Search Results (3,742)

Background: Chemoresistance remains a major obstacle in managing cholangiocarcinoma (CCA). The cannabis plant contains several phytocannabinoids, including cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN), which exhibit anticancer properties. However, to the best of our knowledge, their effects on CCA have not been previously investigated. This study aimed to explore the molecular mechanisms underlying the anticancer effects of CBD, CBG, and CBN in CCA cells. Methods: KKU-100 and KKU-452 cells were treated with varying concentrations of CBD, CBG, and CBN for 24 and 48 h. Cytotoxicity was assessed using the MTT assay, and half maximal inhibitory concentration (IC₅₀) values were calculated. KKU 452 cells were further analyzed for apoptosis, mitochondrial membrane potential (MMP), and Ki67 expression using flow cytometry. Proteomics profiling was performed to compare the effect of these cannabinoids with those of gefitinib and cisplatin. Results: Monotherapy with CBD, CBG, or CBN induced dose-dependent cytotoxicity at 24 and 48 h with lower IC₅₀ values than those of cisplatin and comparable efficacy to that of gefitinib. At low doses, CBD, CBG, and CBN induced early apoptosis, while higher doses triggered late apoptosis. MMP loss increased by 2.5-, 4.9-, and 1.7-fold, respectively, after 6 h. Ki67, highly expressed in KKU-452 cells (Ki67-positive ratio = 3.16 ± 0.16), was significantly reduced after the cannabinoid treatment, with Ki67-positive ratios of 0.38 ± 0.22, 0.38 ± 0.13, and 0.32 ± 0.23 for CBD, CBG, and CBN, respectively. Proteomics analysis identified 2781 proteins affected by CBD, CBG, CBN, cisplatin, and gefitinib. All three cannabinoids downregulated key upstream regulatory proteins (LARP1, TFEB, and BCR). Similar patterns of LARP1 and TFEB downregulation were also observed with cisplatin and gefitinib. CBN showed the closest similarity to cisplatin, followed by gefitinib, by targeting CDK4/6 and PCGEM1 proteins. CBD and CBG exhibited the greatest similarity to each other, also influencing MASTL expression. Conclusions: CBD, CBG, and CBN exhibit potential anticancer activity in CCA by suppressing proliferation, reducing Ki67 expression, and inducing apoptosis through MMP disruption. The identification of shared molecular targets, including LARP1 and TFEB, provides new mechanistic insight and supports the potential development of cannabinoid-based therapeutic strategies for cholangiocarcinoma. Full article

Inflammation contributes to the rapid progression of high-grade gliomas, indicating that anti-inflammatory strategies targeting NF-κB signaling may offer therapeutic benefit. Cannabidiol (CBD) and celecoxib (CELE) are hydrophobic pharmacological agents whose formulation in lipid carriers may support their combined biological evaluation. In this proof-of-concept study, we investigated liposomal formulations containing CBD, CELE, or both compounds in U-87 MG high-grade glioma cells and in a subcutaneous xenograft model. We assessed cytotoxicity, apoptosis, oxidative stress, Nrf2-dependent responses, NF-κB-centered inflammatory networks, tumor cell invasive properties, and Wnt/β-catenin pathway activity. The nanoformulations induced reactive oxygen species generation by 1.8-fold, which was accompanied by Nrf2 activation. Cationic formulations loaded with the compounds produced more pronounced pro-apoptotic effects (up to 39%) than POPC liposomes, although both types reduced the nuclear translocation of the NF-κB p65 subunit. The CBD + CELE-containing formulation showed a trend toward reduced tumor progression in mice. It is important to note that the in vitro and in vivo nanoformulations were physicochemically related, but not identical, and the in vivo experiment should be interpreted as a preliminary assessment after intratumoral administration. Overall, cationic liposomes co-loaded with CBD + CELE represent a promising platform for further optimization aimed at coordinated modulation of inflammatory, oxidative, and proliferative pathways in glioma. However, additional studies, including tissue distribution, release kinetics, and efficacy in orthotopic glioma models, are needed to fully verify their translational potential. Full article

