Search Results (15)

Background: Growing antibiotic resistance and the limited availability of key components in standard Helicobacter pylori treatments have driven the search for effective alternatives. Minocycline, with its broad-spectrum activity and favorable pharmacokinetics, has emerged as a promising substitute. This meta-analysis compares the safety and efficacy of minocycline-containing bismuth quadruple therapy (MBQT) to conventional first-line BQT regimens, incorporating data from the recent study by Lin et al. Methods: The inclusion criteria were randomized controlled trials (RCTs) with a target population of both treatment-naïve and previously treated patients diagnosed with Helicobacter pylori (H. pylori) infection. The intervention received by eligible patients was a minocycline–bismuth quadruple therapy (MBQT) regimen containing bismuth, minocycline, proton pump inhibitors (PPI), and any additional antibiotic with a minimum period of 2 weeks of administration. We excluded study designs other than RCT and clinical trials that include patients without confirmed H. pylori infection, animal populations, in vitro experiments, and reports of other outcomes that did not include a minimum intervention duration of 2 weeks. A comprehensive literature search was conducted on PubMed, EMBASE, Cochrane Library, and ScienceDirect from inception to 20 May 2025. After screening via Rayyan, data were extracted on an Excel spreadsheet. Quality was assessed using the Cochrane RoB 2.0 tool. Eligible randomized controlled trials (RCTs) were included and analyzed using RevMan 5.4. Outcomes assessed were intention-to-treat and per-protocol eradication rates. Adverse effects were compared among therapies. A random-effects model was used; an I² < 50% and p-value < 0.05 indicated homogeneity and significant results respectively. Results: Five RCTs with 7 interventions involving 2812 patients were included. The pooled odds ratio (OR) for MBQT in intention-to-treat (ITT) analysis was 1.25 (95% CI: 0.96–1.61), showing a non-significant trend. No heterogeneity was detected (I² = 0.0%). In the modified ITT (mITT) analysis (2 studies), MBQT showed higher eradication (OR: 1.70, 95% CI: 0.00–1042.90), but wide CI and high heterogeneity (I² = 70.7%) limited interpretation. All studies were included in the per-protocol (PP) analysis, which showed a statistically significant improvement with MBQT (OR: 1.67, 95% CI: 1.14–2.45) and low heterogeneity (I² = 5.2%), suggesting consistent results. Although not statistically significant, MBQT was associated with a slightly lower rate of adverse events compared to standard therapy (OR: 0.81, 95% CI: 0.59–1.12). I² = 50.6% showed moderate heterogeneity in safety outcomes. Discussion: the number of included RCTs was modest, with only five studies meeting eligibility criteria, and only two contributing to the modified intention-to-treat analysis. The risk-of-bias assessment showed variation in methodological quality across the included studies. Several studies exhibited high risk judgments in critical domains. particularly randomization, deviations from intervention, and selective reporting. Patients who completed the treatment benefited more from MBQT, which also had a comparable safety profile to conventional BQT regimens. In the treatment of H. pylori infection, MBQT may be considered a safe alternative for first-line treatment. Full article

Propiconazole (PRO), a triazole fungicide, controls fungal diseases by disrupting ergosterol production in fungal cells. It is used in crops such as cereals and fruits. However, there are concerns regarding its potential to disrupt the endocrine system and cause reproductive toxicity. This study examined the effects of PRO on mouse testes, germ cells, and GC-1 spermatogonia. After eight weeks, PRO reduced testicular diameter and downregulated key germ cell genes (Sall4, Piwil, Nanos2, and Dazl). A histological examination revealed smaller seminiferous tubules and fewer SALL4+ cells. PRO also impaired steroidogenesis by downregulating genes (StAR, Cyp11a1, 3β-HSD1) and reducing sperm motility, with a decline in Velocity Straight Line (VSL), Linearity (LIN), Straightness (STR), and motile sperm. PRO caused dose-dependent cytotoxicity in GC-1 spermatogonia, decreased proliferation, and increased apoptosis, marked by cleaved caspase-3 and BAX. PRO also induced autophagy, as presented by elevated levels of autophagy-related genes (LC3 and ATG12) and proteins (ATG5 and LC3A/B). 3-Methyladenine (3-MA), an autophagy inhibitor, downregulates levels of autophagy- and apoptosis-related proteins when 3-MA and PRO are simultaneously treated in vitro. This suggests that both apoptosis and autophagy contribute to PRO-induced testicular cytotoxicity. This study is the first to detail that PRO affects sperm motility in mice and induces autophagy-mediated apoptosis in GC-1 spg. Full article

