Search Results (1,444)

Background: Fixed-dose combinations have advanced in many therapeutic areas, including otorhinolaryngology, where hearing disorders are increasingly prevalent. Objectives: The present study focuses on developing and evaluating a new capsule combining nicergoline (NIC), piracetam (PIR), and hawthorn extract (HE) for the management of sensorineural hearing loss. Methods: The first phase methodology comprised preformulation studies (DSC, FTIR, and PXRD) to assess compatibility among active substances and excipients. Subsequently, four formulations were prepared and tested for flowability, dissolution behavior in acidic and neutral media, and stability under oxidative, thermal, and photolytic stress. Quantification of the active substances and flavonoids was performed using validated spectrophotometric and HPLC-UV methods. Results: Among the tested variants, the F1 formulation (4.5 mg NIC, 200 mg PIR, 50 mg HE, 2.5 mg magnesium stearate, 2.5 mg sodium starch glycolate, and 240.5 mg monohydrate lactose per capsule) displayed optimal technological properties, superior dissolution in acidic media, and was further selected for evaluation. The antioxidant activity of the formulation was confirmed through the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, Trolox Equivalent Antioxidant Capacity (TEAC), and iron chelation tests, and was primarily attributed to the flavonoid content of the HE. Acute toxicity tests in mice and rats indicated a high safety margin (LD₅₀ > 2500 mg/kg), while ototoxicity assessments showed no adverse effects on auditory function. Conclusions: The developed formulation displayed good stability, safety, and therapeutic potential, while the applied workflow could represent a model for the development of future fixed-dose combinations. Full article

Alopecia, a prevalent dermatological disorder affecting over half of the global population, is strongly associated with psychological distress. Extracts from Periplaneta americana (L. PA), a medicinal insect resource, exhibit pharmacological activities (e.g., antioxidant, anti-inflammatory, microcirculation improvement) that align with core therapeutic targets for alopecia. This study aimed to systematically investigate the efficacy and mechanisms of PA extracts in promoting hair regeneration. A strategy combining network pharmacology prediction and in vivo experiments was adopted. The efficacy of a Periplaneta americana extract was validated by evaluating hair regrowth status and skin pathological staining in C57BL/6J mice. Transcriptomics, metabolomics, RT-qPCR, and 16s rRNA techniques were integrated to dissect the underlying mechanisms of its hair-growth-promoting effects. PA-011 significantly promoted hair regeneration in depilated mice via multiple mechanisms: enhanced skin superoxide dismutase activity and upregulated vascular endothelial growth factor expression; modulated FOXO/PI3K/AKT signaling pathway and restored skin microbiota homeostasis; and accelerated transition of hair follicles from the telogen to anagen phase. PA-011 exerts hair-promoting effects through synergistic modulation of FOXO/PI3K/AKT signaling and the skin microbiome. As a novel therapeutic candidate, it warrants further systematic investigation for clinical translation. Full article

We consider the problem of privately updating a message out of K messages from N replicated and non-colluding databases where a user has an outdated version of the message ${\hat{W}}_{\theta }$ of length L bits that differ from the current version $W_{\theta }$ in at most f bits. The user also has a cache containing coded combinations of the K messages (with a pre-specified structure), which are unknown to the N databases (unknown prefetching). The cache Z contains ℓ linear combinations from all K messages in the databases with $r=\frac{\mathcal{l}}{L}$ being the caching ratio. The user needs to retrieve $W_{\theta }$ correctly using a private information retrieval (PIR) scheme without leaking information about the message index $\theta$ to any individual database. Our objective is to jointly design the prefetching (i.e., the structure of said linear combinations) and the PIR strategies to achieve the least download cost. We propose a novel achievable scheme based on syndrome decoding where the cached linear combinations in Z are designed to be bits pertaining to the syndrome of $W_{\theta }$ according to a specific linear block code. We derive a general lower bound on the optimal download cost for $0\le r\le 1$, in addition to achievable upper bounds. The upper and lower bounds match for the cases when r is exceptionally low or high, or when $K=3$ messages for arbitrary r. Such bounds are derived by developing novel cache-aided arbitrary message length PIR schemes. Our results show a significant reduction in the download cost if $f<{\displaystyle \frac{L}{2}}$ when compared with downloading $W_{\theta }$ directly using typical cached-aided PIR approaches. Full article