Background/Objectives: Noninvasive determination of glioma molecular profiles is clinically crucial for assessing therapeutic efficacy and predicting disease outcomes. This study aimed to evaluate the potential of morphological magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and dynamic contrast-enhanced perfusion-weighted imaging (DCE-PWI) in predicting TP53 gene status and X-linked alpha-thalassemia intellectual disability syndrome (ATRX) gene status in isocitrate dehydrogenase (IDH)-mutant gliomas. Methods: A retrospective analysis was performed on 106 IDH-mutant glioma patients using morphological MRI, DWI, MRS, and DCE-PWI data. Statistical comparisons of imaging parameters across molecular status groups were conducted, and logistic regression models were developed to predict molecular status, with diagnostic performance evaluated by receiver operating characteristic (ROC) curve analysis. Five-fold stratified cross-validation with 1000 bootstrap resamples was employed to assess model generalizability Results: Among 106 IDH-mutant gliomas, the TP53-mutant group showed a greater proportion of tumors with >33% enhancement (p = 0.018), higher Cho/Cr (p < 0.001), and higher Cho/NAA (p = 0.005) than the TP53-wildtype group. Multivariable analysis demonstrated that the Cho/Cr ratio was an independent predictor of TP53 mutation in IDH-mutant gliomas (odds ratio [OR] = 2.037, p = 0.021), with the model achieving an apparent AUC of 0.741. DCE-PWI parameters showed no significant differences across molecular subgroups. Ve was significantly elevated in ATRX-mutant tumors (median 57.16 vs. 30.63, p = 0.029). Ktrans, Kep, Vp, and iAUC showed no significant differences between groups (all p > 0.05). Furthermore, multivariable analysis showed that ADC values (OR = 1.005, p = 0.017) and the Cho/NAA ratio (OR = 3.073, p = 0.023) emerged as independent predictors of ATRX mutation, with the model achieving an apparent AUC of 0.863. Five-fold cross-validation demonstrated that the Cho/Cr model for TP53 prediction achieved a mean AUC of 0.717 ± 0.043 (Bootstrap 95% CI: 0.616–0.814), and the ADC + ChoNAA model for ATRX prediction achieved 0.865 ± 0.124 (95% CI: 0.780–0.953). All predictors remained significant across all five folds. Pooled confusion matrices yielded sensitivities of 0.623 and 0.757, specificities of 0.696 and 0.909, and accuracies of 0.654 and 0.840, respectively. Conclusions: Multimodal MRI techniques (morphological MRI, DWI, MRS, and DCE-PWI) can help predict TP53 and ATRX status without surgery. Higher Cho/Cr and Cho/NAA ratios were independently associated with TP53 mutation, whereas lower ADC and higher Cho/NAA independently predicted ATRX mutation. These findings suggest that a focused imaging protocol may be sufficient for preoperative molecular profiling in this tumor type. Full article