Water-based drilling fluids (WBMs) are widely applied in petroleum engineering due to their lower cost and reduced environmental impact compared to oil-based muds. However, their performance is severely limited in shale formations, where hydration and swelling of clay minerals lead to wellbore instability. In this study, two novel imidazoline-type inhibitors were synthesized from fatty acids: A-Lin (derived from linoleic acid) and A-Lau (derived from lauric acid). The synthesis involved amidation followed by cyclization, and the products were characterized using FTIR and TGA. Their performance as shale hydration inhibitors was evaluated in WBM formulations and compared with commercial additives (Amine NF and Glycol). The FTIR spectra confirmed successful imidazoline ring formation, while TGA demonstrated good thermal stability up to 150 °C, with A-Lin exhibiting superior resistance due to its unsaturated structure. Rheological tests showed that the synthesized additives reduced plastic viscosity, thereby improving cuttings transport efficiency. Swelling tests revealed that A-Lin achieved the lowest final swelling (6.3%), outperforming both commercial inhibitors and the saturated A-Lau analogue. Furthermore, A-Lin provided the best lubricity coefficient (0.148), reducing torque and drag during drilling. Overall, A-Lin demonstrated strong potential as an efficient, thermally stable, and environmentally compatible shale inhibitor for advanced WBM formulations. Compared to conventional inhibitors such as KCl, glycol, and amine-based additives, A-Lin uniquely combines superior swelling inhibition, enhanced lubricity, and good thermal stability, highlighting its novelty as an imidazoline derivative derived from renewable fatty acids Full article

Background: Chronic-Phase Chronic Myeloid Leukemia (C-PCML) is defined by the presence of the BCR-ABL1 fusion gene, which encodes a tyrosine kinase protein that drives the uncontrolled proliferation and survival of leukemic stem cells (LSCs). Nilotinib, a tyrosine kinase inhibitor, targets the activity of BCR-ABL1 by reducing aberrant signaling pathways, which drive the regeneration of LSCs. Despite nilotinib’s action, a population of resilient LSCs persist in the bone marrow (BM) and can indeed drive relapse and progression in CML patients. Methods: Our study investigated the gene expression profiling (GEP) of BM CD34+/lin− cells from 79 CP-CML patients at diagnosis, compared to the BM CD34+/lin− cells from the same patients after 12 months of nilotinib treatment and to the normal counterpart cells from 10 donors (CTRLs). Results: GEP analyses identified 3012 significantly differentially expressed genes across these comparisons. Among these, we focused on certain key genes associated with eight crucial KEGG pathways: CML, cell cycle, JAK-STAT, PI3K-Akt, MAPK, Ras, NF-kB, and ABC transporters. Within these pathways, we observed the up-regulation of several genes at diagnosis compared to both 12 months of nilotinib treatment and the CTRLs. Conclusions: We observed that certain transcriptome features present at diagnosis persisted after 12 months of nilotinib treatment, compared to CTRLs. This suggests that nilotinib may exert selective pressure, potentially supporting the survival and self-renewal of LSCs. Future insights into these pathways could help identify therapeutic targets to improve outcomes in CML. Full article