Annona amazonica R.E. Fries (synonyms Annona amazonica var. lancifolia R.E. Fries), popularly known in Brazil as “envireira”, is a tropical tree belonging to the Annonaceae family and is traditionally used as a food source. In this work, the in vitro and in vivo anti-liver cancer effects of essential oil (EO) from A. amazonica leaves were investigated for the first time. The chemical composition of the EO was evaluated via GC–MS and GC–FID. The alamar blue assay was used to evaluate the cytotoxicity of EOs against different cancerous and noncancerous cell lines. Cell cycle analyses, YO-PRO-1/PI staining, and rhodamine 123 staining were performed via flow cytometry in HepG2 cells treated with EO. The in vivo antitumor activity of EO was evaluated in NSG mice that were xenografted with HepG2 cells and treated with EO at a dose of 60 mg/kg. The major constituents (>5%) of the EO were (E)-caryophyllene (32.01%), 1,8-cineole (13.93%), α-copaene (7.77%), α-humulene (7.15%), and α-pinene (5.13%). EO increased apoptosis and proportionally decreased the number of viable HepG2 cells. The induction of DNA fragmentation and cell shrinkage together with a significant reduction in the ΔΨm in EO-treated HepG2 cells confirmed that EO can induce apoptosis. A significant 39.2% inhibition of tumor growth in vivo was detected in EO-treated animals. These data indicate the anti-liver cancer potential of EO from A. amazonica leaves. Full article

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

MicroRNA-211 (miR-211) is a versatile regulatory molecule that plays critical roles in cellular homeostasis and disease progression through the post-transcriptional regulation of gene expression. This review comprehensively examines miR-211’s multifaceted functions across various biological systems, highlighting its context-dependent activity as both a tumor suppressor and oncogene. In physiological contexts, miR-211 regulates cell cycle progression, metabolism, and differentiation through the modulation of key signaling pathways, including TGF-β/SMAD and PI3K/AKT. miR-211 participates in retinal development, bone physiology, and protection against renal ischemia–reperfusion injury. In pathological conditions, miR-211 expression is altered in various diseases, particularly cancer, where it may be a useful diagnostic and prognostic biomarker. Its stability in serum and differential expression in various cancer types make it a promising candidate for non-invasive diagnostics. The review also explores miR-211’s therapeutic potential, discussing both challenges and opportunities in developing miRNA-based treatments. Understanding miR-211’s complex regulatory interactions and context-dependent functions is crucial for advancing its clinical applications for diagnosis, prognosis, and targeted therapy in multiple diseases. Full article

Phosphatidylinositol-3-kinase (PI3K) inhibition has emerged as a therapeutic option against indolent lymphoma, including relapsed follicular lymphoma (FL). While inhibition of active signaling in the lymphoma cell represents the primary mode of action, PI3K inhibition also exerts immunomodulatory effects. Here we have analyzed 17 consecutive advanced treatment line FL patients treated with the delta-selective PI3K inhibitor idelalisib in a retrospective single-center observational study, with a specific focus on response and immune effects. Eleven patients achieved complete remission (CR) or partial remission (PR) with median response duration of 22 (11–88) months following a median idelalisib exposure of 15 (4–88) months. Disease response persisted in three patients for a median of 37 (21–63) months following cessation of idelalisib without another therapy being initiated. Autoimmune side effects occurred in eight of the eleven patients who responded, compared to none in six patients whose disease did not respond. In conclusion, a time-limited exposure to idelalisib may induce sustained remissions in a portion of patients with recurrent and/or refractory (r/r) FL, suggesting immunomodulatory effects of PI3K inhibition to be involved in the control of the disease. Full article

