Search Results (345)

Helicobacter pylori, a spiral-shaped bacterium found in the stomach, is associated with various gastrointestinal and systemic health conditions. Effective suppression of H. pylori is therefore critical for managing gastrointestinal diseases. In a search for natural products with anti-H. pylori activity, the extract of Atractylodes macrocephala rhizoma showed significant inhibitory effects. Chromatographic purification of A. macrocephala extract yielded thirteen compounds, which were identified as ten sesquiterpenes and three polyacetylenes by spectroscopic analysis. The sesquiterpene compounds belong to the eudesmane or eudesmane lactone types and exhibited structure-dependent efficacy. The major eudesmane lactone sesquiterpene, atractylenolide I (1), showed strong inhibitory activity comparable to metronidazole, a positive control, and atractylenolide III (3) also showed good efficacy. However, structural modification such as hydroxylation, methylation, or acetylation of the sesquiterpenes led to reduced activity. In contrast, polyacetylene derivatives displayed only mild inhibitory effects. Further evaluation of the active compounds against three H. pylori strains such as 51, 43504, and 26695 showed that atractylenolide I (1) had potent inhibitory effects against all three strains, with MIC₅₀ values of ranging from 27.3 to 48.6 μM and MIC₉₀ values from 45.4 to 87.2 μM. Atractylenolide III (3) exhibited selective activity against strain 51 with MIC₅₀ value of 89.9 μM. Both compounds also exhibited anti-inflammatory activity with IC₉₀ values of 23.3 and 31.1 μM, respectively, although they showed little effect on urease. This is the first report on the anti-H. pylori efficacy of various constituents of A. macrocephala and comparative analysis of inhibitory effects against several strains, which will provide scientific evidence supporting its potential as therapeutic agent for H. pylori-related infection. Full article

The efficient synthetic routes and evaluates cytotoxic profiles of denitroaristolochic acids II–V (DAA-II–V) were demonstrated in this study. Based on retrosynthetic analysis, a modular synthetic strategy was developed through Suzuki–Miyaura coupling, Wittig reaction, and bismuth triflate-catalyzed intramolecular Friedel–Crafts cyclization to efficiently construct the phenanthrene core. Process optimization significantly improved yields: aryl bromide intermediate A reached 50.8% yield via bromination refinement, while arylboronic ester intermediate B overcame selectivity limitations. Combining Darzens condensation with Wittig reaction enhanced throughput, achieving 88.4% yield in the key cyclization. Structures were confirmed by NMR and mass spectra. CCK-8 cytotoxicity assays in human renal proximal tubular epithelial cells revealed distinct toxicological profiles: DAA-III and DAA-IV exhibited IC₅₀ values of 371 μM and 515 μM, respectively, significantly higher than the nitro-containing prototype AA-I (270 μM), indicating that the absence of nitro group attenuates but does not eliminate toxicity, potentially via altered metabolic activation. DAA-II and DAA-V showed no detectable cytotoxicity within assay limits, suggesting reduced toxicological impact. Structure–activity analysis exhibited that the nitro group is not essential for cytotoxicity, with methoxy substituents exerting limited influence on potency. This challenges the conventional DNA adduct-dependent toxicity paradigm, implying alternative mechanisms like oxidative stress or mitochondrial dysfunction may mediate damage in denitro derivatives. These systematic findings provide new perspectives for AA analog research and a foundation for the rational use and safety assessment of Aristolochiaceae plants. Full article

Background/Objectives: Catheter ablation has become the standard of care for patients with symptomatic and drug-refractory atrial fibrillation (AF). Both Class IC and Class III antiarrhythmic drugs (AADs) are effective in preventing early recurrences of AF, but not late recurrences, compared with the usual care. We aimed to compare the effects of two months of Class IC versus Class III AADs following AF catheter ablation on clinical outcomes, including arrhythmia recurrence and safety endpoints. Methods: All patients undergoing AF catheter ablation between January 2015 and November 2024 were screened, and cases meeting the inclusion criteria were included. Primary outcome was defined as atrial tachycardia recurrence-free survival. Results: A total of 98 patients (mean age 54.2 ± 14.0 years; 55.1% male) were enrolled, with 66.3% presenting with paroxysmal atrial fibrillation (AF). The mean left atrial diameter was 38.7 ± 5.1 mm, and 78.6% underwent cryoballoon ablation. Class IC AADs were administered to 62 cases, while the remaining 36 patients received amiodarone following catheter ablation. The rate of atrial tachycardia (ATa) recurrence was comparable between the patients treated with Class IC and Class III AADs (9.7% vs. 19.4%; p = 0.169). Predictors of ATa recurrence were identified as history of direct current cardioversion—DCCV (HR: 5.86; 95%CI: 1.44–23.82)—and LA diameter (HR: 1.17; 95%CI: 1.04–1.31). The most frequent AAD-related adverse event was symptomatic bradycardia (6.1%), which resolved in all cases following dose reduction. Conclusions: Class IC and Class III antiarrhythmics show comparable efficacy in terms of preventing ATa recurrence following AF catheter ablation. AAD-related adverse event rates are negligible for short-term use. Full article