Fallen leaves in cities are often treated as waste; therefore, they are collected, transported outside urban areas, and composted, which contributes to greenhouse gas (GHG) emissions. Instead of this conventional management approach, fallen leaves could be utilized as a feedstock in biogas production, helping to reduce GHG emissions, increase renewable energy generation, and provide fertilizer. The aim of this study was to compare the mono-digestion of fallen leaves from three tree species commonly found in parks and along streets—northern red oak (Quercus rubra L.), small-leaved lime (Tilia cordata Mill.), and Norway maple (Acer platanoides L.)—in both wet and dry anaerobic digestion (AD) systems. A biochemical methane potential (BMP) test was conducted in batch assays for each of the three substrates in both AD technologies at a temperature of 38 ± 1 °C. The highest specific methane yield (SMY) was obtained from Quercus leaves in wet AD technology, with a methane yield of 115.69 ± 4.11 NL kg_VS⁻¹. The lowest SMY (55.23 ± 3.36 NL kg_VS⁻¹) was observed during the dry AD of Tilia leaves. The type of technology had no significant impact on the SMY of Acer and Tilia leaves; however, the methane yield from Quercus leaves in wet AD was significantly higher (p < 0.05) than that from dry AD. Studies on the use of fallen leaves from Tilia cordata, Quercus rubra, and Acer platanoides as substrates in mono-digestion technology have shown their limited suitability for biogas production. Nevertheless, this feedstock may be more effectively used as a co-substrate, mainly due to the low concentrations of ammonia (NH₃) and hydrogen sulfide (H₂S) in the biogas produced from these leaves, both of which are considered inhibitors of the AD process. Full article

RNA-binding proteins (RBPs) play critical roles in regulating post-transcriptional gene expression, managing processes such as mRNA splicing, stability, and translation. In normal intestine, RBPs maintain the tissue homeostasis, but when dysregulated, they can drive colorectal cancer (CRC) development and progression. Understanding the molecular mechanisms behind CRC is vital for developing novel therapeutic strategies, and RBPs are emerging as key players in this area. This review highlights the roles of several RBPs, including LIN28, IGF2BP1–3, Musashi, HuR, and CELF1, in CRC. These RBPs regulate key oncogenes and tumor suppressor genes by influencing mRNA stability and translation. While targeting RBPs poses challenges due to their complex interactions with mRNAs, recent advances in drug discovery have identified small molecule inhibitors that disrupt these interactions. These inhibitors, which target LIN28, IGF2BPs, Musashi, CELF1, and HuR, have shown promising results in preclinical studies. Their ability to modulate RBP activity presents a new therapeutic avenue for treating CRC. In conclusion, RBPs offer significant potential as therapeutic targets in CRC. Although technical challenges remain, ongoing research into the molecular mechanisms of RBPs and the development of selective, potent, and bioavailable inhibitors should lead to more effective treatments and improved outcomes in CRC. Full article

Neuroblastoma (NB) is the most commonly diagnosed extracranial solid tumor in children, accounting for 15% of all childhood cancer deaths. Although the 5-year survival rate of patients with a high-risk disease has increased in recent decades, NB remains a challenge in pediatric oncology, and the identification of novel potential therapeutic targets and agents is an urgent clinical need. The RNA-binding protein LIN28B has been identified as an oncogene in NB and is associated with a poor prognosis. Given that LIN28B acts by negatively regulating the biogenesis of the tumor suppressor let-7 miRNAs, we reasoned that selective interference with the LIN28B/let-7 miRNA interaction would increase let-7 miRNA levels, ultimately leading to reduced NB aggressiveness. Here, we selected (−)-epigallocatechin 3-gallate (EGCG) out of 4959 molecules screened as the molecule with the best inhibitory activity on LIN28B/let-7 miRNA interaction and showed that treatment with PLC/PLGA-PEG nanoparticles containing EGCG (EGCG-NPs) led to an increase in mature let-7 miRNAs and a consequent inhibition of NB cell growth. In addition, EGCG-NP pretreatment reduced the tumorigenic potential of NB cells in vivo. These experiments suggest that the LIN28B/let-7 miRNA axis is a good therapeutic target in NB and that EGCG, which can interfere with this interaction, deserves further preclinical evaluation. Full article

