Search Results (11,577)

Luteolin is a natural flavonoid compound with multifaceted pharmacological properties, including anti-oxidant, anti-inflammatory, antiviral, and anti-tumor activities. Network pharmacology analysis has been utilized to decipher the underlying mechanisms and multitargets of luteolin against coronavirus disease 2019 (COVID-19). This review aims to provide a systematic and comprehensive summary of luteolin, as a potential novel remedy with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity, as well as its anti-oxidant mechanisms. We systematically delineate the epidemiological profile, genomic architecture, and replicative dynamics of SARS-CoV-2, thereby constructing a multiscale framework to decode its pathogenic mechanisms. Employing a multi-level network pharmacology analytical strategy, we identify 46 core targets through protein interaction network construction, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Molecular investigations reveal luteolin’s dual antiviral mechanisms, including direct targeting of SARS-CoV-2 proteins and host-directed intervention through suppression of angiotensin-converting enzyme 2 receptor engagement/transmembrane protease serine 2-mediated viral priming. The polypharmacological profile of luteolin demonstrates synergistic effects in blocking viral entry, replication, and host inflammatory cascades. This phytochemical repurposing study of luteolin provides a novel mechanistic paradigm for developing multitarget antiviral agents, highlighting the translational value of natural compounds in combating emerging viral variants. Full article

Objectives: Immunotherapy combining agonists of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway with PD-1/PD-L1 blockade shows promising preclinical results, although in clinical practice, it faces pharmacokinetic barriers, systemic toxicity, and an immunosuppressive tumor microenvironment (TME). Recent advances in and expansion of the cGAS-STING pathway as a therapeutic target have further highlighted its central role in innate and adaptive immune activation. The aim of this paper is to review combination strategies of STING and PD-1/PD-L1 checkpoint blockade therapies, triple-therapy strategies using a third component such as chemotherapy, radiotherapy, photodynamic therapy (PDT), and others, and the use of nanoparticles as carriers for these drugs. Methods: Reports in the literature on the mechanisms of STING + PD-1/PD-L1 synergy, as well as with the use of a third component and delivery systems, were analyzed. Current challenges and limitations, as well as prospects for the development of these therapies, are noted. Results: Activation of the cGAS-STING synergizes with blocking the PD-1/PD-L1 axis. The addition of a third component further enhances the anti-tumor effect through a stronger induction of immunogenic cell death (ICD), increased production of interferons and pro-inflammatory cytokines, repolarization of macrophages, and enhanced infiltration of T lymphocytes. Conclusions: Therapy with STING agonists and PD-1/PD-L1 checkpoint inhibitors, supported by nanotechnology vehicles and using a third therapeutic component, overcomes key pharmacological and immunological limitations. This multimodal immunotherapeutic strategy holds high translational promise, offering more effective and safer solutions in cancer immunotherapy. Full article

Background/Objectives: IBDs are chronic relapsing inflammatory intestinal disorders whose precise etiology is still only poorly defined: critical for their pathogenesis is the CCL20/CCR6 axis, whose modulation by small molecules may represent an innovative therapeutic approach. The aim of the present work is to test the potential efficacy of two molecules, MR120, a small selective CCR6 antagonist, active in TNBS- and chronic DSS-induced murine models of intestinal inflammation, and its derivative MR452, a well-tolerated agent endowed with improved anti-chemotactic in vitro properties, in the adoptive transfer colitis model. To the best of our knowledge, this is the first attempt to use adoptive transfer colitis to test modulators of the CCL20/CCR6 axis. Methods and Results: The induction of colitis in immunocompromised mice receiving CD4⁺CD25⁻ T cells i.p. resulted in a moderate inflammation and was met with limited protective responses following daily subcutaneous administration of MR120 or MR452 for 8 weeks. Both compounds significantly reduced colonic myeloperoxidase activity, and MR452 also lowered CCL20 levels in the gut, but they failed to prevent the increase in the Disease Activity Index, colon wall thickening, and macroscopic inflammation score. Conclusions: Our findings suggest that, despite the beneficial effects played by MR120 against subacute TNBS- and chronic DSS-induced colitis, the pharmacological targeting of the CCL20/CCR6 axis in the adoptive transfer model has a negligible effect in ameliorating the IBD-like phenotype driven by the altered intestinal immune homeostasis and by the disrupted function of immune-suppressive Treg cells. Full article