Background: Colorectal cancer (CRC) is a prevalent global malignancy with particularly challenging treatment outcomes in advanced stages. Oxaliplatin (OXA) is a frontline chemotherapeutic agent for CRC. However, 15% to 50% of stage III patients experience recurrence due to drug resistance. Elucidating the molecular mechanisms underlying OXA resistance is, therefore, crucial for improving CRC prognosis. The role of DIRAS1, a RAS superfamily member with reported tumor-suppressive functions in various cancers, remains poorly defined in CRC. Methods: The effects of DIRAS1 on CRC cell proliferation and migration were evaluated using MTT, wound healing, and colony formation assays. Stable cell lines with knockdown or overexpression of DIRAS1 and PHB1 were established via plasmid and lentiviral systems. Drug sensitivity to OXA was assessed through cytotoxicity assays and IC₅₀ determination. Clinical relevance was validated through immunohistochemical analysis of CRC tissue samples. Transcriptomic sequencing was performed to explore downstream regulatory mechanisms. Results: DIRAS1 expression was positively correlated with OXA resistance and was significantly upregulated following prolonged chemotherapy exposure. Silencing DIRAS1 reduced the IC₅₀ of OXA in vitro and increased tumor sensitivity to OXA in vivo. Transcriptome analysis identified PHB1 as a downstream effector of DIRAS1. Functional studies revealed that PHB1 contributes to chemoresistance by maintaining mitochondrial stability. Conclusions: This study identifies DIRAS1 as a key contributor to OXA resistance in CRC by modulating PHB1 expression and mitochondrial function. Targeting the DIRAS1–PHB1 axis may offer a novel therapeutic strategy to overcome chemoresistance in CRC. Full article

Background: Effective pain management in children is essential, particularly when administering local anaesthesia. This study was undertaken to compare pain perception in children after application of pre-cooled and plain topical anaesthetic gel during local anaesthetic administration. Methods: A randomised, single-blinded controlled trial was conducted among 51 children between the ages of 6 and 12, visiting the paediatric clinic, Jazan (REC-45/10/1070). Children were allocated into one of the following three groups using a simple randomisation having a 1:1:1 allocation ratio into Group I (n = 17): Plain topical anaesthetic gel, Group II (n = 17): Pre-Cooled topical anaesthetic gel, and Group III (n = 17). An ice pack was applied for a period of 1 min at the injection site. The intensity of pain and the behaviour of the children were assessed using Face, Leg, Activity, Cry, Consolability (FLACC), the Modified Wong–Baker Scale (WBS) and the Frankel Behaviour Rating Scale (FBRS). Results: A significant difference in FBRS scores was observed during anaesthesia, with the highest median score [3 (3,3)] in the pre-cooled topical anaesthetic gel group (p value < 0.001). FLACC scores varied significantly among groups, with the ice pack group [3 (3, 3)] and [4 (4, 5)] showing the highest median score (p value < 0.001). WBS scores also differed significantly between groups (p value < 0.001) with a lower value in the pre-cooled topical gel group [0 (0, 0), 2 (0, 2)]. Conclusions: This study concluded that, the use of a pre-cooled topical anaesthetic gel before LA administration reduced the pain better than that of plain anaesthetic gel and ice pack application at the injection site during infiltration. Full article

Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N⁵,N³-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC₅₀ to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors. Full article

