the Rat Testis.

BACKGROUND: Human and animal evidence suggests that environmental toxicants may have an adverse impact on male reproductive health, reducing the population's reproductive output. Owing to the renewed attraction for natural products, some of them constitute effective alternatives to mitigate these effects. Propolis is a candidate for this use because of its intrinsic properties. In many situations, it improved the testicular damage and alleviated the toxic effects induced by environmental contaminant exposure. OBJECTIVE: The aim of this study was to investigate possible alterations of testicul

Causal relationship between gut microbiota and adenomyosis: metagenomics sequencing and Mendelian randomization.

BACKGROUND: Emerging evidence implicates the gut microbiota in the pathogenesis of adenomyosis (AM); however, whether this association is causal and through which mechanisms it operates remain largely unknown. METHODS: To interrogate potential causal relationships, we performed a two-sample Mendelian randomization (MR) analysis leveraging inverse-variance weighting (IVW) as the primary estimator, complemented by MR-Egger, weighted median, and weighted mode approaches, to evaluate the causal effects of gut microbial taxa and microbiota-derived metabolic pathways on AM. We further conducted med

Iron deprivation in cancer--potential therapeutic implications.

Iron is essential for normal cellular function. It participates in a wide variety of cellular processes, including cellular respiration, DNA synthesis, and macromolecule biosynthesis. Iron is required for cell growth and proliferation, and changes in intracellular iron availability can have significant effects on cell cycle regulation, cellular metabolism, and cell division. Perhaps not surprisingly then, neoplastic cells have been found to have higher iron requirements than normal, non-malignant cells. Iron depletion through chelation has been explored as a possible therapeutic intervention i

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… This latter enzyme catalyzes the reduction of ribonucleotides to deoxyribonucleotides, which is the rate-limiting step in DNA synthesis. Iron is also required for macromolecule biosynthesis, necessary for cell growth and division. … Recently, an alternative form of the R2 subunit has been discovered that specifically functions to supply deoxyribonucleotides for DNA repair in response to DNA damage. …

Screening of traditional Chinese medicine monomers as ribonucleotide reductase M2 inhibitors for tumor treatment.

BackgroundRibonucleotide reductase (RR) is a key enzyme in tumor proliferation, especially its subunit-RRM2. Although there are multiple therapeutics for tumors, they all have certain limitations. Given their advantages, traditional Chinese medicine (TCM) monomers have become an important source of anti-tumor drugs. Therefore, screening and analysis of TCM monomers with RRM2 inhibition can provide a reference for further anti-tumor drug development.AimTo screen and analyze potential anti-tumor TCM monomers with a good binding capacity to RRM2.MethodsThe Gene Expression Profiling Interactive An

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… Ribonucleotide reductase (RR), the only multi-subunit enzyme existing in all biological cells that can catalyze the reduction of ribonucleotides to corresponding deoxyribonucleotides, is the rate-limiting enzyme of DNA synthesis. … Deoxyribonucleotide triphosphate (dNTP), the building block for DNA synthesis, is in high demand in tumors. As the key enzyme of DNA synthesis, RR not only participates in DNA synthesis and repair via producing dNTP but is also involved in cell cycle regulation[ 5 , 54 ]. …

Venetoclax enhances DNA damage induced by XPO1 inhibitors: A novel mechanism underlying the synergistic antileukaemic effect in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a highly heterogeneous haematologic malignancy with poor prognosis. We previously showed synergistic antileukaemic interaction between exportin 1 (XPO1) inhibitor KPT-330 (Selinexor) and Bcl-2 inhibitor venetoclax (ABT-199) in preclinical models of AML, which was partially meditated by Mcl-1, although the full mechanism of action remains unknown. In this study, using real-time RT-PCR and Western blot analysis, we show that inhibition of XPO1 via KPT-330 or KPT-8602 (Eltanexor) decreases the mRNA and protein levels of c-Myc, CHK1, WEE1, RAD51 and RRM2. KPT-330 a

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… downregulate c‐Myc. 20 , 21 , 22 In addition, KPT‐330 has been shown to induce DNA damage in cancer cells. 23 CHK1, WEE1 and RAD51 are important components of the DNA damage response (DDR) network. 24 In addition, ribonucleotide reductase (RR) catalyses the reduction in ribonucleotides into corresponding deoxyribonucleotides …

New approaches for cancer treatment: antitumor drugs based on gene-targeted nucleic acids.