Congenital ichthyoses, now grouped under the acronym EDD (Epidermal Differentiation Disorders), include nonsyndromic forms (nEDD) that may be caused by loss-of-function mutations in the CDSN gene encoding corneodesmosin (CDSN-nEDD, formerly Peeling skin syndrome type 1). It is characterized by skin peeling, inflammation, itching and food allergies, while no specific therapy is currently available. High levels of KLK5, the serine protease that initiates the desquamation cascade, are found in the epidermis of CDSN-nEDD patients. Thus, we hypothesized that KLK5 inhibition would alleviate the symptoms of CDSN-nEDD and could serve as a new pharmacological target. A human epidermal equivalent (HEE) model for CDSN-nEDD was developed using shRNA-mediated CDSN knockdown. This model was characterized and used to assess the role of KLK5 knockdown on CDSN-nEDD. Also, Klk5^−/− mice were crossed with Cdsn^epi−/− mice, the murine model of CDSN-nEDD, to examine in vivo the effect(s) of Klk5 deletion in CDSN-nEDD. Both models recapitulated the CDSN-nEDD desquamating phenotype. Elimination of KLK5 aggravated the CDSN-nEDD phenotype. Epidermal proteolysis was surprisingly elevated, while severe ultrastructural (corneo)desmosomal alterations increased epidermal barrier permeability and stratum corneum detachment was manifested. Based on these results, we concluded that targeting epidermal proteolysis with KLK5 ablation cannot compensate for the loss of corneodesmosin and rescue over-desquamation of the CDSN-nEDD. Possibly, in the absence of KLK5, other proteases take over which increases the severity of over-desquamation in CDSN-nEDD. The translational outcome is that over-desquamation may not always be rescued by eliminating epidermal proteolysis, but fine protease modulation is more likely required. Full article

In the last decades, extracts of Viscum album L., commonly known as European mistletoe, have attracted increasing interest for their immunomodulatory, anti-inflammatory and antioxidant activities. Nowadays, they are mainly used in complementary cancer treatments. A targeted LC-MRM-MS was selected to determine the chemical composition and the activities of a V. album homeopathic mother tincture (MT#39998). Results showed a complex chemical composition, which was compared with that of other similar extracts. The LC-MRM-MS data were confirmed and complemented by HPLC analysis. Viscotoxins content was evaluated because of their cytotoxicity. MT#39998 was tested for its cytotoxic and antioxidant effect, before and after viscotoxins removal. The composition of MT#39998 in viscotoxins was similar to that of other products already present in the market and its safety was confirmed by estimation of LD₅₀ based on in vitro IC₅₀ values (LD₅₀ was >2 g/kg). The aim of this study is to report a case study on a plant extract. The study was based on the chemical composition, including the metabolome, and on the pharmacological data, including toxicity and antioxidant activities, to validate the current utilization. Full article