Background The prevalence of obesity is increasing all over the world, resulting in a global health emergency. The impact of obesity on the risk of SARS-CoV-2 infection and symptom severity, especially among high-risk working populations such as health workers, deserves further studies. Methods A multicentric retrospective cohort study was conducted among health workers at four Italian University Hospitals belonging to the ORCHESTRA Project. Data were collected through an online survey, investigating sociodemographic and clinical data, until September 2022. Results The questionnaire was filled out by 5777 health workers. The median age was 46 years old (I–III quartile 20–72) and 75.5% were females. Data on BMI was available for 5470 participants. Overweight and obese subjects amounted to 23.4% and 9.8%, respectively. Naïve health workers were the majority (57.4%). Overweight and obese subjects were at a higher risk of infection only before vaccination with respect to normoweight subjects (RRR = 1.28 (IC 95% 1.01–1.62, p = 0.039) and 1.36 (1.00–1.86, p = 0.047), respectively). Major acute and post-acute COVID-19 symptoms were more common among obese subjects, as compared to those with a normal weight (35.2% vs. 23.5%, and 14.2% vs. 9.3%). BMI did not reduce antibody levels after vaccination. On the contrary, overweight and obese health workers had a significantly higher RGM after the third dose (1.12 and 1.48, respectively; normal weight as reference). Conclusions Overweight and obese subjects are at a higher risk of SARS-CoV-2 infection. However, SARS-CoV-2 vaccination fosters a high antibody response even in these individuals. Vaccination against SARS-CoV-2 should be prioritized in subjects with a high BMI, especially in highly exposed workers, such as health workers. Full article

To address the clinical challenges posed by symbiotic drug-resistant bacterial infections and tumor microenvironments, this study designed and synthesized novel carbazole/benzindole-based photosensitizers A1–A4, systematically evaluating their antitumor and antibacterial therapeutic potential through chemo-photodynamic therapy. Especially, compound A4 demonstrated potent Type I/II reactive oxygen species (ROS) generation capabilities. In vitro experiments revealed that A4 concentration-dependently inhibited HT-29 cells under hypoxic conditions (IC₅₀ = 0.89 μM) with a prominent photodynamic index (PI > 9.23), and substantially promoted cancer cell programmed death. In antibacterial evaluations, A4 achieved the complete eradication of dermal MRSA infections within 7 days through ROS-mediated membrane disruption under illumination. In the HT-29 xenograft model, the PDT–chemotherapy synergy strategy achieved a tumor suppression rate of 96%. This work establishes an innovative strategy for the combinatorial management of multidrug-resistant infections and solid tumors. Full article

Objective: The aim of this study is to investigate uterine prolapse (UP) among women attending a semi-urban health center for routine gynecological examinations. Specifically, the study explores the potential association between UP and various established or suspected risk factors, including age, menopausal status, number and mode of deliveries, birth weight, smoking habits, and body mass index (BMI). Furthermore, it examines the relationship between the presence or severity of UP and the scores of specific questionnaires and their subscales. Finally, the study seeks to develop a predictive model for the likelihood of UP based on questionnaire responses. Methods: A quantitative study was conducted at the gynecological department of a health center in Greece from January 2021 to October 2022. A total of 134 women were recruited using convenience sampling during routine gynecological visits. The degree of prolapse was classified according to the International Continence Society (ICS) Pelvic Organ Prolapse Quantification (POP-Q) classification system. Data collection also included the use of validated instruments: the Australian Pelvic Floor Questionnaire (APFQ), the Urogenital Distress Inventory-6 (UDI-6), the Pelvic Floor Distress Inventory-20 (PFDI-20), and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7). The data were processed with the Statistical Package for the Social Sciences (SPSS) v25. Results: Of the 134 participants, 21 (15.7%) aged 21 to 82 showed signs of UP, while 113 women (84.3%) did not. The average age of the women with UP was 55 years. Fourteen (10.4%) of these women were diagnosed with UP stage I, three of them (2.2%) with stage II, and four of them (3%) with stage III UP. There were no stage IV UP incidents. The risk factors associated with the disease include age, mode of delivery, parity, and duration of menopause. Regarding parity, every subsequent birth after the first one increases the likelihood of a UP incident by approximately 125%. Conclusions: Most women with UP did not exhibit severe symptoms, as UP typically does not manifest symptoms until it reaches a final stage. Considering the population aging and the increase in morbidity, a regular pelvic organ prolapse (POP) checkup should be established to facilitate early recognition, prevention, and treatment of symptoms. This study offers a potential tool for non-invasive screening to facilitate identifying UP in women early, which has not been previously reported. Full article