Experimental evidence has shown that gallic acid (GA), a naturally occurring polyphenolic compound, and docetaxel (DTX), a taxane chemotherapeutic agent, each possess antitumor activity against multiple cancer types. Although both compounds have been investigated individually, their combined effects in triple-negative breast cancer (TNBC) have received limited attention, and the molecular basis of their interaction remains unclear. The present study examined the in vitro effects of GA and DTX in MDA-MB-231 TNBC cells while simultaneously assessing their comparative cytotoxicity in HaCaT human keratinocytes. Evaluation of treatment efficacy included measurement of cell viability by the MTT assay and assessment of drug interactions using the Chou–Talalay combination index (CI) method. Apoptosis together with cell-cycle distribution was subsequently examined using both Annexin V/PI flow cytometry and TALI^® image-based cytometry. Additional analyses included β-tubulin immunofluorescence (IF), caspase-9 immunocytochemistry, ELISA, wound-healing assays, quantitative real-time PCR, and bioinformatic analyses to investigate treatment-associated biological alterations. Combined exposure to GA and DTX produced a significant reduction in cell viability and exhibited synergistic activity in MDA-MB-231 cells. The coordinated biological response to the combined treatment was characterized by increased apoptotic cell death, arrest of the cell cycle at the G2/M phase, extensive disorganization of the β-tubulin network, and enhanced caspase-9 immunoreactivity. Beyond its effects on cell survival, the combined regimen substantially decreased the release of IL-6, IL-8, and TNF-α, limited wound-healing capacity, and reshaped the expression profile of the apoptosis- and cell cycle-related genes BCL2, BAX, CASP9, and CDKN1A. Bioinformatic analyses further revealed enrichment of apoptosis- and cell-cycle-associated pathways that were generally consistent with the experimental observations. The overall pattern of experimental responses indicates that combining GA with DTX enhances the in vitro antitumor efficacy of DTX in TNBC cells by simultaneously influencing apoptotic pathways, cell-cycle regulation, inflammatory cytokine secretion, and cellular migratory capacity. Although the bioinformatic findings provide supportive hypothesis-generating evidence, additional studies using three-dimensional models, in vivo experiments, and functional validation approaches are necessary to confirm the underlying molecular mechanisms and to further define the translational potential of this therapeutic combination. Full article

The integration of artificial intelligence (AI) and machine learning (ML) is fundamentally transforming pharmaceutical sciences, shifting drug formulation and nanocarrier design from traditional empirical approaches toward predictive, data-driven methodologies. By enabling the analysis of large, complex datasets, AI technologies are accelerating decision-making, improving formulation efficiency, and supporting the development of more effective therapeutic systems. Despite these advances, the successful clinical translation of advanced nanomedicines, including polymeric nanoparticles and mRNA–lipid nanoparticle platforms, remains limited by challenges such as biological barriers, highly sensitive formulation parameters, scalability issues, and the limited interpretability of many computational models. This review provides a comprehensive overview of AI applications throughout the pharmaceutical development lifecycle. It explores how classical machine learning algorithms and deep learning architectures optimize conventional dosage forms, enhance formulation development, and enable the rational design of targeted nanocarriers. Particular emphasis is placed on predicting critical quality attributes, encapsulation efficiency, physicochemical properties, drug-release behavior, therapeutic efficacy, and early-stage nanotoxicity. Furthermore, we critically assess the regulatory considerations, manufacturing constraints, data quality issues, and tumor microenvironment heterogeneity that continue to impede bench-to-clinic translation. Ultimately, overcoming these challenges requires moving beyond isolated algorithmic optimization toward an integrated framework that combines computational intelligence, robust experimental validation, and continuous clinical feedback. Such a synergistic approach is expected to drive the next generation of precision nanomedicine and facilitate the safe and effective translation of AI-enabled pharmaceutical innovations into clinical practice. Full article

Background/objectives: Colorectal cancer (CRC) remains a cause of cancer-related mortality worldwide, with therapeutic progress hindered by poor tumor selectivity and acquired drug resistance. This study investigated the anticancer efficacy of simvastatin, administered as a free drug or encapsulated within mesoporous SBA-16 nanoparticles (NPs), against HT-29 colorectal cancer cells in two-dimensional monolayer and three-dimensional spheroid culture models. Methods: SBA-16 NPs achieved drug-loading efficiency of 73.83% and accelerated cumulative release of 91.93% within 30 min, compared to 35.24% for the free drug. Cell viability and proliferation were assessed via MTT and clonogenic assays, while interleukin-6 (IL-6) levels were measured by ELISA to evaluate anti-inflammatory activity. Results: Simvastatin-loaded SBA-16 NPs reduced the IC₅₀ from 27.86 µg/mL to 4.43 µg/mL, representing a 6.29-fold enhancement in cytotoxic potency (p < 0.001), and significantly inhibited colony formation and suppressed IL-6 secretion, indicating modulation of inflammatory pathways implicated in tumor progression. In the 3D spheroid model, the nanoparticle formulation induced dose-dependent inhibition superior to the free drug. Conclusions: These findings demonstrate that SBA-16 nanocarriers substantially amplify simvastatin’s anticancer efficacy through improved drug solubilisation and rapid release kinetics under sink conditions, with possible—but not directly proven—enhanced cellular interaction/internalisation and modulation of tumor-associated inflammatory signaling. Direct uptake, penetration, mechanistic cell-death, normal-cell selectivity, and in vivo studies are warranted to confirm clinical applicability. Full article