Originally discovered in C. elegans, LIN28 is an evolutionarily conserved zinc finger RNA-binding protein (RBP) that post-transcriptionally regulates genes involved in developmental timing, stem cell programming, and oncogenesis. LIN28 acts via two distinct mechanisms. It blocks the biogenesis of the lethal-7 (let-7) microRNA (miRNA) family, and also directly binds messenger RNA (mRNA) targets, such as IGF-2 mRNA, and alters downstream splicing and translation events. This review focuses on the molecular mechanism of LIN28 repression of let-7 and current strategies to overcome this blockade for the purpose of cancer therapy. We highlight the value of the LIN28/let-7 pathway as a drug target, as multiple oncogenic proteins that the pathway regulates are considered undruggable due to their inaccessible cellular location and lack of cavities for small molecule binding. Full article

Several tumor types have been efficiently treated with PARP inhibitors (PARPis), which are now approved for the treatment of ovarian, breast, prostate, and pancreatic cancers. The BRCA1/2 genes and mutations in many additional genes involved in the HR pathway may be responsible for the HRD phenomenon. The aim of the present study was to investigate the association between genomic loss of heterozygosity (gLOH) and alterations in 513 genes with targeted and immuno-oncology therapies in 406 samples using an NGS assay. In addition, the %gLOHs of 24 samples were calculated using the Affymetrix technology in order to compare the results obtained via the two methodologies. HR variations occurred in 20.93% of the malignancies, while BRCA1/2 gene alterations occurred in 5.17% of the malignancies. The %LOH was highly correlated with alterations in the BRCA1/2 genes, since 76.19% (16/21) of the BRCA1/2 positive tumors had a high %LOH value (p = 0.007). Moreover, the LOH status was highly correlated with the TP53 and KRAS statuses, but there was no association with the TMB value. Lin’s concordance correlation coefficient for the 24 samples simultaneously examined via both assays was 0.87, indicating a nearly perfect agreement. In conclusion, the addition of gLOH analysis could assist in the detection of additional patients eligible for treatment with PARPis. Full article

Lin28 is a pluripotency factor that regulates cancer cell stem-like phenotypes to promote cancer development and therapy-resistant tumor progression. It acts through its cold shock domain and zinc knuckle domain (ZKD) to interact with the Let-7 pre-microRNA and block Let-7 biosynthesis. Chemical inhibition of Lin28 from interacting with Let-7 presents a therapeutic strategy for cancer therapy. Herein, we present the computer-aided development of small molecules by in silico screening 18 million compounds from the ZINC20 library, followed by the biological validation of 163 predicted compounds to confirm 15 new Lin28 inhibitors. We report three lead compounds, Ln7, Ln15, and Ln115, that target the ZKD of both Lin28A and Lin28B isoforms and block Lin28 from binding Let-7. They restore Let-7 expression and suppress tumor oncogenes such as SOX2 in cancer cells and show strong inhibitory effects on cancer cell stem-like phenotypes. However, minimal impacts of these compounds were observed on Lin28-negative cells, confirming the on-target effects of these compounds. We conclude from this study the discovery of several new Lin28 inhibitors as promising candidate compounds that warrant further drug development into potential anticancer therapies. Full article

Tumours develop therapy resistance through complex mechanisms, one of which is that cancer stem cell (CSC) populations within the tumours present self-renewable capability and phenotypical plasticity to endure therapy-induced stress conditions and allow tumour progression to the therapy-resistant state. Developing therapeutic strategies to cope with CSCs requires a thorough understanding of the critical drivers and molecular mechanisms underlying the aforementioned processes. One such hub regulator of stemness is Lin28, an RNA-binding protein. Lin28 blocks the synthesis of let-7, a tumour-suppressor microRNA, and acts as a global regulator of cell differentiation and proliferation. Lin28also targets messenger RNAs and regulates protein translation. In this review, we explain the role of the Lin28/let-7 axis in establishing stemness, epithelial-to-mesenchymal transition, and glucose metabolism reprogramming. We also highlight the role of Lin28 in therapy-resistant prostate cancer progression and discuss the emergence of Lin28-targeted therapeutics and screening methods. Full article