Luminal B breast cancer (LBBC) represents an aggressive, high-grade ER+ disease, associated with a high proliferation rate, higher mutation burden, and higher probability of eliciting the immune response. Clinical and pathological data from 89 patients of stage II-III, triple-negative (TN), and luminal B-like BC (LB-like BC) were included in the analysis. All patients were submitted to neoadjuvant chemotherapy (NACT). Quantitative and qualitative evaluations of TILs (Tumor-Infiltrating Lymphocytes) were performed on tissue microarrays constructed from pretreatment core-needle biopsy tumor specimens. The proportion of stromal TILs, CD8, CD4, and PD-L1 positive (+) immune cells (IC), as well as the number of FOXP3, CTLA4, and HSP-70+ IC, was observed concerning tumor immunophenotype, traditional clinicopathological prognostic factors, and tumor response to NACT. There was no statistically significant difference in the proportion of stromal TILs between the LB-like and TNBC (p = 0.344) cohorts. However, a higher CD4/CD8 ratio was associated with the TNBC biology (p = 0.018) and within the LB-like BC cohort with a high proliferation index and metastatic nodal involvement (p = 0.045, p = 0.015). Within the LB-like BC cohort, a higher expression of PD-L1 and HSP70+ IC was associated with a high proliferation index of tumor cells (p = 0.018, p = 0.040), massive metastatic nodal involvement (p = 0.002, p = 0.026), and higher stages of disease (p = 0.004, p = 0.042). Better response to NACT was associated with higher numbers of HSP70+ IC and higher proportions of CD8+ cells within the LB-like BC cohort (p = 0.045, p = 0.012). Routine evaluation of immune markers and HSP70 may help identify high-risk patients of LB-like breast cancer who would have a better response to NACT. Full article

Background/Objectives: Recent advancements in the treatment of LACC have focused on improving outcomes through systemic treatment intensification. Therefore, this review aims to analyze the brachytherapy (BT) techniques employed in recent studies that are likely to change upcoming clinical guidelines, and to discuss the evolving role of IGABT in optimizing patient outcomes. Methods: This review focuses on BT practices reported across main phase III trials—OUTBACK, INTERLACE, CALLA, and KEYNOTE A18—compared with the EMBRACE I study. Analyzed parameters include BT modality, dose prescription techniques, imaging guidance, and overall treatment time (OTT). Results: In EMBRACE I, MRI-based IGABT was mandatory, with 43% of patients receiving an intracavitary/interstitial (IC/IS) applicator; cumulative EQD2 D90 HR-CTV was 90 Gy with a median OTT of 46 days. The OUTBACK trial relied predominantly on point A-based BT, with limited use of volume-based BT (28%). The INTERLACE trial reported mixed BT approaches: 70% point A-based, 30% volume-based, and 20% 2D BT. A median cervical dose of 79.4 Gy was reported. CALLA maintained strong protocol adherence, with 60% volume-based BT and a median tumor EQD2 dose of 83 Gy, although lower in the Japan cohort. In the KEYNOTE A 18 cohort, volume-based BT was performed in 88% of patients, with a median D90 HR-CTV dose of 87 Gy; IC/IS applicators were used in 23% of cases. Conclusions: Across these major studies, the following consistent pattern emerges: the quality and technique of BT impact survival outcomes and toxicity profile in LACC. MRI-based IGABT—with the use of IC/IS applicators when needed—is essential. Full article

We report the synthesis and characterization of five novel metal complexes. Three of them are vanadium complexes with the general formula [VO(Lⁿ)₂], where Lⁿ are Schiff bases derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with either 4-(2-aminoethyl)morpholine (L¹), 3-morpholinopropylamine (L²) or 1-(2-aminoethyl)piperidine (L³). The two other metal complexes are [Ni(L¹)₂] and [Fe(L¹)₂]Cl. They were characterized by analytical, spectroscopic (Fourier transform infrared, UV-visible absorption), and mass spectrometric techniques as well as by single-crystal X-ray diffraction (for all [VO(Lⁿ)₂] complexes and [Ni(L¹)₂]). While, in the crystal structure, the V(IV)O complexes show distorted square–pyramidal geometry with the ligands bound as bidentate through quinolate NO donors, the Ni(II) complex shows octahedral geometry with two ligand molecules coordinated through NNO donors. Stability studies in aqueous media revealed that the vanadium complexes are not stable, undergoing oxidation to VO₂(L), which was corroborated by ⁵¹V NMR and MS. This behavior is also observed in organic media, though at a significantly slower rate. The Ni complex exhibited small spectral changes over time in aqueous media. Nonetheless, all compounds show enhanced stability in the presence of bovine serum albumin (BSA). Fluorescence studies carried out for the Ni(II) and Fe(III) complexes indicate reversible binding to albumin. The cytotoxicity of the L¹ metal complexes was assessed on melanoma (B16F10 and A375) and colon cancer (CT-26 and HCT-116) cell lines, with 5-fluorouracil (5-FU) as a reference drug. The V- and Ni complexes showed the lowest IC₅₀ values (<10 μM) in either A375 or HCT-116 cells after 48 h of incubation, while the Fe(III) complex presented minimal antiproliferative effects. The complexes were generally more cytotoxic to human than murine cancer cells. Synergistic in vitro studies with 5-FU revealed antagonism in most cases, except in A375 cells, where an additive effect was observed for the combination with the V-complex. Overall, these compounds show promising potential for cancer treatment, mostly for melanoma. Full article