Cutaneous leishmaniosis (CL) remains a major neglected tropical disease, with current therapies constrained by toxicity, high cost, and variable efficacy. Here, we evaluated an immunochemotherapy strategy combining topical amphotericin B (AmB) with the therapeutic DNA vaccine HisAK70 in a murine model of Leishmania major infection. BALB/c mice were subcutaneously infected and treated with topical AmB cream alone, AmB plus HisAK70, or paromomycin (PM) as a reference therapy. Therapeutic efficacy was assessed through lesion progression, parasite burden in draining lymph nodes and spleen, and immunological markers associated with parasite control. Both PM and the combined AmB + HisAK70 treatment significantly reduced lesion progression and markedly decreased parasite burden compared with infected controls, demonstrating effective control of local infection and systemic dissemination. Importantly, the combination therapy enhanced the efficacy of AmB alone, supporting the beneficial contribution of vaccine-driven immune modulation to therapeutic outcome. Therapeutic efficacy was associated with reduced arginase activity in infected tissues and an increased IFN-γ/IL-4 ratio, indicative of a protective Th1-oriented immune response. Together, these findings highlight immunochemotherapy as a promising strategy for CL treatment, integrating localized topical drug delivery with targeted immune activation to improve therapeutic efficacy while potentially reducing systemic toxicity. Full article

Osteoarthritis (OA) is a prevalent chronic joint disease lacking disease-modifying drugs. Animal models with distinct pathogenic mechanisms—monosodium iodoacetate (MIA) for metabolic toxicity and collagenase-induced osteoarthritis (CIOA) for matrix degradation—are essential for therapeutic evaluation. In this study, topical application of neoagarohexaose (NA6) at 5 and 10 mg/kg twice daily was assessed in MIA- and CIOA-induced mouse OA models. NA6 at both doses reduced paw swelling, improved serum oxidative stress markers (catalase (CAT), malondialdehyde (MDA), myeloperoxidase (MPO)), ameliorated cartilage damage and Osteoarthritis Research Society International (OARSI) scores, and decreased inflammatory cell infiltration. Immunohistochemistry showed that NA6 downregulated interleukin-1β (IL-1β) and interleukin-6 (IL-6), upregulated NAD(P)H:quinone oxidoreductase 1 (NQO1), and restored the compensatorily elevated heme oxygenase-1 (HO-1) toward baseline levels. The high-dose NA6 (10 mg/kg) showed comparable or favorable efficacy at the tested doses relative to the positive control diclofenac. These results demonstrate that NA6 exerts anti-inflammatory, antioxidant, and chondroprotective effects in both OA models, supporting its potential as a topical therapeutic candidate for OA symptom management and structural protection. Full article

Oral ulcerations are complex pathological lesions with multifactorial etiology and diverse clinical manifestations. Current treatment options are mostly symptomatic with a different adverse effect. Therefore, this study aimed to develop a mucoadhesive oral gel containing Potentilla erecta L. ethanol extract (PEOG) and evaluate its healing effects in a rat model of oral ulceration. Dried rhizomes of Potentilla erecta were extracted with 70% ethanol using ultrasonic extraction, followed by low-pressure evaporation. The extract was incorporated into a gel base composed of poloxamer 407 and carbomer 934. Rheological characterization was performed to assess the viscoelastic and flow properties of the formulation. Therapeutic efficacy was evaluated through macroscopic assessment of ulcer healing, histopathological analysis, and determination of systemic oxidative stress biomarkers. Animals were assigned to three groups: untreated control, gel base (GB), and PEOG-treated. Rats were sacrificed on days 0, 3, 6, and 10 for blood and tissue sampling. PEOG treatment significantly accelerated ulcer healing, resulting in a marked reduction in ulcer size compared with controls. Histopathological findings indicated enhanced collagen deposition, while biochemical analyses suggested attenuation of oxidative stress. These results demonstrate that PEOG possesses considerable ulcer-healing potential and may represent a promising mucoadhesive formulation for the treatment of oral ulcerations. Full article