This study investigates how phospholipid headgroups influence passive membrane penetration and structural impact of four nitrogen-, sulfur-, and oxygen-containing heterocycles (NSO-HETs)—N-methyl-2-pyrrolidone (PIR), 1,4-dioxane (DIOX), oxane (OXA), and phenol (PHE). Using all-atom molecular dynamics simulations combined with Accelerated Weight Histogram free energy calculations, the passive transport of NSO-HETs across DPPC, DPPE, DPPA, and DPPG bilayers was characterized. DPPG showed the highest membrane affinity, increasing permeability (logP_memb/bulk) by 27–64% compared to DPPE, associated with the lowest permeability and tightest lipid packing. Free energy barriers are also decreased in DPPG relative to DPPE; PIR’s central barrier dropped from 19.2 kJ/mol (DPPE) to 16.6 kJ/mol (DPPG), while DIOX’s barrier decreased from 7.2 to 5.2 kJ/mol. OXA exhibited the lowest central barriers (1.2–2.2 kJ/mol) and uniquely accumulated at higher concentrations in the bilayer center than in bulk water, with free energy ranging from −3.4 to −5.9 kJ/mol. PHE and OXA caused significant bilayer thinning (up to 11%) and reduced lipid tail order, especially in DPPE and DPPA. Concentration effects were most pronounced in DPPE, where high solute loading disrupted lipid order and altered free energy profiles. These results highlight the crucial role of headgroup identity in modulating NSO-HET membrane permeability and structural changes. Full article

Vibrio parahaemolyticus is a major foodborne pathogen worldwide, responsible for seafood-associated poisoning. Among its toxin genes, tdh2 is the most critical. To investigate the role of tdh2 in V. parahaemolyticus under gastrointestinal conditions, we constructed tdh2 deletion and complementation strains and compared their survival under acid (pH 3 and 4) and bile stress (2%). The results showed that tdh2 expression was significantly upregulated under cold (4 °C) and bile stress (0.9%). Survival assays and PI staining revealed that the tdh2 mutant strain (VP: △tdh2) was more sensitive to acid and bile stress than the wild-type (WT), and this sensitivity was rescued by tdh2 complementation. These findings suggest that tdh2 plays a protective role in enhancing V. parahaemolyticus tolerance to acid and bile stress. In the VP: △tdh2 strain, seven genes were significantly upregulated and six were downregulated as a result of tdh2 deletion. These genes included VPA1332 (vtrA), VPA1348 (vtrB), VP2467 (ompU), VP0301 and VP1995 (ABC transporters), VP0527 (nhaR), and VP2553 (rpoS), among others. Additionally, LC-MS/MS analysis identified 12 differential metabolites between the WT and VP: △tdh2 strains, including phosphatidylserine (PS) (17:2 (9Z,12Z) /0:0 and 20:1 (11Z) /0:0), phosphatidylglycerol (PG) (17:0/0:0), flavin mononucleotide (FMN), and various nucleotides. The protective mechanism of tdh2 may involve preserving cell membrane permeability through regulation of ompU and ABC transporters and enhancing electron transfer efficiency via regulation of nhaR. The resulting reduction in ATP, DNA, and RNA synthesis—along with changes in membrane permeability and electron transfer due to decreased FMN—likely contributed to the reduced survival of the VP: △tdh2 strain. Meanwhile, the cells actively synthesized phospholipids to repair membrane damage, leading to increased levels of PS and PG. This study provides important insights into strategies for preventing and controlling food poisoning caused by tdh⁺ V. parahaemolyticus. Full article

Ribosome biogenesis is a highly coordinated, multi-step process that assembles the ribosomal machinery responsible for translating mRNAs into proteins. It begins with the rate-limiting step of RNA polymerase I (Pol I) transcription of the 47S ribosomal RNA (rRNA) genes within a specialised nucleolar region in the nucleus, followed by rRNA processing, modification, and assembly with ribosomal proteins and the 5S rRNA produced by Pol III. The ribosomal subunits are then exported to the cytoplasm to form functional ribosomes. This process is tightly regulated by the PI3K/RAS/MYC oncogenic network, which is frequently deregulated in many cancers. As a result, ribosome synthesis, mRNA translation, and protein synthesis rates are increased. Growing evidence supports the notion that dysregulation of ribosome biogenesis and mRNA translation plays a pivotal role in the pathogenesis of cancer, positioning the ribosome as a promising therapeutic target. In this review, we summarise current understanding of dysregulated ribosome biogenesis and function in cancer, evaluate the clinical development of ribosome targeting therapies, and explore emerging targets for therapeutic intervention in this rapidly evolving field. Full article