Currently, the main way to fight cancer is still chemotherapy. This method of treatment is at the height of its capacity, so, setting aside the need for further improvements in traditional treatments for neoplasia, it is vital to develop now approaches toward treating malignant tumors. This paper reviews innovational experimental approaches to treating malignant malformations based on the use of gene-targeted drugs, such as antisense oligonucleotides (asON), small interfering RNA (siRNA), ribozymes, and DNAzymes, which can all inhibit oncogene expression. The target genes for these drugs are t

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… suppressor genes [102, 103] asOn Increase of tumor cell lifespan htert Hyperactivation of the telomere repeat elongation machinery and, as a result, an increase in the malignancy and the lifespan of transformed cells [109] asOn, ribozymes DnA synthesis arrest RRR2 or RRM2 controls the amount of deoxyribonucleotides … O-methyl asOn, PnA [111] and a 2’5’-oli- goadenilate oligonucleotide [112]. the 2’-O-methyl asO n suppressed hTERT expression in a cell culture by 97% [111], and the 2’5’-oligoadenilate oligonucleotide caused a 50% re- gression of tumors [112]. ribonucleotidereductase catalyzes the synthesis of 2’-deoxyribonucleotides …

Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and prot

miRNAs as predictive biomarkers of response to treatment in pediatric patients with acute lymphoblastic leukemia.

MicroRNAs (miRNAs/miRs) are promising prognostic biomarkers in pediatric acute lymphoblastic leukemia (ALL). The present study aimed to identify miRNAs that could serve as prognostic biomarkers or as novel therapeutic targets in ALL. The expression levels of 84 miRNAs were assessed in the bone marrow aspirates of 10 pediatric patients with newly diagnosed ALL at diagnosis and on day 33 of induction of the ALL Intercontinental Berlin-Frankfurt-Münster 2009 protocol, and associations with established prognostic factors were evaluated. The levels at diagnosis of 25 miRNAs were associated with ≥2

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… RRM2 is an essential enzyme for DNA synthesis and cell homeostasis as it catalyzes the formation of deoxyribonucleotides from ribonucleotides, and imbalanced deoxyribonucleoside triphosphate pools hinder proper DNA replication and repair ( 22 ). …

Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment.

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsi

Review: Oncolytic virotherapy, updates and future directions.

Oncolytic viruses (OVs) are viral strains that can infect and kill malignant cells while spare their normal counterparts. OVs can access cells through binding to receptors on their surface or through fusion with the plasma membrane and establish a lytic cycle in tumors, while leaving normal tissue essentially unharmed. Multiple viruses have been investigated in humans for the past century. IMLYGIC™ (T-VEC/Talimogene Laherparepvec), a genetically engineered Herpes Simplex Virus, is the first OV approved for use in the United States and the European Union for patients with locally advanced or no

Oral chemotherapy agents in cats: clinical uses, administration and side effects.

PRACTICAL RELEVANCE: Cancer is a very common disease in cats, and many feline patients will require chemotherapy as part of their treatment plan, either as a sole agent or as part of multimodality therapy. Although some general practitioners might be reluctant to undertake injectable chemotherapy, oral chemotherapy may feel like a more acceptable treatment option to manage in practice. CLINICAL CHALLENGES: The small body size of many cats means that tablet sizes made for the human market are less appropriate, which creates dosing challenges. The administration of oral medication can also be a

Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies.

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic a

Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs.