Background/Objectives: Burn injuries in children represent a significant clinical challenge, as current standard-of-care agents such as silver sulfadiazine (SSD) present limitations, including delayed re-epithelialization. This study aimed to evaluate the therapeutic potential of Castanea sativa (sweet chestnut) flower extract—rich in polyphenols and flavonoids with documented antioxidant, anti-inflammatory, and antimicrobial properties but previously uncharacterized in burn wound healing—applied topically on second-degree burn wounds in a juvenile rat model, comparing its efficacy to SSD and their combination. Methods: Forty five-week-old female Wistar albino juvenile rats were randomly allocated into five groups (n = 8): burn control (Group C), SSD monotherapy (Group BS), vaseline vehicle/sham (Group Sham), 5% chestnut flower extract (Group BCs), and SSD combined with extract (Group BSCs). All topical treatments were applied once daily for 14 days. Healing outcomes were assessed by macroscopic wound closure analysis, systemic organ stress markers (ALT, AST, BUN), oxidative stress indices (MDA, SOD, CAT, GPx, GSH), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), and histopathological/immunohistochemical analyses (Ki-67, VEGF). Results: All active treatment groups demonstrated significant reductions in organ damage markers, oxidative stress burden, and pro-inflammatory cytokine levels, alongside enhanced antioxidant enzyme activity, compared to Group C (p < 0.001). Extract-treated groups exhibited more pronounced suppression of oxidative and inflammatory parameters than SSD monotherapy. The combination group (BSCs) achieved optimal wound healing outcomes, including near-complete re-epithelialization, superior collagen organization, and prominent angiogenesis, corroborated by the highest Ki-67 proliferation index and VEGF expression scores (p < 0.001). Conclusions:C. sativa flower extract significantly accelerates burn wound healing via antioxidant and anti-inflammatory mechanisms. When combined with SSD, a synergistic effect is observed that overcomes the re-epithelialization delays associated with SSD monotherapy. These findings support C. sativa flower extract as a promising candidate for further preclinical and clinical investigation in pediatric burn management, supporting the ethnopharmacological relevance of this plant in traditional wound care practices; further safety and efficacy validation is required before clinical translation. Full article

Background/Objectives: Faricimab is a novel bispecific antibody simultaneously inhibiting vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2). Its efficacy in vitrectomized eyes with diabetic macular edema (DME), a setting with altered intravitreal pharmacokinetics, remains poorly characterized. We evaluated the 12-month outcomes of intravitreal faricimab (IVF) for DME in eyes vitrectomized for proliferative diabetic retinopathy (PDR). Methods: We retrospectively reviewed 12 consecutive eyes of 11 patients (mean age 59.4 ± 10.5 years) with DME after pars plana vitrectomy (PPV) for PDR who received IVF (6 mg/0.05 mL) between September 2022 and August 2024 with at least 12 months of follow-up. Best-corrected visual acuity (BCVA, logMAR) and central retinal thickness (CRT) were assessed at baseline (BL), 6 months (M6), and 12 months (M12). Results: Eight eyes were treatment-naïve and 4 had been switched from prior anti-VEGF therapy. Two eyes (16.7%) required a change in therapy: one for intraocular inflammation and one for inadequate anatomical response. In the 10 eyes that continued IVF, the mean number of injections was 4.1 ± 1.9. CRT decreased significantly from 489.5 ± 95.9 µm at BL to 328.5 ± 74.7 µm at M6 (p = 0.0065) and 307.0 ± 64.3 µm at M12 (p = 0.0023; repeated-measures ANOVA with Dunnett’s post hoc test). Mean BCVA improved from 0.33 ± 0.26 to 0.23 ± 0.21 logMAR at M12 (p = 0.0894). Conclusions: In this small retrospective study of vitrectomized eyes with DME after PPV for PDR, IVF was associated with significant anatomical improvement, while visual acuity remained stable over 12 months, with a relatively low injection burden. Faricimab may be a useful therapeutic option in this challenging population, although larger prospective studies are warranted to confirm these findings. Full article