Background/Objectives: Alterations in DNA damage repair mechanisms can impair the therapeutic effectiveness of cisplatin. MicroRNAs (miRNAs), key regulators of DNA damage repair processes, have been proposed as promising biomarkers for predicting the response to platinum-based chemotherapy (CT) in non-small cell lung cancer (NSCLC). In this study, by using a bioinformatics approach, we identified six miRNAs, which were differentially expressed (DE) between NSCLC patients characterized as responders and non-responders to platinum-based CT. We further validated the differential expression of the selected miRNAs on tumor and matched normal tissues from patients with resected NSCLC. Methods: Two miRNA microarray expression datasets were retrieved from the Gene Expression Omnibus (GEO) repository, comprising a total of 69 NSCLC patients (N = 69) treated with CT and annotated data from their response to treatment. Differential expression analysis was performed using the Linear Models for Microarray Analysis (Limma) package in R to identify DE miRNAs between responders (N = 33) and non-responders (N = 36). Quantitative real-time PCR (qRT-PCR) was used to assess miRNA expression levels in clinical tissue samples (N = 20). Results: Analysis with the Limma package revealed 112 DE miRNAs between responders and non-responders. A random-effects meta-analysis further identified 24 miRNAs that were consistently up- or downregulated in at least two studies. Survival analysis using the Kaplan–Meier plotter (KM plotter) indicated that 22 of these miRNAs showed significant associations with prognosis in NSCLC. Functional and pathway enrichment analysis revealed that several of the identified miRNAs were linked to key pathways implicated in DNA damage repair, including the p53, Hippo, PI3K and TGF-β signaling pathways. We finally distinguished a six-miRNA signature consisting of miR-26a, miR-29c, miR-34a, miR-30e-5p, miR-30e-3p and miR-497, which were downregulated in non-responders and are involved in at least three DNA damage repair pathways. Comparative expression analysis on tumor and matched normal tissues from surgically treated NSCLC patients confirmed their differential expression in clinical samples. Conclusions: In summary, we identified a signature of six miRNAs that are suppressed in NSCLC and may serve as a predictor of cisplatin response in NSCLC. Full article

Background/Objectives: Selective serotonin reuptake inhibitors (SSRIs), widely prescribed for anxiety disorders, may negatively impact the gut microbiota, contributing to dysbiosis. Considering the gut–brain axis’s importance in mental health, probiotics could represent an effective adjunctive strategy. This study evaluated the effects of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 on microbiota composition, metabolic activity, and immune markers in fecal samples from patients with anxiety on SSRIs, using the SHIME^® (Simulator of the Human Intestinal Microbial Ecosystem) model. Methods: The fecal microbiotas of four patients using sertraline or escitalopram were inoculated in SHIME^® reactors simulating the ascending colon. After stabilization, a 14-day probiotic intervention was performed. Microbial composition was assessed by 16S rRNA sequencing. Short-chain fatty acids (SCFAs), ammonia, and GABA were measured, along with the prebiotic index (PI). Intestinal barrier integrity was evaluated via transepithelial electrical resistance (TEER), and cytokine levels (IL-6, IL-8, IL-10, TNF-α) were analyzed using a Caco-2/THP-1 co-culture system. The statistical design employed in this study for the analysis of prebiotic index, metabolites, intestinal barrier integrity and cytokines levels was a repeated measures ANOVA, complemented by post hoc Tukey’s tests to assess differences across treatment groups. For the 16S rRNA sequencing data, alpha diversity was assessed using multiple metrics, including the Shannon, Simpson, and Fisher indices to evaluate species diversity, and the Chao1 and ACE indices to estimate species richness. Beta diversity, which measures microbiota similarity across groups, was analyzed using weighted and unweighted UniFrac distances. To assess significant differences in beta diversity between groups, a permutational multivariate analysis of variance (PERMANOVA) was performed using the Adonis test. Results: Probiotic supplementation increased Bifidobacterium and Lactobacillus, and decreased Klebsiella and Bacteroides. Beta diversity was significantly altered, while alpha diversity remained unchanged. SCFA levels increased after 7 days. Ammonia levels dropped, and PI values rose. TEER values indicated enhanced barrier integrity. IL-8 and TNF-α decreased, while IL-6 increased. GABA levels remained unchanged. Conclusions: The probiotic combination of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 modulated gut microbiota composition, metabolic activity, and inflammatory responses in samples from individuals with anxiety on SSRIs, supporting its potential as an adjunctive strategy to mitigate antidepressant-associated dysbiosis. However, limitations—including the small pooled-donor sample, the absence of a healthy control group, and a lack of significant GABA modulation—should be considered when interpreting the findings. Although the SHIME^® model is considered a gold standard for microbiota studies, further clinical trials are necessary to confirm these promising results. Full article