The leaves and stems of Bauhinia guianensis Aubl. are used in traditional Amazonian phytotherapy for the treatment of pain and inflammation. This study investigates the anti-inflammatory and antinociceptive effects of hydroethanolic extracts from B. guianensis Aubl. leaves and stems (HELBg and HESBg, respectively) in vivo models of inflammation and hyperalgesia. Danio rerio experimental animals were submitted to the acute inflammation test, induced by intraperitoneal (ip.) administration of carrageenan 20 μg/animal (abdominal edema); the groups were previously treated orally with saline solution 2 μL/animal (SS), dimethyl sulfoxide 2 μL/animal (DMSO), indomethacin 10 mg/kg, HELBg 100 mg/kg and HESBg 100 mg/kg, n = 12 per experimental group to evaluate the inhibition of edema and alteration histopathology of the liver, intestine and kidney of these animals. The antinociceptive effect was observed from the body curvature index and the behavioral responses of Danio rerio, after an experimental protocol for the induction of hyperalgesia, by ip. administration of 10 μL/animal of 2.5% acetic acid; the animals were orally treated orally with saline solution 2 μL/animal (SS), dimethyl sulfoxide 2 μL/animal (DMSO), morphine 2.5 mg/kg, HELBg 100 mg/kg and HESBg 100 mg/kg, and n = 5 per experimental group. In carrageenan-induced edema, the group treated with HESBg inhibited edema formation over the 3 h of the experiment. Maximum edema was inhibited by 54% (p < 0.05) when compared to the control group. Both HELBg and HESBg prevented body curvature index changes (t_(df=3,8) = 6.96 and t_(df=3,8) = 6.61, respectively, both p < 0.0001). In the behavioral parameters sensitive to antinociceptive pharmacological modulation, due to the abdominal constriction induced by acetic acid, the administration of HELBg and HESBg resulted in an improvement in swimming activity, with the following results: increase in distance covered (F_(df=3,16) = 6.50 and F_(df=3,16) = 7.72, respectively, both p < 0.0001), decrease in freezing time (F_(df=3,16) = 2.04 and F_(df=3,16) = 1.28, respectively, both p < 0.0059), increase in the number of ascents to the upper area of the tank (F_(df=3,16) = 33.02 and F_(df=3,16) = 35.62, respectively, both p < 0.0009) and decreased time spent in that area (F_(df=3,16) = 101.19 and F_(df=3,16) = 103.59, respectively, both p < 0.0038). It is reasonable to suppose that both extracts modulated the variations induced by carrageenan and acetic acid through the inhibition of prostaglandin biosynthesis, thereby decreasing the release of inflammatory mediators, the sensitization of peripheral nociceptors, and, consequently, the perception of pain. These results suggest that HELBg and HESBg have anti-inflammatory and antinociceptive activities, likely of peripheral origin and associated with the inhibition of prostaglandin biosynthesis. Full article

Background/Objectives: Liver fibrosis is a progressive consequence of chronic liver injury that can evolve into cirrhosis, liver failure, or hepatocellular carcinoma, representing a major global health burden. Fibrogenesis is driven by hepatic stellate cell (HSC) activation, excessive extracellular matrix deposition, and structural disruption of liver tissue, with transforming growth factor-β (TGF-β) signaling and inflammatory mediators as central pathways. Current therapies primarily target the underlying causes, which may halt disease progression but rarely reverse established fibrosis. This review aims to outline current and emerging therapeutic strategies for liver fibrosis, informing both clinical practice and future research directions. Methods: A narrative synthesis of preclinical and clinical evidence was conducted, focusing on pharmacological interventions, microbiota-directed strategies, and innovative modalities under investigation for antifibrotic activity. Results: Bile acids, including ursodeoxycholic acid and derivatives, modulate HSC activity and autophagy. Farnesoid X receptor (FXR) agonists, such as obeticholic acid, reduce fibrosis but are limited by adverse effects. Fatty acid synthase inhibitors, exemplified by denifanstat, show promise in metabolic dysfunction-associated steatohepatitis (MASH). Additional strategies include renin–angiotensin system inhibitors, omega-3 fatty acids, and agents targeting the gut–liver axis. Microbiota-directed interventions—probiotics, prebiotics, symbiotics, antibiotics (e.g., rifaximin), and fecal microbiota transplantation—are emerging as potential modulators of barrier integrity, inflammation, and fibrogenesis, though larger clinical trials are required. Reliable non-invasive biomarkers and innovative trial designs, including adaptive platforms, are essential to improve patient selection and efficiently evaluate multiple agents and combinations. Conclusions: Novel modalities such as immunotherapy, gene editing, and multi-targeted therapies hold additional potential for fibrosis reversal. Continued translational efforts are critical to establish safe, effective, and accessible treatments for patients with liver fibrosis. Full article