Background: Dry Eye Disease (DED) is a multifactorial condition with an impact on quality of life and an often suboptimal response to conventional lubricants. This study aimed at evaluating the real-world efficacy, tolerability, and patient adherence of a therapy with a novel ophthalmic solution containing Ribohyal, a riboflavin–hyaluronic acid complex, used in patients with DED. Methods: This national survey included data from adult patients with clinically diagnosed DED treated with Lacrinova eye drops (4 times/day for 3 months) whose data were collected from 82 Italian ophthalmologists. Patients were assessed before (T0) and after treatment (T1). Outcomes included patient-reported symptoms for 9 domains (0–10 numerical rating scale), objective clinical parameters (best-corrected visual acuity [BCVA], break-up time [BUT], and corneal fluorescein staining [CFS]), and treatment acceptability. Results: Data from 2993 patients (5986 eyes) were analyzed. Improvements were observed across all 9 symptom domains, with reductions ranging from 53% to 60% (all p < 0.001). BCVA and BUT significantly improved (from 0.08 ± 0.22 at T0 to 0.06 ± 0.19 logMAR at T1 and from 9.20 ± 4.49 to 11.85 ± 4.66 s at T1, respectively, both p < 0.001). The prevalence of CFS decreased from 42.0% to 23.4% (p < 0.001). Treatment acceptability was high, with mean scores of 8.88± 1.49 for tolerability, 8.55 ± 1.63 for adherence, and 8.62 ± 1.55 for perceived efficacy. No relevant adverse events were reported. Conclusions: Lacrinova eye drops demonstrated significant improvements in both symptoms and clinical signs of DED, with excellent tolerability and adherence. These findings support its use as an effective therapeutic option in routine clinical practice, although controlled studies are warranted to confirm the efficacy. Full article

The introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) has significantly enhanced the prognosis for patients with rheumatoid arthritis (RA). Nevertheless, improving quality of life remains a major clinical challenge requiring the implementation of multidirectional therapeutic measures. Pain reduction plays a particularly important role in this context, representing one of the primary treatment goals for many patients. Scientific evidence indicates that effective pain management is a crucial predictive factor for the improvement of mental and physical health in patients with RA. The aim of this literature review was to summarise the mechanisms of action of Janus kinase inhibitors (JAKi), with particular emphasis on their modulation of pain generation and transmission. Furthermore, the study aimed to compare the results of clinical studies and assess the actual effectiveness of these drugs in reducing pain in clinical practice. JAKi exhibit peripheral analgesic effects by directly reducing the production of pro-nociceptive cytokines and modulating macrophage polarisation. Moreover, they influence central pain processing mechanisms by modulating the IL-6/JAK/STAT3 pathway and by reducing microglial and astrocyte proliferation in the dorsal horn of the spinal cord. The results of randomised clinical trials confirm that JAKi provide rapid, clinically significant pain reduction. Some studies also point to the persistence of this effect over a longer period, and to their greater efficacy compared with conventional disease-modifying antirheumatic drugs (cDMARDs) and bDMARDs. The efficacy of this group of drugs has also been noted in patients with an inadequate response to prior therapy with biological drugs. A key focus of future research remains determining the optimal timing for introducing JAKi in the treatment of RA and identifying predictive factors to enable the selection of patients most likely to benefit from this class of drugs. Full article

