LKB1 inhibits telomerase activity resulting in cellular senescence through histone lactylation in lung adenocarcinoma.

Despite the confirmed role of LKB1 in suppressing lung cancer progression, its precise effect on cellular senescence is unknown. The aim of this research was to clarify the role and mechanism of LKB1 in restraining telomerase activity in lung adenocarcinoma. The results showed that LKB1 induced cellular senescence and apoptosis either in vitro or in vivo. Overexpression of LKB1 in LKB1-deficient A549 cells led to the inhibition of telomerase activity and the induction of telomere dysfunction by regulating telomerase reverse transcriptase (TERT) expression in terms of transcription. As a transcription factor, Sp1 mediated TERT inhibition after LKB1 overexpression. LKB1 induced lactate production and inhibited histone H4 (Lys8) and H4 (Lys16) lactylation, which further altered Sp1-related transcriptional activity. The telomerase inhibitor BIBR1532 was beneficial for achieving the optimum curative effect of traditional chemotherapeutic drugs accompanied by the glycolysis inhibitor 2DG. These data reveal a new mechanism by which LKB1 regulates telomerase activity through lactylation-dependent transcriptional inhibition, and therefore, provide new insights into the effects of LKB1-mediated senescence in lung adenocarcinoma. Our research has opened up new possibilities for the creation of new cancer treatments.

Telomere-related DNA damage response pathways in cancer therapy: prospective targets.

Maintaining the structural integrity of genomic chromosomal DNA is an essential role of cellular life and requires two important biological mechanisms: the DNA damage response (DDR) mechanism and telomere protection mechanism at chromosome ends. Because abnormalities in telomeres and cellular DDR regulation are strongly associated with human aging and cancer, there is a reciprocal regulation of telomeres and cellular DDR. Moreover, several drug treatments for DDR are currently available. This paper reviews the progress in research on the interaction between telomeres and cellular DNA damage repair pathways. The research on the crosstalk between telomere damage and DDR is important for improving the efficacy of tumor treatment. However, further studies are required to confirm this hypothesis.

A real-world disproportionality analysis of mesalazine data mining of the public version of FDA adverse event reporting system.

Background: Mesalazine, a preparation of 5-aminosalicylic acid, is a medication widely used in clinical practice as a first-line therapy in the treatment of mild and moderate inflammatory bowel disease. However, the long-term safety of mesalazine in large sample population was unknown. The current study was to assess mesalazine -related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of mesalazine -associated AEs. Results: Out of 14,149,980 reports collected from the FDA Adverse Event Reporting System database, 24,284 reports of mesalazine -associated AEs were identified. A total of 170 significant disproportionality preferred terms conforming to the four algorithms simultaneously were retained. The most common AEs included colitis ulcerative, diarrhoea, condition aggravated, crohn's disease, fatigue, abdominal pain, nausea, haematochezia, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as dizziness, drug ineffective, drug hypersensitivity, infection, off label use, weight decreased, decreased appetite, arthralgia, rash might also occur. The median onset time of mesalazine -related AEs was 1,127 days (interquartile range [IQR] 1,127-1,674 days), and most of the cases occurred 2 years later (n = 610, 70.93%) and within the first 1 month (n = 89, 10.35%) after mesalazine initiation. Conclusion: Results of our study were consistent with clinical observations. We also found potential new and unexpected AEs signals for mesalazine, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of mesalazine.

The regulations of telomerase reverse transcriptase (TERT) in cancer.