Objective: This study aimed to identify plasma exosomal microRNAs (miRNAs) associated with weight loss and type 2 diabetes (T2D) remission following low-calorie diet (LCD) intervention. Methods: A 6-month dietary intervention targeting T2D remission was conducted among individuals with T2D. Participants underwent a 3-month intensive weight loss phase consuming LCD (815–835 kcal/day) and a 3-month weight maintenance phase (N = 32). Sixteen participants were randomly selected for characterization of plasma-derived exosomal miRNA profiles at baseline, 3 months, and 6 months using small RNA sequencing. Linear mixed-effects models were used to identify differentially expressed exosomal miRNAs between responders and non-responders. Pathway enrichment analyses were conducted using target mRNAs of differentially expressed miRNAs. Logistic regression models assessed the predictive value of differentially expressed miRNAs for T2D remission. Results: Among the 16 participants, 6 achieved weight loss ≥10% and 12 achieved T2D remission. Eighteen exosomal miRNAs, including miR-92b-3p, miR-495-3p, and miR-452b-5p, were significantly associated with T2D remission and weight loss. Pathway analyses revealed enrichment in PI3K-Akt pathway, FoxO signaling pathway, and insulin receptor binding. The addition of individual miRNAs including miR-15b-3p, miR-26a-5p, and miR-3913-5p to base model improved the area under the curve values by 0.02–0.08 at 3 months and by 0.02–0.06 at 6 months for T2D remission. Conclusions: This study identified exosomal miRNAs associated with T2D remission and weight loss following LCD intervention. Several exosomal miRNAs might serve as valuable predictors of T2D remission in response to LCD intervention. Full article

This paper presents a structured and experimentally validated approach to the parameter identification, modeling, and real-time speed control of a brushless DC (BLDC) motor. Electrical parameters, including resistance and inductance, were measured through DC and AC testing under controlled conditions, respectively, while mechanical and electromagnetic parameters such as the back electromotive force (EMF) constant and rotor inertia were determined experimentally using an AVL dynamometer. The back EMF was obtained by operating the motor as a generator under varying speeds, and inertia was identified using a deceleration method based on the relationship between angular acceleration and torque. The identified parameters were used to construct a transfer function model of the motor, which was implemented in MATLAB/Simulink R2024b and validated against real-time experimental data using sinusoidal and exponential input signals. The comparison between simulated and measured speed responses showed strong agreement, confirming the accuracy of the model. A proportional–integral (PI) controller was developed and implemented for speed regulation, using a low-cost National Instruments (NI) USB-6009 data acquisition (DAQ) and a Kelly controller. A first-order low-pass filter was integrated into the control loop to suppress high-frequency disturbances and improve transient performance. Experimental tests using a stepwise reference speed profile demonstrated accurate tracking, minimal overshoot, and robust operation. Although the modeling and control techniques applied are well known, the novelty of this work lies in its integration of experimental parameter identification, real-time validation, and practical hardware implementation within a unified and replicable framework. This approach provides a solid foundation for further studies involving more advanced or adaptive control strategies for BLDC motors. Full article

Breast cancer remains one of the most prevalent malignancies worldwide, and radiation therapy is a central component of its management. However, intrinsic or acquired resistance to radiation significantly compromises therapeutic efficacy. This systematic review aimed to identify and evaluate molecular mechanisms and interventions that influence radiation sensitivity in breast cancer models. A comprehensive PubMed search was conducted using the terms “breast cancer” and “radiation resistance” for studies published between 2002 and 2024. Seventy-nine eligible studies were included. The most frequently investigated mechanisms included the dysregulation of the PI3K/AKT/mTOR and MAPK signaling pathways, enhanced DNA damage repair via non-homologous end joining (NHEJ), and the overexpression of cancer stem cell markers such as CD44⁺/CD24⁻/low and ALDH1. Several studies highlighted the role of non-coding RNAs, particularly the lncRNA DUXAP8 and microRNAs such as miR-21, miR-144, miR-33a, and miR-634, in modulating radiation response. Components of the tumor microenvironment, including cancer-associated fibroblasts and immune regulators, also contributed to radiation resistance. By synthesizing current evidence, this review provides a consolidated resource to guide future mechanistic studies and therapeutic development. This review highlights promising molecular targets and emerging strategies to enhance radiosensitivity and offers a foundation for translational research aimed at improving outcomes in radiation-refractory breast cancer. Full article