Background: Alcohol use is a major global health burden and is causally linked to several wholly alcohol-attributed conditions, including alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). Current therapeutic options remain limited. Dihydromyricetin (DHM), a plant-derived flavonoid with antioxidant and anti-inflammatory properties, has emerged as a potential candidate for mitigating alcohol-induced toxicity. This systematic review aimed to comprehensively evaluate the therapeutic effects of DHM across alcohol-related conditions. Methods: A systematic literature search was conducted in PubMed from inception through December 2025 for studies investigating the effects of DHM or DHM-containing extracts on alcohol-related outcomes. Both preclinical (in vitro and in vivo) and clinical studies were considered. Study quality was assessed qualitatively due to heterogeneity precluding use of a standardized risk-of-bias tool. Results were synthesized narratively by outcome category; meta-analysis was not performed. This review was unregistered with no prior protocol. Results: A total of 22 studies were included, comprising 8 in vitro, 17 in vivo, and 2 clinical studies, with some studies contributing data to more than one category. Across models, DHM consistently attenuated ethanol-induced cytotoxicity, oxidative stress, inflammation, and hepatic steatosis. DHM improved liver injury biomarkers (e.g., AST and ALT), enhanced antioxidant defenses, and modulated key signaling pathways including Nrf2 and AMPK. Additionally, DHM supported mitochondrial function and intestinal barrier integrity. However, findings related to ethanol metabolism and neurobehavioral outcomes were inconsistent. Clinical evidence was limited to two small trials using Hovenia dulcis extracts, which demonstrated reductions in hangover severity and selected inflammatory markers but did not directly evaluate isolated DHM. Conclusions: DHM demonstrates robust preclinical efficacy in mitigating alcohol-induced injury, particularly in hepatic outcomes. Despite promising mechanistic and experimental evidence, clinical data remain limited. The certainty of evidence is constrained by preclinical study heterogeneity, the absence of formal risk-of-bias assessment, and the lack of clinical trials using isolated DHM. Well-designed clinical trials using standardized DHM formulations are needed to establish its complete therapeutic potential in alcohol-related disorders. Full article

Background: Corallopyronin A (CorA) is a bacterial RNA polymerase inhibitor that binds a site distinct from rifamycins, but its activity across the ESKAPEE pathogen panel and its translational potential remain incompletely defined. Methods: CorA activity was evaluated against representative ESKAPEE pathogens using broth microdilution assays ± polymyxin B nonapeptide (PMBN). Activity was benchmarked against rifampin (Rif). Resistance, cross-resistance, serum activity, in vivo efficacy in the Galleria mellonella wax moth larva model, and biofilm disruption were assessed. Results: CorA inhibited Acinetobacter baumannii (minimal inhibitory concentration [MIC] = 16–32 µg/mL), including MDR isolates, with susceptibility enhanced 4–32-fold by efflux disruption or membrane permeabilization. In contrast, most other Gram-negative ESKAPEE pathogens required PMBN for activity, while Gram-positive organisms were intrinsically susceptible. Rif was consistently more potent than CorA across the panel. Rif-resistant A. baumannii and Klebsiella pneumoniae remained fully susceptible to CorA, confirming the absence of cross-resistance. Fractional inhibitory concentration (FIC) index analysis revealed pharmacological indifference between CorA and Rif, with no synergy or antagonism detected. CorA activity was abolished in 50% serum conditions and was not restored by PMBN, consistent with serum sequestration; no efficacy was observed in a G. mellonella infection model at doses up to 20 mg/kg despite Rif demonstrating significant protection. Notably, CorA reduced established A. baumannii biofilms by ∼3–4 log colony-forming units per mL (CFU/mL) across concentrations ≥4× MIC after 24 h of treatment. Conclusions: CorA exhibits selective activity against A. baumannii and retains efficacy against Rif-resistant strains. While high serum binding reduces in vitro activity and efficacy was not observed in the G. mellonella model at a lower dose than in other in vivo models, established in vivo activity against other pathogens demonstrates that serum binding does not preclude therapeutic utility. These findings highlight both the translational considerations for CorA against ESKAPEE pathogens and potential niches for its application, including filarial nematodes, biofilm-associated infections and combination strategies. Full article