Tricyclic and tetracyclic lactone derivatives of thieno[2,3-b]pyrazine or thieno[2,3-b]quinoline, and 2H-pyrones were prepared using different methodologies. Pd/Cu-catalyzed Sonogashira coupling using Et₃N as a base, of methyl 7-bromothieno[2,3-b]pyrazine-6-carboxylate and (het)arylalkynes to yield the Sonogashira ester products, gave also the corresponding tricyclic lactones as minor products. However, the major products did not cyclize with TFA. Tricyclic lactones were then obtained by a tandem one-pot Sonogashira coupling and 6-endo-dig lactonization of 7-bromothieno[2,3-b]pyrazine-6-carboxylic acid with (het)arylalkynes, in good yields. Halogenated tricyclic lactones were synthesized by halocyclization using CuX and NXS. Tetracyclic lactones were synthesized through a Rh(III)-catalyzed formal [4+2] cycloaddition, between thieno[2,3-b]quinoline-2-carboxylic acid and internal alkynes, triggered by C-H activation, with the carboxylic group acting as a directing group. Using the SRB assay, the antitumor activity of both Sonogashira products and lactones was evaluated across five human cancer cell lines (CaCo-2, MCF-7, AGS, HeLa, NCI-H460). The best-performing compound was a Sonogashira product showing a GI₅₀ < 10 µM in all tumor cell lines and low toxicity in PLP2 cells. Additionally, antiparasitic testing against Trypanosoma brucei and Leishmania infantum revealed some compounds with IC₅₀ < 11 µM, though some level of cytotoxicity was observed in THP-1—derived macrophages. Full article

Long-chain acyl-CoA synthetase (LACS) is a crucial enzyme involved in cellular lipid metabolism, playing a significant role in plant development and adaptation to environmental stress. However, our understanding of the CaLACS gene family in pepper remains limited. In this study, we identified nine members of the CaLACS gene in the ‘UCD-10X-F1’ pepper genome and named them CaLACS1-CaLACS9 based on their chromosomal distribution. Phylogenetic analysis revealed that the subfamily I-A includes CaLACS1, CaLACS3, and CaLACS7; the subfamily I-C contains CaLACS2; the subfamily II comprises CaLACS4 and CaLACS8; and the subfamily III consists of the remaining members. Collinearity analysis showed that there were twelve collinear pairs between six CaLACS genes and five AtLACS genes, and two fragment replication gene pairs in the nine CaLACS genes of pepper. Furthermore, numerous cis-acting elements associated with stress response, hormonal regulation, development, and light response were identified in the promoter regions of the CaLACS genes. RNA-seq analysis indicated that CaLACS genes exhibit tissue specificity and are widely expressed in pepper leaves following treatment with exogenous plant hormones, and under conditions of cold, heat, drought, and salt stress. Additionally, virus-induced gene silencing (VIGS) technology was employed to further investigate the roles of CaLACS6 and CaLACS9. Silencing these target genes in pepper seedlings increased their sensitivity to cold stress, as evidenced by the accumulation of reactive oxygen species (ROS), reduced antioxidant defense capacity, and decreased expression levels of cold-responsive and ROS-related genes. The findings of this study provide valuable insights into the functional roles of the CaLACS gene family and highlight CaLACS6 and CaLACS9 as promising candidate genes for enhancing cold tolerance in pepper. Full article

Cyclodextrins (CDs) have largely been investigated during the last decades for their outstanding properties, such as biocompatibility and biodegradability, with wide applications in the pharmaceutical field, among which the formation of inclusion complexes (ICs) with natural or synthetic lipophilic compounds. This review prioritizes the research of recent years (2022–2025), being focused on (1) systematization of the research of ICs based on the structure of the secondary metabolite, namely (i) polyphenols (PPs), (ii) terpenes and terpenoids (TTs), and (iii) alkaloids (Alks); (2) for each type of inclusion complex, the following aspects have been discussed: benefits of complexation, composite materials, and in vitro/in vivo and theoretical studies; and (3) pharmacokinetics and pharmacodynamics, risks, limitations, and perspectives of cyclodextrin inclusion complexes with secondary metabolites. Full article