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex(GM-CSF)]), is almost complete, wi

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… mechanisms that permit unimpeded viral replication. 3 UL39 is the HSV gene encoding for the large subunit of ribonucleotide reductase (RR), the main rate limiting enzyme for viral DNA synthesis and replication, controlling the nucleotide substrate pool by regulating the conversion of ribonucleotides to deoxyribonucleotides …

Crosstalk of thioredoxin system and programmed cell death: from pathophysiology to novel therapy.

The thioredoxin (Trx) system, an integral component of cellular redox regulation, preserves protein dithiol-disulfide equilibrium through its conserved Cys-Gly-Pro-Cys active site and is involved in key cellular functions, including cell proliferation, apoptosis, and signal transduction. In cancer biology, the thioredoxin system plays dual roles: overexpression can suppress oxidative stress and promote tumor growth, whereas dysfunction can trigger programmed cell death (PCD). However, a critical area for future research is to delineate how Trx modulates the intricate networks of PCD, and to id

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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… De novo nucleotide biosynthesis is governed by RNR, which catalyzes the pivotal conversion of ribonucleotides to deoxyribonucleotides as the rate‐determining step [ 113 ]. …

Recombinant Oncolytic Viruses: Hexagonal Warriors in the Field of Solid Tumor Immunotherapy.

In the past decade, research on recombinant oncolytic viral agents in the treatment of solid tumors has evolved from the initial stage of simple genetic engineering to the current stage of multiple pipelines of parallel clinical application and combination therapy. Compared with T-VEC, the classical therapeutic agent that only expresses GM-CSF, which was approved in 2015, most new oncolytic virus designs include diverse gene constructs to reduce toxic effects, enhance multiple antitumor immunity, avoid immune clearance, or enhance tumor targeting. The single route of administration that activa

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… During the process of viral replication, the ICP6 protein participates in the reduction of ribonucleotides to deoxyribonucleotides, providing raw materials for the synthesis of viral DNA, and is a key link in the DNA replication of viruses within host cells. …

Transcript-Targeted Therapy Based on RNA Interference and Antisense Oligonucleotides: Current Applications and Novel Molecular Targets.

The development of novel target therapies based on the use of RNA interference (RNAi) and antisense oligonucleotides (ASOs) is growing in an exponential way, challenging the chance for the treatment of the genetic diseases and cancer by hitting selectively targeted RNA in a sequence-dependent manner. Multiple opportunities are taking shape, able to remove defective protein by silencing RNA (e.g., Inclisiran targets mRNA of protein PCSK9, permitting a longer half-life of LDL receptors in heterozygous familial hypercholesteremia), by arresting mRNA translation (i.e., Fomivirsen that binds to UL1

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… It consists of a large subunit (RNR1) and a small subunit (RNR2) associated to form a heterodimeric tetramer whose function is to remove the 2′-hydroxyl group of the ribose ring of nucleoside diphosphates catalyzing the formation of deoxyribonucleotides from ribonucleotides [ 120 ]. …

Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics.

Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18-21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normal

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… However, initial studies of As-ODNs, which utilized deoxyribonucleotides, were disappointing, as they were limited by a number of factors such as the poor solubility of ODNs, weak permeation across biological membranes and rapid degradation by endo and exo nucleases [ 5 ]. …

Decoding iron deficiency in cancer: mechanisms, immune modulation, and therapeutic potential.

Iron is a vital micronutrient in many biological functions, including DNA metabolism, oxygen transport, and cellular energy generation. In this context, it is intimately linked to cancer biology. However, although many studies have comprehensively investigated and reviewed the effects of excess iron on tumor initiation and progression, the potential interrelations of iron deficiency with tumors have been largely neglected and need to be better defined. Recent studies have highlighted the complex relationship between iron deficiency and tumor biology. Iron deficiency in specific tumor types can

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… oxidative stress | Hydrogen peroxide accumulation | Increased oxidative stress leading to DNA damage and inflammatory responses | Increased oxidative stress in the TME may promote inflammation and tumor progression Fe-sulfur cluster enzyme | Ribonucleotide reductase | Reduction of ribonucleotides to deoxyribonucleotides …