Objectives: Alpinia japonica (A. japonica) is traditionally used for digestive disorders, but its hypolipidemic mechanisms remain unclear. This study investigated the lipid-lowering effects of its fruit (SJGS), rhizome (SJGJ), and leaf (SJY) extracts, exploring their bioactive constituents and organ-specific mechanisms. Methods: Sprague Dawley rats (n = 8/group) fed a high-fat diet received SJGS, SJGJ, or SJY (200 mg/kg/day) for 4 weeks. Serum lipids (TC, TG), liver enzymes (AST, ALT), and intestinal barrier markers (DAO) were measured. Gut microbiota (16S rDNA sequencing), hepatic histopathology, and ileal tight junction proteins were analyzed. Transcriptomics and qPCR assessed ileal gene expression. LC-MS identified chemical constituents, while network pharmacology predicted compound-target interactions. Results: All extracts significantly reduced serum TC (↓ 27–33%), TG (↓ 29–38%), AST/ALT (↓ 22–30%), and DAO (↓ 35–42%) versus controls (p < 0.05). They improved hepatic steatosis, enhanced intestinal barrier function, and modulated gut microbiota (↑ α-diversity, ↓ Firmicutes/Bacteroidetes ratio). Transcriptomics revealed PPAR signaling as the core pathway: SJGS/SJGJ downregulated fatty acid oxidation genes (ACSL1, ACOX1, ACADM), while SJY upregulated APOA1 (2.3-fold). LC-MS identified 33–48 compounds/part, with seven shared constituents. Network analysis prioritized three flavonoids (pinocembrin, luteolin, galangin) targeting TNF, AKT1, and PPAR pathways. Conclusions: The findings suggest A. japonica extracts ameliorate hyperlipidemia through distinct mechanisms—SJGS/SJGJ may inhibit fatty acid oxidation, while SJY potentially enhances APOA1-mediated clearance. Shared flavonoids likely contribute to these effects via PPAR signaling, supporting its traditional use. This study provides a scientific basis for the sustainable utilization of A. japonica resources. Full article

Background: Chronic pain represents a major therapeutic challenge due to the limited efficacy and tolerability of conventional pharmacological treatments. Equisetum arvense L., a medicinal plant with potent antioxidant properties, and palmitoylethanolamide (PEA), an endogenous fatty acid amide with well-established anti-inflammatory and analgesic effects, are increasingly recognised as promising nutraceutical agents. Methods: This prospective, single-centre clinical trial aimed to evaluate the efficacy and safety of a novel oral supplement (Assonal^®PEA) combining 600 mg of PEA and 300 mg of Equisetum arvense L. in improving the reduction of pain and quality of life in patients with chronic pain, also obtaining information on the patient’s state of satisfaction after the treatment. Fifty patients suffering from chronic pain (low back pain and radiculopathy) for two months were enrolled and received the supplement over eight weeks in a tapered regimen (two tablets daily for two weeks, followed by one tablet daily). Results: Clinical outcomes were evaluated using validated instruments, including the Numeric Pain Rating Scale (NPRS), Verbal Rating Scale (VRS), Short-Form McGill Pain Questionnaire (SF-MPQ), Global Perceived Effect (GPE), and EuroQol-5D-5L. Results showed a significant decrease in pain intensity (NPRS: −3.8 points; VRS: −2.1 points; p < 0.0001), along with meaningful improvements in patient-perceived benefit, pain descriptors, and quality of life (EQ-5D-5L: +35%; p < 0.0001). Conclusions: These findings endorse the use of this novel PEA–Equisetum arvense formulation as a safe, well-tolerated, and potentially effective supplementary intervention for managing chronic pain. No adverse events were reported, and the overall response rate reached 94%. Full article

Introduction/aim: N-acetylgalactoseamine-conjugated small interfering RNAs (GalNAc-siRNAs) are an emerging class of drugs possessing an extensive clinical potential because of their high target specificity to the asialoglycoprotein receptor (ASGPR) in hepatocytes. Overall, GalNAc-sRNAs are well-tolerated across species but differences in pharmacokinetic (PK) and pharmacodynamic (PD) properties have been observed. Furthermore, despite GalNAc-siRNA’s high liver specificity, distribution into off-target organs does occur. Through whole-body physiologically based pharmacokinetic (PBPK) modeling, this study seeks to mechanistically address species differences, establish clinical PK-PD relationships, and characterize off-target organ accumulation, ultimately expediting the preclinical-to-clinical translation of GalNAc-sRNAs in drug development. Materials/Methods: For model development, validation, and establishment of species’ translations, three in-house GalNAc-siRNAs with PK data from different biospecimens, as well as downstream effects on mRNA and target proteins in mouse, monkey, and human, were leveraged. A WB-PBPK-PD legacy model, developed as an extension to the generic model for large molecules in the platform Open Systems Pharmacology Suite, was further validated and applied to address the specific aims of this study. Results: The model successfully quantified the PK-PD relationships across species and characterized accumulation in off-target organs. The model further sheds light on species-specific differences, such as liver permeability, subcutaneous absorption rate, as well as PD-related mechanisms. Moreover, the model confirmed previously established compound-specific pharmacokinetic differences and similarities. Conclusions: This PBPK-PD can serve as a framework for future investigations of novel GalNAc-siRNAs across species. Full article

Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD), with amyloid-β (Aβ) deposition and neurofibrillary tangles driving both central and peripheral inflammatory responses. This study investigated the neuroprotective and anti-inflammatory effects of Vitex trifolia (VT), Plantago major (PM), Apocyni Veneti Folium (AVF), and Eucommiae folium (EF) using network pharmacology and a co-culture model of PC12 neuronal and Caco-2 intestinal epithelial cells. Bioactive compounds were identified via high-performance liquid chromatography (HPLC) and screened with network pharmacology analysis, yielding 27 for VT, 10 for PM, 6 for AVF, and 3 for EF. Molecular docking confirmed strong binding affinities between the key bioactive compounds and AD-related targets. A co-culture system of PC12 neuronal and Caco-2 intestinal epithelial cells was established to evaluate the effects of VT, PM, AVF, and EF extracts (at concentrations of 10 µg/mL, 20 µg/mL, and 50 µg/mL) and donepezil hydrochloride (positive-control) on Aβ_25–35-induced neurotoxicity and lipopolysaccharide (LPS)-induced intestinal inflammation, to assess cell viability, and effects on oxidative stress, mitochondrial function, and inflammatory markers. The VT, PM, AVF, and EF extracts activated phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3β (GSK-3β) signaling, enhanced phosphorylation of AMP kinase, suggesting inhibition of Aβ accumulation and tau hyperphosphorylation (p < 0.05). However, donepezil hydrochloride only enhanced AMPK phosphorylation. The extracts reduced lipid peroxidation and acetylcholinesterase by about 5-fold. JC-1 staining confirmed preserved mitochondrial membrane potential, while hematoxylin and eosin staining indicated improved intestinal barrier integrity (p < 0.05). PM and AVF reduced the number of mast cells (p < 0.05). In conclusion, these findings highlight the multi-target potential of VT, PM, AVF, and EF in mitigating both neuronal and intestinal inflammation. Their dual regulatory effects on the gut–brain axis suggest promising therapeutic applications in AD through the modulation of central and peripheral immune responses. Full article

Paediatric hypertension presents significant perioperative challenges due to its variable aetiology and potential for end-organ damage. The prevalence varies with age and is associated with both primary and secondary causes, which differ markedly from adult hypertension. This review outlines the classification, diagnosis, and causes of paediatric hypertension to provide context for its management in the perioperative setting. Emphasis is placed on the identification and preoperative optimisation of hypertension, intraoperative blood pressure control, and the management of hypertensive crises. Specific perioperative strategies, including anaesthetic planning, pharmacological interventions, and postoperative monitoring, are discussed. Specific conditions such as phaeochromocytoma and aortic coarctation require tailored pharmacological strategies and close interdisciplinary collaboration. Postoperative care in an intensive care setting is essential for monitoring complications and achieving long-term blood pressure control. Effective perioperative management of paediatric hypertension requires early identification, thorough preoperative assessment, and prompt intraoperative and postoperative intervention. Multidisciplinary care and an understanding of paediatric specific pathophysiology are key to reducing morbidity and improving outcomes. Full article

Breast cancer (BC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options for triple-negative breast cancer (TNBC). The RNA-binding protein non-POU domain-containing octamer-binding protein (NONO) has emerged as a critical regulator of tumorigenesis, but its role in immune signaling remains unexplored. We analyzed the effect of NONO protein by modulating its expression using short hairpin RNA (shRNA) and a chemical inhibitor (R)-SKBG-1. We demonstrate that NONO depletion in MDA-MB-231 TNBC cells leads to cytoplasmic DNA accumulation, micronuclei formation, and activation of the cyclic GMP-AMP synthase—stimulator of interferon genes (cGAS/STING) pathway, resulting in enhanced modulation of the immune response. NONO-deficient cells showed increased cGAS and STING activation, Tank-binding kinase 1 (TBK1) phosphorylation, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) nuclear localization, and transcription of pro-inflammatory genes such as CC Motif Chemokine Ligand 5 (CCL5). These effects were recapitulated by pharmacological inhibition using (R)-SKBG-1, confirming NONO’s immunosuppressive function. Our findings establish NONO as a key modulator of immune activation in TNBC and suggest that its inhibition may enhance anti-tumor immunity. This work paves the way for potential combination strategies involving NONO inhibitors and immune checkpoint blockade, particularly in tumors with homologous recombination deficiencies or limited immune infiltration. Full article