Abnormal activation of telomerase occurs in most cancer types, which facilitates escaping from cell senescence. As the key component of telomerase, telomerase reverse transcriptase (TERT) is regulated by various regulation pathways. TERT gene changing in its promoter and phosphorylation respectively leads to TERT ectopic expression at the transcription and protein levels. The co-interacting factors play an important role in the regulation of TERT in different cancer types. In this review, we focus on the regulators of TERT and these downstream functions in cancer regulation. Determining the specific regulatory mechanism will help to facilitate the development of a cancer treatment strategy that targets telomerase and cancer cell senescence. As the most important catalytic subunit component of telomerase, TERT is rapidly regulated by transcriptional factors and PTM-related activation. These changes directly influence TERT-related telomere maintenance by regulating telomerase activity in telomerase-positive cancer cells, telomerase assembly with telomere-binding proteins, and recruiting telomerase to the telomere. Besides, there are also non-canonical functions that are influenced by TERT, including the basic biological functions of cancer cells, such as proliferation, apoptosis, cell cycle regulation, initiating cell formation, EMT, and cell invasion. Other downstream effects are the results of the influence of transcriptional factors by TERT. Currently, some small molecular inhibitors of TERT and TERT vaccine are under research as a clinical therapeutic target. Purposeful work is in progress.

Review of treatment options for a multidrug-resistant fungus: Candida auris.

Candida auris is a widely distributed, highly lethal, multidrug-resistant fungal pathogen. It was first identified in 2009 when it was isolated from fluid drained from the external ear canal of a patient in Japan. Since then, it has caused infectious outbreaks in over 45 countries, with mortality rates approaching 60%. Drug resistance is common in this species, with a large proportion of isolates displaying fluconazole resistance and nearly half are resistant to two or more antifungal drugs. In this review, we describe the drug resistance mechanism of C. auris and potential small-molecule drugs for treating C. auris infection. Among these antifungal agents, rezafungin was approved by the US Food and Drug Administration (FDA) for the treatment of candidemia and invasive candidiasis on March 22, 2023. Ibrexafungerp and fosmanogepix have entered phase III clinical trials.

Recent Advances in Polypeptide Antibiotics Derived from Marine Microorganisms.

In the post-antibiotic era, the rapid development of antibiotic resistance and the shortage of available antibiotics are triggering a new health-care crisis. The discovery of novel and potent antibiotics to extend the antibiotic pipeline is urgent. Small-molecule antimicrobial peptides have a wide variety of antimicrobial spectra and multiple innovative antimicrobial mechanisms due to their rich structural diversity. Consequently, they have become a new research hotspot and are considered to be promising candidates for next-generation antibiotics. Therefore, we have compiled a collection of small-molecule antimicrobial peptides derived from marine microorganisms from the last fifteen years to show the recent advances in this field. We categorize these compounds into three classes-cyclic oligopeptides, cyclic depsipeptides, and cyclic lipopeptides-according to their structural features, and present their sources, structures, and antimicrobial spectrums, with a discussion of the structure activity relationships and mechanisms of action of some compounds.

Short-chain fatty acids in diseases.

Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract.

The role of transketolase in human cancer progression and therapy.

Transketolase (TKT) is an enzyme that is ubiquitously expressed in all living organisms and has been identified as an important regulator of cancer. Recent studies have shown that the TKT family includes the TKT gene and two TKT-like (TKTL) genes; TKTL1 and TKTL2. TKT and TKTL1 have been reported to be involved in the regulation of multiple cancer-related events, such as cancer cell proliferation, metastasis, invasion, epithelial-mesenchymal transition, chemoradiotherapy resistance, and patient survival and prognosis. Therefore, TKT may be an ideal target for cancer treatment. More importantly, the levels of TKTL1 were detected using EDIM technology for the early detection of some malignancies, and TKTL1 was more sensitive and specific than traditional tumor markers. Detecting TKTL1 levels before and after surgery could be used to evaluate the surgery's effect. While targeted TKT suppresses cancer in multiple ways, in some cases, it has detrimental effects on the organism. In this review, we discuss the role of TKT in different tumors and the detailed mechanisms while evaluating its value and limitations in clinical applications. Therefore, this review provides a basis for the clinical application of targeted therapy for TKT in the future, and a strategy for subsequent cancer-related research.