Aims: Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a cornerstone of drug therapy after myocardial infarction (MI) and improve left ventricular function and survival. We aimed to elucidate the impact of early treatment with the ACE inhibitor ramipril on the hematopoietic response after MI, as well as on the chronic systemic and vascular inflammation. Methods and Results: In a mouse model of MI, induced by permanent ligation of the left anterior descending artery, immediate initiation of treatment with ramipril (10 mg/k/d via drinking water) reduced cardiac inflammation and the number of circulating inflammatory monocytes, whereas left ventricular function was not altered significantly, respectively. This effect was accompanied by enhanced retention of hematopoietic stem cells, Lin⁻Sca1⁻c-Kit⁺CD34⁺CD16/32⁺ granulocyte–macrophage progenitors (GMP) and Lin⁻Sca1⁻c-Kit⁺CD150⁻CD48⁻ multipotent progenitors (MPP) in the bone marrow, with an upregulation of the niche factors Angiopoetin 1 and Kitl at 7 d post MI. Long-term ACE inhibition for 28 d limited vascular inflammation, particularly the infiltration of Ly6C^high monocytes/macrophages, and reduced superoxide formation, resulting in improved endothelial function in mice with ischemic heart failure. Conclusion: ACE inhibition modulates the myeloid inflammatory response after MI due to the retention of myeloid precursor cells in their bone marrow reservoir. This results in a reduction in cardiac and vascular inflammation with improvement in survival after MI. Full article

Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) in vitro. Previously, a lentivirus induction strategy of introducing Oct4, Sox2, Nanog and Lin28 (OSNL) into the iPSC process has been shown as a possible way to produce chicken iPSCs from chicken embryonic fibroblasts, but the induction efficiency of this method was found to be significantly limiting. In order to help resolve this efficiency obstacle, this study seeks to clarify the associated regulation mechanisms and optimizes the reprogramming strategy of chicken iPSCs. This study showed that glycolysis and the expression of glycolysis-related genes correlate with a more efficient reprogramming process. At the same time, the transcription factors Oct4, Sox2 and Nanog were found to activate the expression of glycolysis-related genes. In addition, we introduced two small-molecule inhibitors (2i-SP) as a “glycolysis activator” together with the OSNL cocktail, and found that this significantly improved the induction efficiency of the iPSC process. As such, the study identifies direct molecular connections between core pluripotency factors and glycolysis during the chicken iPSC induction process and, with its results, provides a theoretical basis and technical support for chicken somatic reprogramming. Full article

Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan–Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs’ potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment. Full article

Renal transplantation is life-changing in many aspects. This includes changes to the gut microbiome likely due to exposure to immunosuppressive drugs and antibiotics. As a consequence, renal transplant recipients (RTRs) might suffer from intestinal dysbiosis. We aimed to investigate the gut microbiome of RTRs and compare it with healthy controls and to identify determinants of the gut microbiome of RTRs. Therefore, RTRs and healthy controls participating in the TransplantLines Biobank and Cohort Study (NCT03272841) were included. We analyzed the gut microbiome using 16S rRNA sequencing and compared the composition of the gut microbiome of RTRs to healthy controls using multivariate association with linear models (MaAsLin). Fecal samples of 139 RTRs (50% male, mean age: 58.3 ± 12.8 years) and 105 healthy controls (57% male, mean age: 59.2 ± 10.6 years) were collected. Median time after transplantation of RTRs was 6.0 (1.5–12.5)years. The microbiome composition of RTRs was significantly different from that of healthy controls, and RTRs had a lower diversity of the gut microbiome (p < 0.01). Proton-pump inhibitors, mycophenolate mofetil, and estimated glomerular filtration rate (eGFR) are significant determinants of the gut microbiome of RTRs (p < 0.05). Use of mycophenolate mofetil correlated to a lower diversity (p < 0.01). Moreover, significant alterations were found in multiple bacterial taxa between RTRs and healthy controls. The gut microbiome of RTRs contained more Proteobacteria and less Actinobacteria, and there was a loss of butyrate-producing bacteria in the gut microbiome of RTRs. By comparing the gut microbiome of RTRs to healthy controls we have shown that RTRs suffer from dysbiosis, a disruption in the balance of the gut microbiome. Full article