Background: The fibromyalgia syndrome (FMS) is classified as a functional somatic syndrome and is characterized primarily by chronic pain in multiple body regions and physical and/or mental fatigue. The German S3-guideline recommends a multimodal therapy for severe forms. Since research on non-pharmacologic complementary, naturopathic, and integrative therapy approaches shows positive and promising effects, integrative methods are firmly anchored in the S3 guideline. Objective/Methods: Aim of the present study was to investigate whether a multimodal integrative treatment program can be effective in reducing the primary symptoms of FMS (pain and fatigue) and improving psychological aspects such as quality of life (QoL), anxiety, depression, and perceived stress. Another aim of the study is to explore whether potential effects appear only in the short term (immediately after discharge) or persist long term (six months after discharge). The treatment concept is based on mind–body medicine and elements of classical European naturopathy (including fasting interventions) and focusses on stress reduction and lifestyle modification. Results: Of N = 134 originally included longstanding fibromyalgia patients (mean time since diagnosis 9.2 ± 8.5 years), 101 data sets could be analyzed. Results show a significant improvement in both short-term and long-term pain and fatigue intensity (about 12% improvement). Long-term reductions in pain intensity appear to be supported by medical fasting interventions. Regarding psychological aspects and quality of life, there are long-lasting reductions regarding anxiety, depression, perceived stress, and helplessness and a long-lasting increase in self-efficacy, quality of life and current working ability. Conclusions: The two-weeks inpatient stay therefore leads to significant improvements in all mentioned aspects. Therefore, the concept may be a promising component for integration into medical guidelines and thus in the care of FMS patients. Future research including randomized controlled trials is necessary to further evaluate the program. Full article

Apoptosis is a genetically controlled process vital for homeostasis. This study examined the apoptotic response in the gut of Apis mellifera (A. mellifera) larvae to infection by Ascosphaera apis (A. apis) and its impact on host resistance and pathogen virulence. Here, Worker larvae of A. mellifera were inoculated with purified A. apis spores. We then quantified the expression of key apoptosis-related genes (AmCaspase-3, AmBax, and AmBcl-2) in the host gut and detected apoptotic cells via TUNEL assay. To functionally assess the role of apoptosis, larvae were treated with either the apoptosis inhibitor Z-VAD-FMK or the activator PAC-1, after which host survival, expression of apoptosis-associated genes, and the fungal virulence factor gene Ste11-like were analyzed. Our results showed that infection with A. apis significantly upregulated the expression of AmCaspase-3 and AmBax (p < 0.05) at 1–3 days post-inoculation (dpi), while the expression of AmBcl-2 was significantly reduced at 1 and 3 dpi (p < 0.05). Consistent with this, TUNEL assays revealed a markedly stronger green fluorescence signal in the guts of inoculated larvae at 3 dpi compared to uninfected controls, with clear co-localization of TUNEL and nuclear signals, confirming increased apoptosis. Pharmacological inhibition of apoptosis significantly enhanced the survival rate of A. apis-infected larvae, whereas apoptosis activation decreased larval survival. Accordingly, inhibiting apoptosis significantly suppressed the expression of AmCaspase-3 and AmBax (p < 0.001) and upregulated AmBcl-2 (p < 0.001). Conversely, apoptosis activation upregulated AmCaspase-3 (p > 0.05) and AmBax (p < 0.001), while significantly down-regulating AmBcl-2. Furthermore, apoptosis inhibition significantly down-regulated the fungal virulence gene Ste11-like, while its activation had the opposite effect. In summary, A. apis infection induces apoptosis in the larval gut by activating AmCaspase-3 and AmBax and suppressing AmBcl-2. Inhibiting this apoptotic response enhanced host survival by modulating the expression of host apoptosis-related genes and the fungal Ste11-like virulence factor. These findings provide new insights into the host response to A. apis and suggest a potential strategy for controlling chalkbrood disease. Full article